Sam Goldstein, Cecil R Reynolds

Handbook of
Neurodevelopmental and Genetic Disorders

in Children
Handbook of
Neurodevelopmental
and Genetic Disorders
in Children
Second Edition
Edited by
Sam Goldstein
Cecil R. Reynolds
THE GUILFORD PRESS

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provide information that is complete and generally in accord with the standards
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possibility of human error or changes in behavioral, mental health, or medical
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has been involved in the preparation or publication of this work warrants that the
information contained herein is in every respect accurate or complete, and they are
not responsible for any errors or omissions or the results obtained from the use of such
information. Readers are encouraged to confirm the information contained in this
book with other sources.
Library of Congress Cataloging-in-Publication Data
Handbook of neurodevelopmental and genetic disorders in children / edited by Sam

Goldstein, Cecil R. Reynolds.–2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-60623-990-2 (hardcover : alk. paper)
1. Developmental disabilities—Genetic aspects—Handbooks, manuals,
etc. 2. Developmental neurobiology—Handbooks, manuals, etc. 3. Genetic
disorders in children—Handbooks, manuals, etc. 4. Pediatric neuropsychology—
Handbooks, manuals, etc. I. Goldstein, Sam. II. Reynolds, Cecil R.
[DNLM: 1. Mental Retardation. 2. Child Development Disorders,
Pervasive. 3. Child. 4. Congenital Abnormalities. 5. Genetic Diseases,
Inborn. 6. Mental Disorders. WS 107 H2365 2011]
RJ506.D47H36 2011
618.92′8588042—dc22
2010024244
For Allyson and Ryan,
and for the thousands of children and families
with whom I have had the privilege to work
—S. G.
To Julia, always
—C. R. R.
About the Editors
Sam Goldstein, PhD, is Assistant Clinical Instructor in the Department of Psychiatry at

the University of Utah School of Medicine and Affiliate Research Professor of Psychol-
ogy at George Mason University. As a neuropsychologist, he specializes in child devel-
opment, school psychology, and traumatic brain injuries. Dr. Goldstein is also Clinical
Director of the Neurology, Learning, and Behavior Center in Salt Lake City, where
he provides assessment, case management, and treatment for individuals experiencing
diverse neuropsychological impairments throughout the lifespan. He holds Fellow and
Diplomate status in organizations spanning many disciplines. Dr. Goldstein is Editor-
in-Chief of the Journal of Attention Disorders and serves on the editorial boards of
six journals. He is the author or editor of over 30 books and more than 100 scholarly
publications.
Cecil R. Reynolds, PhD, is Emeritus Professor of Educational Psychology, Professor

of Neuroscience, and Distinguished Research Scholar at Texas A&M University. He
maintained a clinical practice treating trauma victims and individuals with traumatic
brain injury for 25 years before retiring from clinical work. Dr. Reynolds is past presi-
dent of the National Academy of Neuropsychology (NAN) and of the American Psycho-
logical Association (APA) Divisions of Evaluation, Measurement, and Statistics; Clini-
cal Neuropsychology; and School Psychology. He has been an editor or associate editor
of several journals, is currently editor-in-chief of Psychological Assessment, and serves
on the editorial boards of 11 journals. He is the author or editor of over 50 books and
more than 300 scholarly publications; is a creator of numerous widely used psychologi-
cal tests of behavior, cognition, and personality; and has received many awards from
NAN, APA, and other organizations.
vii
Contributors
Angela Giacoletti Argento, PhD, Department of Physical Medicine and Rehabilitation,

University of Michigan, Ann Arbor, Michigan
David A. Baker, PsyD, Department of Pediatric Behavioral Health, Primary Children’s Medical
Center, Salt Lake City, Utah
Barbara C. Banz, MS, Department of Psychology, Colorado State University, Fort Collins,
Colorado
Bonnie J. Baty, MS, Department of Pediatrics, Division of Medical Genetics, University of
Utah, Salt Lake City, Utah
Thomas L. Bennett, PhD, Center for Neurorehabilitation Services, and Department of
Psychology, Colorado State University, Fort Collins, Colorado
Brandi Berry, MA, Department of Educational Psychology, University of Nebraska–Lincoln,
Lincoln, Nebraska
Erin D. Bigler, PhD, Departments of Psychology and Neuroscience, Brigham Young University,
Provo, Utah
Michael B. Brown, PhD, Department of Psychology, East Carolina University, Greenville,
North Carolina
Robert T. Brown, PhD, Department of Psychology, University of North Carolina
at Wilmington, Wilmington, North Carolina
Ronald T. Brown, PhD, Departments of Public Health, Psychology, and Pediatrics, Temple
University, Philadelphia, Pennsylvania
Jennifer L. Bruno, PhD, Department of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Stanford, California
John C. Carey, MD, Department of Pediatrics, Division of Medical Genetics, University
of Utah, Salt Lake City, Utah
Suzanne B. Cassidy, MD, Genetic Medicine Central California, Fresno, California
Gina B. Christopher, PhD, Department of Educational Psychology, University of Texas at
Austin, Austin, Texas
ix
x Contributors
Blythe Corbett, PhD, Vanderbilt Kennedy Center, Department of Psychiatry, Vanderbilt

University, Nashville, Tennessee
Sean Cunningham, MS, Neurology, Learning, and Behavior Center, Salt Lake City, Utah
Brian P. Daly, PhD, Department of Public Health, Temple University, Philadelphia,
Pennsylvania
Deana B. Davalos, PhD, Department of Psychology, Colorado State University, Fort Collins,
Colorado
Mario Gaspar De Alba, MD, Center for Development and Learning, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina
Melissa L. DeVries, PhD, Neurology, Learning, and Behavior Center, Salt Lake City, Utah
Elisabeth M. Dykens, PhD, Vanderbilt Kennedy Center and Department of Psychology and
Human Development, Vanderbilt University, Nashville, Tennessee
Phyllis Anne Teeter Ellison, EdD, Department of Educational Psychology, University
of Wisconsin–Milwaukee, Milwaukee, Wisconsin
Jami Givens, MA, Department of Educational Psychology, University of Nebraska–Lincoln,
Lincoln, Nebraska
Sam Goldstein, PhD, Neurology, Learning, and Behavior Center, Salt Lake City, Utah
Joan Gunther, PsyD, MIND Institute, Department of Psychiatry and Behavioral Sciences,
University of California at Davis, Sacramento, California
Randi J. Hagerman, MD, MIND Institute, Department of Pediatrics, University of California
at Davis, Sacramento, California
Julie Hammer, PhD, Center for Development and Learning, University of North Carolina
at Chapel Hill, Chapel Hill, North Carolina
Heather Cody Hazlett, PhD, Department of Psychiatry, University of North Carolina
Stephen R. Hooper, PhD, Center for Development and Learning, University of North Carolina
Maile Ho-Turner, PhD, Honolulu, Hawaii
Joseph E. Hornyak, MD, PhD, Department of Physical Medicine and Rehabilitation, University
of Michigan, Ann Arbor, Michigan
Alicia Hughes, PhD, Department of Psychology, Temple University, Philadelphia, Pennsylvania
Randy W. Kamphaus, PhD, College of Education, Georgia State University, Atlanta, Georgia
Valerie Van Horn Kerne, MA, Department of Educational Psychology, University of Texas at
Austin, Austin, Texas
Shelli R. Kesler, PhD, Department of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Stanford, California
Lori A. Long, MA, Division of Advanced Studies in Learning, Technology, and Psychology
in Education, Mary Lou Fulton Institute and Graduate School of Education, Arizona State
University, Tempe, Arizona
Melissa J. Mathews, MA, Department of Clinical Psychology, University of Massachusetts,
Amherst, Amherst, Massachusetts
Joan W. Mayfield, PhD, Our Children’s House at Baylor, Dallas, Texas
William M. McMahon, MD, Department of Psychiatry, University of Utah School of Medicine,
Salt Lake City, Utah
Kathleen K. McMillan, MEd (retired), Jacksonville Schools, Jacksonville, North Carolina
Kathryn N. North, MD, Department of Pediatrics, University of Sydney, Sydney, Australia,
and Children’s Hospital at Westmead, Westmead, New South Wales, Australia
Contributors xi
Nancy L. Nussbaum, PhD, Department of Educational Psychology, College of Education,

University of Texas at Austin, Austin, Texas
Jonathan M. Payne, PsyD, Institute for Neuroscience and Muscle Research, Children’s Hospital
at Westmead, Westmead, New South Wales, Australia
Steven R. Pliszka, MD, Division of Child and Adolescent Psychiatry, University of Texas
at San Antonio, San Antonio, Texas
M. Paige Powell, PhD, Psychology Service, Department of Pediatrics, Baylor College
of Medicine, Texas Children’s Hospital, Houston, Texas
Dawn Reinemann, PhD, Holy Family Memorial, Manitowoc, Wisconsin
Cecil R. Reynolds, PhD, private practice, Bastrop, Texas
Russell P. Saneto, DO, PhD, Division of Pediatric Neurology, Departments of Neurology and
Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, Washington
Timothy Schulte, PsyD, Department of Graduate Psychology, James Madison University,
Harrisonburg, Virginia
Adam Schwebach, PhD, Neurology, Learning, and Behavior Center, Salt Lake City, Utah
Laura Shank, PsyD, Department of Physical Medicine and Rehabilitation, University of
Michigan, Ann Arbor, Michigan
Julien T. Smith, PhD, Children’s Neurodevelopmental Services, Inc., Salt Lake City, Utah
Susan M. Swearer, PhD, Department of Educational Psychology, University of
Nebraska–Lincoln, Lincoln, Nebraska
Anthony Swentosky, MS, Department of Psychology, University of Rhode Island, Kingston,
Rhode Island
Genevieve Verdi, MEd, Department of Psychology, University of Rhode Island, Kingston,
Rhode Island
Susan E. Waisbren, PhD, Department of Psychiatry, Children’s Hospital, Harvard Medical
School, Boston, Massachusetts
Cixin Wang, PhD, Department of Educational Psychology, University of Nebraska–Lincoln,
Lincoln, Nebraska
Seth A. Warschausky, PhD, Department of Physical Medicine and Rehabilitation, University of
Michigan, Ann Arbor, Michigan
Lisa L. Weyandt, PhD, Department of Psychology, University of Rhode Island, Kingston,
Rhode Island
Timothy B. Whelan, PhD, Neuropsychology Service, Baystate Medical Center, Springfield,
Massachusetts
Elizabeth Wilde, PhD, Cognitive Neuroscience Laboratory, Baylor College of Medicine,
Houston, Texas
David L. Wodrich, PhD, ABPP, Division of Advanced Studies in Learning, Technology, and
Psychology in Education, Mary Lou Fulton Institute and Graduate School of Education,
Arizona State University, Tempe, Arizona
Preface
Thirteen years ago, we entertained the idea of creating a handbook as a desk refer-
ence for practicing neuropsychologists and members of related professions, to cover the
broad spectrum of neurodevelopmental and genetic disorders in children. At the time,
no such volume existed. In 1999, with the assistance and support of our esteemed col-
leagues, we were able to publish the first edition of this volume. We are pleased that
this volume has been so well received and is in the small company of volumes for which
second editions are completed.
This text grew out of our mutual interest in educating our students and fellow clini-
cians about the powerful role played by genetics in shaping the development and lives of
many children. It was our intent that the text would serve as a ready and comprehensive
reference, assisting clinicians to understand, evaluate, and ultimately help children with
neurodevelopmental and genetic disorders.
In our daily work as scientist-practitioners, we actively blend research, training, and
clinical practice. As we participate in, read, and review current research, our clinical
practice—what we do and how we do it—changes. As we train our students, our self-
perceptions, our ideas, and our clinical practice are sharpened. The pace at which these
processes take place has continued to increase since the first edition of this volume
was published. Society has increasingly acknowledged the powerful biological bases for
many childhood problems. Since the publication of the first edition of this volume, the
lay and professional communities have slowly worked toward balancing the contribu-
tions of biology and experience in their understandings of children’s development and
outcome. As the eminent neuropsychologist John Weery noted years ago, biology is
not destiny. The longitudinal work of Emmy Werner and others has demonstrated that
even problems with significant biological bases can be and are affected greatly in their
outcome by environmental consequences. We recognize as clinicians that biology very
powerfully influences the neurodevelopment and behavior of many children with such
problems as attention-deficit/hyperactivity disorder, learning disabilities, and anxiety
disorders. However, we continue to believe strongly that the daily lives of all children
are equally powerful in shaping the consequences of those conditions. The individual
child’s day-to-day life within the family, in the school, and on the playground—not
xiii
xiv Preface
whether he or she demonstrates certain symptoms or diagnoses—is what determines his

or her ultimate life course.
The dramatic and rapid growth in medicine, psychology, and education is greatly
improving our ability to prepare all children, even those with significant differences, for
their adult lives. Clinicians in the next 50 years will increasingly be expected to possess
expertise not just in diagnosis and intervention, but in the medical and biological phe-
nomena that have an impact on children’s growth and development. We are very pleased
with the breadth and scope of this second edition. We have added several new chapters,
and many of our contributors have graciously updated and rewritten the chapters they
contributed to the first edition.
Acknowledgments
We wish to thank our colleagues for their scholarly and thoughtful contributions to this
second edition. We also wish to thank Kathleen Gardner for her editorial organization,
management, and secretarial skills, and Rochelle Serwator, Senior Editor at The Guil-
ford Press, for her guidance, support, and friendship.
Sam G oldstein, PhD

C ecil R. R eynolds, PhD
Contents
Part I. Background
1. Introduction 3
Sam Goldstein and Cecil R. Reynolds
2. Neuropsychological Assessment in Genetically Linked 9

Neurodevelopmental Disorders
Cecil R. Reynolds and Joan W. Mayfield
3. Neurodevelopmental Disorders and Medical Genetics: An Overview 33

Bonnie J. Baty, John C. Carey, and William M. McMahon
4. Neuroimaging and Genetic Disorders 58

Shelli R. Kesler, Elizabeth Wilde, Jennifer L. Bruno, and Erin D. Bigler
5. Integrative Developmental Neuropsychology: A General Systems 84

and Social-Ecological Approach to the Neuropsychology of Children
with Neurogenetic Disorders
Timothy B. Whelan and Melissa J. Mathews
Part II. Disorders Primarily Affecting

Learning and Behavior
6. Learning Disabilities 105

Sam Goldstein, Adam Schwebach, and Sean Cunningham
7. Attention-Deficit/Hyperactivity Disorder 131

Sam Goldstein
xv
xvi Contents
8. Oppositional, Conduct, and Aggressive Disorders 151

Lisa L. Weyandt, Genevieve Verdi, and Anthony Swentosky
9. Gilles de la Tourette Syndrome 171

Alicia Hughes, Brian P. Daly, and Ronald T. Brown
10. Anxiety Disorders 188

Steven R. Pliszka
11. Mood Disorders 209

Susan M. Swearer, Cixin Wang, Jami Givens, Brandi Berry,
and Dawn Reinemann
12. Autism Spectrum Disorders 228

Blythe Corbett and Joan Gunther
Part III. Disorders with Broader-S pectrum Effects
13. Turner Syndrome 261

M. Paige Powell and Timothy Schulte
14. Fragile X Syndrome and Fragile X–Associated Disorders 276

Randi J. Hagerman
15. The Mucopolysaccharidoses 293

Michael B. Brown
16. Noonan Syndrome 311

Phyllis Anne Teeter Ellison
17. Neurofibromatosis Type 1 322

Jonathan M. Payne and Kathryn N. North
18. Sickle Cell Disease 338

Julien T. Smith and David A. Baker
19. Down Syndrome 362

Heather Cody Hazlett, Julie Hammer, Stephen R. Hooper,
and Randy W. Kamphaus
20. Klinefelter Syndrome 382

Heather Cody Hazlett, Mario Gaspar De Alba, and Stephen R. Hooper
21. Phenylketonuria 398

Susan E. Waisbren
22. Rett Syndrome: A Truly Pervasive Developmental Disorder 425

Robert T. Brown and Kathleen K. McMillan
Contents xvii
23. Lesch–Nyhan Syndrome: A Sex-Linked Inborn Error of Metabolism 445

David L. Wodrich and Lori A. Long
24. Seizure Disorders 460

Thomas L. Bennett, Deana B. Davalos, Maile Ho-Turner,
and Barbara C. Banz
25. Prader–Willi Syndrome 484

Elisabeth M. Dykens, Suzanne B. Cassidy, and Melissa L. DeVries
26. Disorders of Mitochondrial Metabolism 512

Russell P. Saneto
27. Major Structural Anomalies of the Neocortex 539

Nancy L. Nussbaum, Gina B. Christopher, and Valerie Van Horn Kerne
28. Spina Bifida Myelomeningocele 554

Angela Giacoletti Argento, Seth A. Warschausky, Laura Shank,
and Joseph E. Hornyak
29. Inborn Errors of Metabolism: A Brief Overview 570

Robert T. Brown
Index 579
As human beings, our greatness lies not so much in being
able to remake the world—that is the myth of the atomic
age—as in being able to remake ourselves.
—Mohandas Gandhi
Most intellectuals today have a phobia of any explanation

of the mind that invokes genetics.
—Stephen P inker
I think I have discovered the secret of life—you just hang

around until you get used to it.
—C harles M. Schulz
Part I
Background
Chapter 1
Introduction
Sam Goldstein
Cecil R. Reynolds
Neuropsychology is the study of brain– of the studies and their appearance in main-
behavior relationships, and a clinical neu- stream medical and psychological journals
ropsychologist is a clinician who applies the indicated the need for even broader perspec-
results of knowledge in this area to diag- tives and interdisciplinary approaches to the
nosis and treatment of neurodevelopmental diagnosis and treatment of children’s neu-
disorders, among other central nervous sys- rodevelopmental disorders (ironically, at a
tem (CNS) disturbances (e.g., CNS diseases, time when the politics and costs of health
traumatic brain injury, cerebrovascular ac- care were giving rise to the managed care
cidents, etc.). Clinical neuropsychology as model, which promotes singularity of treat-
practiced today traces its roots principally to ment!).
the 1940s, although the influence of earlier A review of these 42 studies, which may
practitioners such as A. R. Luria is clearly not necessarily have represented all pub-
evident. As a clinical discipline, therefore, lished studies dealing with these two issues,
it is relatively young, but it is a burgeoning revealed the increasing importance of a si-
specialty within the broader discipline of multaneous view and understanding of these
psychology. two issues for neuropsychologists, physi-
As part of our preparation for the first edi- cians, and other medical and mental health
tion of this text, we completed a MEDLINE professionals. For example, Mazzocco and
search over a 4-year period from January Holden (1996) provided a neuropsychologi-
1993 through July 1997, which yielded over cal profile of females with the fragile X per-
6,000 peer-reviewed research studies con- mutation. Devenny and colleagues (1996)
cerning chromosomal and genetic disorders provided a longitudinal study of individu-
in children. Over 4,000 studies published als with Down syndrome, and in doing so,
during the very same period of time were defined the neurocognitive changes in this
identified as specifically dealing with the population over four decades. Lanoo, De-
neuropsychological evaluation and treat- Paepe, Leroy, and Thiery (1996) provided
ment of children. Yet only 42 studies dealing data reflecting a profile characterized by dif-
with both issues were found in this database. ficulty with sustained visual attention and
Even given the relative youth of the field, this problems with visual construction, over and
seemed too few papers. However, the nature above the visual acuity problems and other
3
4 BACKGROUND
phenomena associated with Marfan syn- stand how the biology functions. Equally the
drome. Davalos and colleagues (1996) of- same research has been crucial in its demon-
fered a neuropsychological profile reflecting stration that environmental influences are also
a pattern of mild mental retardation, con- ubiquitous. (p 396)
structional apraxia, and expressive language
impairment in a group of children presenting
with proportionate short stature, delayed Nature and Nurture
bone age, and peculiar faces. These children
were subsequently identified as experienc- There are few topics as inflammatory, po-
ing Floating–Harbor syndrome. And Ross, lemic, or controversial in psychology and
Stefanatos, Roeltgen, Kushner, and Cutler related sciences as the so-called “nature–
(1995) offered a longitudinal study provid- nurture controversy.” Briefly stated, this
ing a profile of neurocognitive changes in controversy revolves around whether human
females with Turner syndrome. development and human behavior (both
As part of our work for this second edi- overt and covert) are determined by human
tion, we completed a number of new search- beings’ genetic constitution (nature) or by
es from January 2004 to January 2009. We the environment (nurture) in which people
began with a Google search using the key- grow and develop. Few, if indeed any, con-
word “genetic disorders,” which identified temporary scientists approach this question
over 17 million citations. We then searched in such simplistic terms. The arguments now
Google Scholar with the keyword “chromo- tend to center around the relative contribu-
some disorders,” which produced over 5 mil- tions of nature and nurture to human devel-
lion citations. Searching MEDLINE with the opment and behavior, and the mechanisms
“chromosome disorders” keyword resulted of interaction and plausibility of transaction
in approximately 37,000 references. Finally, between them. It is also acknowledged that
we identified 201 new studies dealing with for specific human attributes, the answers
will vary.
neuropsychological evaluation during this
A genotype may be considered the raw
time period, but fewer than two dozen new
material and blueprints (genes and chromo-
studies, dealing with both genetic disorders
somes) provided through the melding of the
and neuropsychological evaluation. These
parental genotypes. Except in the case of mo-
studies are very similar in breadth and scope
nozygotic twins and cloning, no two human
to studies published earlier. For example, a
genotypes are alike. The human organism
number of researchers have examined the
then grows and develops in a unique envi-
neuropsychological characteristics of spe-
ronment to produce the visible, assessable,
cific genetic disorders (Adams et al., 2007;
acting phenotype—the expression of the
Azzam et al., 2005). Other researchers have
genotype in the unique environment. Attri-
examined risk factors (Gothelf et al., 2007),
butes known to be “genetically determined”
as well as familial characteristics (Gam-
can often be altered in the course of devel-
bardella et al., 2008; Veltman et al., 2005).
opment or even later in life. Height, known
When the contributions of genetics to more
to have strong heritability in the human
common and diverse childhood problems,
population, can be altered dramatically in
such as learning disabilities and attention-
an individual by manipulation of diet. As
deficit/hyperactivity disorder (ADHD), are
subsequent chapters of this volume indicate,
examined along with the genetic role in
many outcomes for some genetic disorders
many lower-incidence problems, the impor-
are entirely dependent on, or at least strong-
tance of understanding and beginning to
ly determined by, changes in environment.
develop a cohesive genetic–environmental
Phenylketonuria (PKU) is a classic example.
model becomes clear immediately. As Rutter
When phenylalanines are eliminated from
(1997) has noted,
the diet of youngsters with PKU, the out-
Quantitative genetic research has been most comes for intellect, school adjustment, and
informative in showing the importance of other behavioral variables are all much im-
genetic influences on virtually all forms of proved. Even behaviors as complex as adult
human behavior. Behavior has to have a bio- sexual behaviors and preference, which are
logical basis and it is necessary that we under- strongly genetically influenced, can be altered
Introduction 5
by significant changes in maternal stress lev- The latter proposition requires some elab-
els at particular times during pregnancy (for oration. Psychological variables such as in-
a review, see Houshyar & Kaufman, 2005). telligence and personality are measured in
There are certain critical periods during ges- interval scales of measurement, which have
tation when hormonal releases affect cell no true zero point denoting the absence of
migration and organ development in a pre- the trait, such as zero reflects on a ratio scale
programmed fashion. Mothers under very of measurement. With a true zero point,
high levels of stress may alter those hormon- the actual amount of a characteristic (e.g.,
al release patterns in ways that affect adult height) can be determined, and such state-
sexual behavior in their offspring. It seems ments as “A height of 6 feet is twice a height
that few components of human behavior are of 3 feet” are accurate. However, interval
too simple to be influenced by environment, scales, having no true zero point, begin mea-
or too complex to be related to the genotype. surement at the midpoint of a characteris-
The complexity of the interaction and poten- tic’s distribution—the only point we can lo-
tial transaction is virtually incomprehensible cate definitively. We then measure outward
when we recall that no two combinations of toward the two ends of a distribution, each
genotype and environment have been or ever of which is asymptotic to its axis. That is,
will be identical. we do not know where intelligence begins or
To many scientists, ourselves included, it ends, and an IQ of 100 does not reflect twice
does appear that as our skills, insights, and the intelligence of an IQ of 50. Herein lies
techniques of investigation continue to grow the clinician’s opportunity to intervene and
in number and in sophistication, we learn potentially create meaningful results, even
that our biology has a more pronounced im- under the adversity of strong genetic deter-
pact on our behavior than we would prefer mination. To increase an individual’s intel-
to believe. Even at the extremes of the hered- lectual level by a full 20% may mean an in-
itary influences argued by some scientists, crease of 10, 20, 30, 40, or even more points
there is much room for change, intervention, on a psychometric scale. The same may hold
and environmental influence. true for other human characteristics that
Take the controversial case of the heri- present as complex behavioral phenomena.
tability of human intelligence. The debate As subsequent chapters of this book de-
about this begins with differences of opin- scribe, many genetic disorders have high
ion about the very nature of the phenome- degrees of variable expressivity, often (but
non (for a review, see Naglieri & Goldstein, not always) for unknown reasons. We be-
2009). Moreover, the extremes of the vari- lieve many of these reasons to be treatment-
ous scientific arguments place the nature– related, or at least associated with biological
nurture contributions to intelligence at 80% and environmental interplay. Early involve-
and 20% and at 20% and 80%, respectively ment of clinicians who understand brain–
(e.g., see Herrnstein & Murray, 1994; Jens- behavior relationships is necessary if chil-
en, 1980; Reynolds & Brown, 1984). One dren with neurodevelopmental disorders
may argue urgently for relative contribution are to have the maximum developmental
and interaction within these two extremes, opportunities. All of this may be taken to
but even in the most extreme genetic view mean that although genetics or biology may
(i.e., the view that 80% of the variance in be destiny, it need not be.
human intelligence is genotype variation), The human brain represents the product
two propositions remain inescapable: of a construction project that has been going
on for 6 billion years. In its physical form
1. Heritability statistics only apply to and function, the brain represents millions
groups, and the genetic influence on in- upon millions of trial-and-error adaptive
telligence for an individual may be more adjustments. Consisting of an estimated
or less than the group heritability. 100 billion neurons and many more glial
2. Even if 80% of an individual’s intellectu- cells organized into thousands of regions,
al level is genetically determined, changes the human brain governs body function and
in intellectual level as a function of en- movement in a seamlessly integrated man-
vironmental influences and transaction ner; even more importantly, it regulates cog-
may be enormous. nition. Not surprisingly, although the brains
6 BACKGROUND
of different species may not look exactly concerning the influence of human genetics
alike, they all work according to the same upon behavior, clinicians will be increasing-
principles and mechanisms. These neurons ly called upon to guide mental health, medi-
and glial cells communicate via a nearly infi- cal, and educational professionals in blazing
nite number of synaptic connections, yet the new trails to improve the quality of life for
entire organ in a human being weighs only children and adults with genetic disorders
about 3 pounds. Gram for gram, the human affecting their behavior and development.
brain delivers an array of motoric, behav- Clinicians who work with children must be
ioral, cognitive, and emotional capacities knowledgeable about developmental psy-
that is nearly impossible to fathom in light chology as well.
of its size. Because the brain is the center of The primary objective of this expanded
our consciousness and being, it is fitting that second edition, as of the first edition, is to
an increasing scientific literature is being de- provide readers with a stand-alone compen-
voted to understanding and facilitating its dium concerning the impact of genetics on
development and operation—in particular, neurodevelopment in children. In planning
to appreciating the developmental disorders this second edition, we have continued to
and conditions that adversely affect chil- recognize that this primary mission entails
dren’s transition into adulthood. creating a text similar in breadth and scope
Cortical development is genetically pre- to those handbooks of neuropsychology that
programmed in many ways. Not all genetic are familiar to each of us. The goal of those
disorders have a full phenotypic impact at texts, as of this one, is to provide a compre-
the same time. Environments may also alter hensive set of resource materials that will be
the timing of development and change as available to readers as needed, organized in
well. As Bigler and Clement (1997) note so a framework that is understandable and im-
well, the process of maturation greatly com- mediately useful in clinical practice. Clinical
plicates the evaluation of neurodevelopmen- child neuropsychologists and related pro-
tal disorders in children and adolescents. fessionals today and in the future must be
The effects of the interaction between age scientist-practitioners; to do so effectively
and genetic expressivity of a disorder with requires a special type of literature.
CNS implications adds to the complexity We have divided the text into three sec-
of all tasks with such children. A common tions. Part I, “Background,” offers our
change in CNS development may have radi- view of the role of neuropsychology in the
cally different implications and outcomes, assessment, treatment, and management of
even in adulthood, if the age of occurrence children with neurobehavioral and genetic
is varied. disorders. In Chapter 2, the role of neurop-
sychology in the assessment of these popula-
tions is discussed. Chapter 3 is an overview
Objectives of This Volume providing readers with a basic model for
understanding genetics, as well as up-to-
Clinicians of the 21st century will need to date information concerning current trends
possess a working knowledge of genetics as and research in the field of human genetics.
well as neuropsychology. Yet, even as we Chapter 4 then examines current research
publish the second edition of this volume, concerning the use of neuroimaging to deter-
the science of what we choose to term behav- mine structural and biochemical differences
ioral genetics remains in its infancy, as our in children with genetic disorders. Finally,
literature review reflects. The 21st century psychosocial issues related to emotional,
clinician will exemplify the biopsychosocial educational, familial, and behavioral prob-
model of the future. Clinicians will continue lems are reviewed and discussed in Chapter
to be called upon to assess the relationship 5. This information lays a firm foundation
between brain function and behavior. They for the following discussions of specific ge-
will be asked to assess function by skills netic disorders in children. A working un-
(e.g., the skills necessary to read efficiently). derstanding of this information is essential
They will be asked to plan treatment, to for all practicing clinicians.
monitor that treatment, and to assess prog- Part II of the volume two contains chap-
ress. As increasing information is gathered ters dealing with seven disorders or groups
Introduction 7
of disorders that have accepted, though as ture of an institutional setting. Increasingly,

yet not completely identified, genetic etiolo- knowledge about the neuropsychological
gies. These disorders have a common theme, functioning of children with neurodevelop-
in that they primarily affect learning and mental disorders and about ways to facili-
behavior; thus topics that often do not find tate their development is intertwined with
their way into genetics and neurobehavioral the public school systems of our nation—
texts are included. The disorders covered and for good reason, for this is increasingly
here are learning disabilities; ADHD; op- where the children are educated.
positional, conduct, and aggressive disor-
ders; Tourette syndrome; anxiety disorders;
mood disorders; and autism spectrum disor- Conclusion
ders. These chapters, as well as those in Part
III, provide readers with an overview of cur- The path to success in life is neither simple
rent genetic, behavioral, and developmental nor easy for the majority of youth in the new
issues; guides to assessment; and discussions millennium. Given the medical community’s
of treatment, care, and management. increasing ability to address the health needs
Part III is by far the lengthiest section: of children with complex genetic and neu-
It contains 17 chapters offering overviews rodevelopmental disorders, their subsequent
of lower-incidence disorders in the general increased survival rates, the increased pub-
population. In this second edition, we have lic recognition of these disorders, and the
expanded this section by adding several greater availability of organized support for
new chapters. Clinicians can expect to see children whose genetic disorders primarily
increasing numbers of children with these affect learning and development, the path
problems, especially within medical settings. to success for these children has perhaps be-
Furthermore, the increasing recognition come somewhat less convoluted and rocky.
of the impact such impairments have upon Ye the increasing educational, social, and
children’s functioning at school has now family pressures placed upon children con-
paved the way for many of these children stitute an entirely new set of burdens for all
to receive specialized services within school youth. Neuropsychologists and related med-
settings. Thus these problems are also likely ical, mental health, and educational profes-
to be faced more and more often by school sionals will play an increasing role in shap-
psychologists, school nurses, and other edu- ing the life path for children with genetic
cational staff members. The approach to and neurodevelopmental disorders.
educating children with such disorders can Although the liabilities of these children
and usually does have a major impact on the are of most interest to many professionals,
quality of their lives. As an example, con- their assets and tenacity in some cases must
sider children with Down syndrome. In the also be well defined and understood. Several
not very distant past, children with Down longitudinal studies over the past few de-
syndrome children were rarely seen in pub- cades have set out to develop an understand-
lic, and most were treated through residen- ing of these assets and their related process-
tial placements in state facilities designed for es. In particular, the complex interaction
children with severe developmental disor- of protective and risk factors with is being
ders. However, not all children with Down examined, the goal of developing a model
syndrome also have mental retardation, and to apply this knowledge in clinical practice
most of those who do have intellectual im- (Rutter & Quinton, 1984; Werner & Smith,
pairment in the mild to moderate range. De- 2001). These studies and others have made
cades of research have shown that children major contributions in two ways. First, they
with Down syndrome are best educated in have identified resources across children’s
a public school setting with maximum ex- lives that predict successful adjustment for
posure to the normal school environment. those exposed to adversity; second, they
Social and behavioral outcomes in particu- have begun the process of clarifying ways
lar are superior for these children when they in which these protective factors promote
are educated in public schools, according adaptation (Wyman, Sandler, Wolchik, &
to a least-restrictive-environment model, as Nelson, 2000). Some of these processes can
opposed to the isolation and restricted na- serve to protect against the negative effects
8 BACKGROUND
of neurodevelopmental and genetic disor- Herrnstein, R., & Murray, H. (1994). The bell
ders, while others simply act to enhance curve. New York: Free Press.
development, regardless of the presence of Houshyar, S., & Kaufman, J. (2005). Resiliency
disability. in maltreated children. In S. Goldstein & R. B.
Brooks (Eds.), Handbook of resilience in children
Knowledgeable professionals offer their (pp. 181–202). New York: Kluwer Academic/Ple-
patients, clients, and students a powerful num Press.
sense of hope by providing accurate infor- Jensen, A. R. (1980). Perspectives on bias in mental
mation, understanding, and support. It is testing. New York: Plenum Press.
true that much remains to be uncovered and Lanoo, E., DePaepe, A., Leroy, B., & Thiery, E.
understood concerning the impact of genet- (1996). Neuropsychological aspects of Marfan
ics and the interaction of genetics with the syndrome. Clinical Genetics, 49, 65–69.
environment in shaping the lives of children. Mazzocco, M. M., & Holden, J. J. (1996). Neurop-
However, identification through careful as- sychological profiles of three sisters homozygous
sessment, intervention and accommodation for the fragile X permutation. American Journal
of Medical Genetics, 64(2), 323–328.
through implementation of thoughtful treat- Naglieri, J., & Goldstein, S. (2009). Understand-
ment, and the provision of support will make ing the strengths and weaknesses of intelligence
a significant positive difference for children and achievement. In J. Naglieri & S. Goldstein
with genetic and neurodevelopmental disor- (Eds.), Practitioner’s guide to assessing intel-
ders. ligence and achievement (pp. 2–10). Hoboken,
NJ: Wiley.
Reynolds, C. R., & Brown, R. T. (1984). Bias in
References mental testing: An introduction to the issues. In
Adams, H. R., Kwon, J., Marshall, F. J., De Blieck, R. T. Brown & C. R. Reynolds (Eds.), Perspec-
E. A., Pearce, D. A., & Link, J. W. (2007). Neu- tives on bias in mental testing (pp. 1–26). New
ropsychological symptoms of juvenile onset Bat- York: Plenum Press.
ten disease: Experiences from two studies. Jour- Ross, J. L., Stefanatos, G., Roeltgen, D., Kushner,
nal of Child Neurology, 22, 621–627. H., & Cutler, G. B. (1995). Ulrich–Turner syn-
Azzam, A., Lerner, D. M., Peters, K. F., Wiggs, E., drome: Neurodevelopmental changes from child-
Rosenstein, D. L., & Biesecker, L. G. (2005). Psy- hood through adolescence. American Journal of
chiatric and neuropsychological characterization Medical Genetics, 58, 74–82.
of Palaster–Hall syndrome. Clinical Genetics, Rutter, M. L. (1997). Nature–nurture integration:
67, 87–92. The example of anti-social behavior. American
Bigler, E. B., & Clement, P. F. (1997). Diagnostic Psychologist, 52, 390–398.
clinical neuropsychology. Austin: University of Rutter, M. L., & Quinton, D. (1984). Long-term
Texas Press. follow-up of women institutionalized in child-
Davalos, I. P., Figuera, L. E., Bobadilla, L., hood: Factors promoting good functioning in
Martinez-Martinez, R., Matute, E., Partida, M. adult life. British Journal of Developmental Psy-
D., et al. (1996). Floating–Harbor syndrome: A chology, 18, 225–234.
neuropsychological approach. Genetic Counsel- Veltman, M. W., Thompson, R. J., Craig, E. E.,
ing, 7, 283–288. Dennis, N. R., Roberts, S. C., Moore, V., et al.
Devenny, D. A., Silverman, W. P., Hill, A. L., (2005). A paternally inherited duplication in the
Jenkins, E., Sersen, E. A., & Wisniewski, K. E. Prader–Willi/Angelman syndrome critical region:
(1996). Normal aging in adults with Down’s syn- A case and family study. Journal of Autism and
drome: A longitudinal study. Journal of Intellec- Developmental Disorders, 35, 117–127.
tual Disability Research, 40, 208–221. Werner, E. E., & Smith, R. S. (2001). Journeys from
Gambardella, S. P., Coppola, A., DiBonaventura, childhood to midlife: Risk, resilience, and recov-
C., Bovo, G., Boaretto, F., Ciampa, E. G., et al. ery. Ithaca, NY: Cornell University Press.
(2008). Familial mesial temporal lobe epilepsy: A Wyman, P. A., Sandler, I., Wolchik, S., & Nelson,
clinical and genetic study of 15 Italian families. K. (2000). Resilience as cumulative competence
Journal of Neurology, 255, 16–23. promotion and stress protection: Theory and
Gothelf, D., Feinstein, G. D., Thompson, T., Gu, intervention. In D. Cicchetti, J. Rappaport, I.
E., Penniman, L., Van Stone, E., et al. (2007). Sandler, & R. Weissberg (Eds.), The promotion
Risk factors for emergence of psychotic disorders of wellness in children and adolescents (pp. 148–
in adolescents with 22q11. 2 deletion syndrome. 167). Washington, DC: Child Welfare League of
American Journal of Psychiatry, 164, 663–669. America.
Chapter 2
Neuropsychological Assessment
in Genetically Linked
Cecil R. Reynolds
Joan W. Mayfield
Children in general have always posed spe- neurological examination that focuses on re-
cial problems in clinical assessment and flexes, muscle tone, and a review of cranial
evaluation, and even more so from a psycho- nerve functions. The neuropsychologist can
metric standpoint. Infancy and childhood add some additional details about higher
are the times of the greatest (and most rapid) cortical functions (i.e., thinking, reasoning,
breadth and depth of change in the human intellectual development, and language de-
lifetime. This alone presents a significant velopment), but our measures, even the most
challenge to those who would assess a child’s sophisticated (e.g., Bayley, 2005), remain
status in order to make predictions about a crude. Except for very low levels of perfor-
child’s future and about interventions that mance, scores on such instruments are rela-
may be required to facilitate growth and tively poor predictors of adult status. Little
development. Children who are developing in the way of localization of function can be
normally or with only mild levels of disabil- accomplished, and higher cortical systems
ity can be difficult to assess accurately, for of brain function are rarely assessed well.
reasons related to the maturity of their lan- In these early years, we clinicians are often
guage development, motor development, so- left with an unsatisfactory feeling about
cial skills, and attention, concentration, and what we have accomplished with such as-
memory skills. As the extent of disability sessments. However, an assessment at even
increases, accurate assessment becomes ever these early stages by a neuropsychologist
more challenging. makes significant contributions to diagnosis
Moreover, certain developmental periods and treatment.
pose special problems. During infancy in With infants changing so rapidly, it is im-
particular, a child’s very limited language perative to have carefully constructed stan-
and motor skills prevent a thorough assess- dards of normality if developmental prob-
ment of cognitive functions and higher corti- lems are to be detected accurately. Minor
cal development. A pediatric neurologist can variants of normal development need not
get a reasonable estimate, but only at a gross be diagnosed as disorders, nor should sig-
level, of neurodevelopmental status from a nificant problems be overlooked. It is in this
9
10 BACKGROUND
context that psychometric testing has the The interaction between the genetic basis
most to offer. Psychologists are accustomed of a disorder on the one hand, and the in-
to using norm-referenced tests, such as the dividual’s environmental circumstances and
Bayley Scales of Infant and Toddler Devel- other biological predispositions (which may
opment, Third Edition (Bayley, 2005). Such or may not be affected by the genetics of
tests have carefully constructed normative the primary disorder) on the other, will also
reference tables that define normal varia- alter the severity of symptoms. Phenylketo-
tions in development, typically considered as nuria (PKU), for example, is an entirely ge-
within two standard deviations of the mean netic disorder. Yet the treatment compliance
of a normally functioning reference group. of both the family and the individual, along
Tests constructed specifically for use with with the child’s temperament, predisposition
infants, despite involving such observation for intellectual development, and numerous
(as opposed to demand performances, as other factors, will act to determine the cog-
with older children and adults), compare rel- nitive symptoms displayed. This will have
evant functions of infants to the distribution implications for whether special education
of the same functions for infants develop- programming for mental retardation, specif-
ing normally. Such quantitative approaches ic learning disabilities, or even serious emo-
are a necessity for accurate diagnosis during tional disturbance is required. Although di-
times of rapid change. Informal or subjec- etary treatment is always indicated for PKU,
tive observations and ratings place far too one cannot assume what other treatments
many cognitive demands on the clinician to will be necessary. Rather, periodic formal
produce consistent, reliable results. neuropsychological testing should be con-
Neuropsychological testing is thus impor- ducted to detect cognitive changes that may
tant to establish the presence of a cognitive require additional forms of intervention,
disorder. Since neuropsychological testing is and that may even provide some suggestive
norm-referenced by chronological age, prog- data about a patient’s dietary compliance.
ress can be monitored via repeated or serial Assessment of behavior and affect through
testing, and changing patterns of symptoma- norm-referenced, age-corrected methods
tology can be detected. The effectiveness (or (e.g., Reynolds & Kamphaus, 2004) are also
lack thereof) of interventions can be docu- necessary, as individuals with genetic disor-
mented as well, and changes can be made as ders are commonly at increased risk of de-
indicated. veloping emotional and behavioral problems
These same quantitative procedures are (see also Warzak, Mayfield, & McAllister,
useful throughout childhood and adoles- 1996).
cence, when cognitive development contin- There is no cure or elimination of all
ues to be rapid and is often uneven. Quanti- symptoms for the disorders treated in this
tative tracking of change, and the detection volume. Rather, most viable treatments
of change through psychometric methods center on symptom management. Neurop-
providing age-corrected deviation scaled sychological and psychological assessment
scores, are necessities. has two primary roles to play beyond assist-
ing in diagnosis. The first, as noted above,
is the evaluation of the severity of symptom
Monitoring and Managing expression; the second is the assessment of
Symptom Expression treatment effects through careful psycho-
metric monitoring of changes in symptom
All of the various disorders addressed in this expression.
volume are believed to have some degree of Historically, neuropsychological evalu-
genetic linkage, and some of these linkages ations were conducted with adults with
are stronger and more obvious than others. known brain damage or injury, to deter-
However, they all show what is termed vari- mine lateralization or localization of le-
able expressivity (i.e., the number and/or the sion or injury. As Lezak (1995) points out,
severity of the symptoms defining the disor- “[the] rapid evolution [of such evaluations]
der vary across individuals). The variability in recent years reflects a growing sensitivity
of symptom expression must be monitored among clinicians to the practical problems
and will have clear treatment implications. of identification, assessment, care, and treat-
Neuropsychological Assessment 11
ment of brain damaged patients” (p. 7)—a What Is Neuropsychology?

comment that pertains as well to any patient
with a compromised central nervous system Neuropsychology is the study of brain–
(CNS), especially if higher cortical functions behavior relationships. It requires accep-
are involved. Neuropsychologists are often tance of the idea that the brain, working as
asked to provide information concerning an interdependent, systemic network, con-
prognosis for recovery, functional ability, trols and is all-inclusively responsible for be-
and course of treatment. However, the prac- havior. Although this premise seems simple
tice of neuropsychology has broadened to enough now, radical behavioral psychology
include the need to clarify conditions where in the 1960s and early 1970s ignored the
brain damage or CNS compromise has not brain, leading some to espouse the view that
been identified; in these cases, evaluations the brain was irrelevant to learning and be-
provide additional information for differen- havior.
tial diagnoses, which result in more effective Neuropsychological assessment examines
treatment planning. the relationship between brain functioning
As neuropsychologists gained more and behavior through tests that tap specific
knowledge about brain–behavior relation- domains of functioning—t ypically much
ships, they applied their knowledge to adults more specific domains than those that are
without known brain damage. After this, represented on general tests of intelligence,
they turned their attention to problems of such as attention, memory, forgetting, sen-
earlier development, which ultimately pro- sory functions, constructional praxis, and
vided an understanding of brain–behavior motor skills (Farmer & Peterson, 1995;
functioning in children (Reitan & Wolfson, Hynd & Reynolds, 2005; Reitan & Wolf-
1974). We agree that “child clinical neu- son, 1985). Neuropsychologists examine
ropsychology has emerged as an important the functioning of the brain based on be-
theoretical, empirical, and methodological havioral expression, and are able to deter-
perspective for understanding and treating mine whether a brain dysfunction exists or
developmental, psychiatric, psychosocial, whether atypical patterns of neocortical de-
and learning disabilities in children and velopment are present.
adolescents” (Teeter & Semrud-Clikeman, A neurologist looks at the anatomical con-
1997, p. 1). In more recent years, school psy- struction of the brain. Working in conjunc-
chologists have become more versed in neu- tion with neurologists, neuropsychologists
ropsychology and its application to children are able to determine the functional seque-
with neurodevelopmental and genetic disor- lae of CNS dysfunction. Neurologists use
ders as well (e.g., D’Amato, Fletcher-Janzen, advanced neuroimaging techniques, includ-
& Reynolds, 2005; Miller, 2010). ing various forms of magnetic resonance im-
The remaining purposes of this chapter aging (MRI), positron emission tomography
are to give a functional definition of neurop- (PET), and single-photon emission comput-
sychology, to provide information concerned tomography (SPECT) of brain regions.
ing the necessary components of a neurop- Working in conjunction with neurologists,
sychological evaluation, and to discuss their neuropsychologists focus on behavior and
relationship to treatment. An overview of cognition in order to offer educational help
neuropsychological assessment processes is and remediation strategies to teachers, coun-
then presented, both historically and in the selors, and parents. Clinical neuropsycholo-
context of current practices that incorpo- gists deal with a variety of issues as caregiv-
rates the basic components of evaluation and ers seek to understand the educational and
encourages integrative, comprehensive as- psychological needs of children and youth
sessment of CNS compromise. Furthermore, who are coping with neurological deficits.
the chapter provides information concerning Parents frequently want to know what they
why children and adolescents are referred for can do to provide the optimal learning en-
neuropsychological evaluations, and how vironment to help their children reach their
the results of such evaluations are relevant to full potential. They seek to understand the
their educational needs (in terms of effective specific deficits experienced by the children.
remediation techniques, educational place- On the basis of a child’s medical, family, and
ment, and parental expectations). developmental history, as well as the specific
12 BACKGROUND
behavioral and educational concerns, a neu- and concentration. Problems with memory,
ropsychological assessment is designed and attention, concentration, and new learning
conducted. are the most common of all complaints fol-
Although this chapter discusses specific lowing CNS compromise and are frequently
neuropsychological tests and batteries of associated with more chronic neurodevel-
tests, neuropsychology is not a set of tech- opmental disorders (e.g., learning disabili-
niques. Rather, it is a way of thinking about ties, attention-deficit/hyperactivity disorder
behavior, often expressed as test scores; in [ADHD]).
essence, it is a paradigm for understanding 2. Testing should sample the relative ef-
behavior. ficiency of the right and left hemispheres of
the brain. Asymmetries of performance are
of interest on their own, but different brain
Components of systems are involved in each hemisphere,
a Neuropsychological Evaluation and these have differing implications for
treatment. Even in a diffuse injury such as
A neuropsychological evaluation of a child anoxia, it is possible to find greater impair-
will differ in design from that of an adult. ment in one portion of an individual’s brain
Of necessity, it will include educational and than in another. Specific neuropsychologi-
behavioral measures that may not be neces- cal tests like those of Halstead and Reitan
sary with adults. The most common neu- or the Luria–Nebraska Neuropsychological
ropsychological batteries and approaches Battery—Children’s Revision (LNNB-CR;
will thus need to be supplemented in specific Golden, 1986) are useful here, along with
ways, depending on the referral questions measures of verbal and nonverbal memory
posed. The following nine general guidelines processes. In neurodevelopmental disorders,
should nevertheless prove useful and are de- uneven development often occurs.
rived from a variety of sources, including 3. Testing should sample both anterior
our own practices, the general teachings of and posterior regions of cortical function.
Lawrence C. Hartlage, and other specific The anterior portion of the brain is genera-
sources—in particular, Rourke, Bakker, tive and regulatory, whereas the posterior
Fisk, and Strang (1983), which we find to be region is principally receptive. Deficits and
remarkably current. their nature in these systems will have a
great impact on treatment choices. Many
1. All (or at least a significant majority) common tests, such as tests of receptive (pos-
of a child’s educationally relevant cogni- terior) and expressive (anterior) vocabulary,
tive skills or higher-order information- may be applied here, along with a systematic
processing skills should be assessed. This and thorough sensory perceptual examina-
will often involve an assessment of general tion and certain specific tests of motor func-
intellectual level (g) via a comprehensive IQ tion. In conjunction with point 2 above, this
test, such as a Wechsler scale, the Kaufman allows for evaluation of the integrity of the
Assessment Battery for Children, Second four major quadrants of the neocortex: right
Edition (KABC-II; Kaufman & Kaufman, anterior, right posterior, left anterior, and
2004), or the Reynolds Intellectual Assess- left posterior.
ment Scales (RIAS; Reynolds & Kamphaus, 4. Testing should determine the presence
2003). Efficiency of mental processing as as- of specific deficits. Any specific functional
sessed by strong measures of g is essential problems a child is experiencing must be de-
to provide a baseline for interpreting all termined and assessed. In addition to such
other aspects of the assessment process. As- problems being of importance in the assess-
sessment of basic academic skills (including ment of children with neurodevelopmen-
reading, writing, spelling, and math) will be tal disorders, traumatic brain injury (TBI),
necessary, along with tests such as the Test stroke, and even some toxins can produce
of Memory and Learning—Second Edition very specific changes in neocortical function
(TOMAL-2; Reynolds & Voress, 2007), that are addressed best by the neuropsycho-
which also have the advantage of including logical assessment. Similarly, research with
performance-based measures of attention children with leukemia suggests the presence
of subtle neuropsychological deficits follow- tact systems also suggests the potential for
ing chemotherapy—deficits that may not be a positive outcome to parents and teachers,
detected by more traditional psychological as opposed to fostering low expectations
measures. Certain transplant patients will and fatalistic tendencies on identification of
display specific patterns of deficits as well. brain damage or dysfunction.
Neuropsychological tests tend to be less g- 7. Testing should assess affect, person-
loaded as a group and to have greater speci- ality, and behavior. Neuropsychologists
ficity of measurement than many common sometimes ignore their roots in psychology
psychological tests. Noting areas of specific and focus on assessing the neural substrates
deficits is important in both diagnosis and of a problem. However, CNS compromise
treatment planning. will results in changes in affect, personality,
5. Testing should determine the acute- and behavior. Some of these changes will
ness versus the chronicity of any problems be transient, some will be permanent, and
or weaknesses found. The “age” of a prob- (because children are growing and develop-
lem is important to diagnosis and to treating beings) some will be dynamic. Some of
ment planning. When a thorough history these changes will be direct (i.e., the results
is combined with the pattern of test results of CNS compromise at the cellular and sys-
obtained, it is possible, with reasonable ac- temic levels), and others will be indirect (i.e.,
curacy, to distinguish chronic neurodevelop- reactions to loss or changes in function, or
mental disorders such as dyslexia or ADHD to how others respond to and interact with
from new, acute problems resulting from the individual). A thorough history, includ-
trauma, stroke, or disease. Particular care ing times of onset of problem behaviors,
must be taken in developing a thorough, can assist in determination of direct versus
documented history when such a determina- indirect effects. As mentioned earlier, com-
tion is made. Rehabilitation and habilitation prehensive approaches such as the Behavior
approaches take differing routes in the de- Assessment System for Children, Second
sign of intervention and treatment strategies, Edition (BASC-2; Reynolds & Kamphaus,
depending on the age of the child involved 2004), which contain behavior rating scales,
and the acuteness or chronicity of the prob- omnibus personality inventories, and direct
lems evidenced. As children with neurodevel- observation scales, seem particularly useful.
opmental disorders age, symptoms will wax Notably, the BASC-2 has added scales to as-
and wane as well, and distinguishing new sess executive functions more thoroughly,
from old symptoms is important when treat- as a reflection of the increasing knowledge
ment recommendations are being made. base regarding the importance of brain–
6. Testing should locate intact complex behavior relationships in general and execu-
functional systems. The brain functions as a tive functions in particular. Such behavioral
series of interdependent, systemic networks changes will also require intervention, and
often referred to as complex functional sys- intervention will be not necessarily be the
tems. Multiple systems are affected by CNS same if the changes noted are direct versus
problems, but some systems are almost al- indirect or if premorbid behavior problems
ways spared except in the most extreme were evident.
cases. It is imperative in the assessment pro- 8. Test results should be presented in ways
cess to locate strengths and intact systems that are useful in school settings, not just to
that can be used to overcome the problems acute care or intensive rehabilitation facili-
the child is experiencing. Treatment follow- ties, or to physicians. Schools are a major
ing CNS compromise involves habilitation context in which children with chronic neu-
and rehabilitation, with the understanding rodevelopmental disorders must function,
that some organic deficits will represent and, as noted above, school psychologists
permanently impaired systems. As the brain are increasingly recognizing the role of neu-
consists of complex, interdependent net- ropsychology in school-based interventions
works of systems that produce behavior, the for children with neurodevelopmental and
ability to ascertain intact systems is crucial genetic disorders. Children who have sus-
to enhancing the probability of designing tained insult to the CNS (e.g., TBI, stroke)
successful treatment. Identification of in- will eventually return to a school or similar
14 BACKGROUND
educational setting. This will be where the Assessment Approaches

greatest long-term impact on a child’s out- and Instruments
come after CNS compromise will be seen
and felt. Results should speak to academic There are two major conceptual approaches
and behavioral concerns, reflecting what a to neuropsychological assessment. In the
child needs to be taught next in school, how first approach, a standard battery of tasks
to teach to the child’s strengths through the designed to identify brain impairment is
engagement of intact complex functional used. The Halstead–Reitan Neuropsycho-
systems, how to motivate the child, and how logical Test Battery for Older Children (for
to manage positive behavioral outcomes. For ages 9–14) and the Reitan–I ndiana Neurop-
a child with TBI, additional information re- sychological Test Battery for Children (for
garding the potential for recovery and the ages 5–8) are the most commonly used bat-
tenuousness of evaluation results immedi- teries. “The second approach to neuropsy-
ately postinjury need to be communicated, chological assessment of children favors the
as does the need for reassessment of both the use of a flexible combination of traditional
child and the intervention program at regu- psychological and educational tests. The
lar intervals. The changing nature of symp- composition of this battery varies depend-
toms in a neurodevelopmental disorder must ing on a number of child variables, includ-
be followed and explained to those who ing the age, history, functioning level, and
believe that symptom expressivity is within presenting problem of the particular child”
an affected individual’s control; such beliefs (Telzrow, 1989, p. 227). The major theoreti-
are all-too-common problems, especially in cal premise of both the Halstead–Reitan and
cases of ADHD, Tourette syndrome, XXY the Reitan–I ndiana batteries is the proposi-
syndrome, and temporal lobe seizure disor- tion that behavior has an organic basis (i.e.,
der, and even in more common psychopatho- the brain controls behavior), and thus that
logical disorders (e.g., depression). performance on behavioral measures can
9. If consulting directly with a school sys- be used to assess brain functioning (Bigler,
tem, an evaluator must be certain that the 1996; Dean, 1985; Grant & Adams, 1986).
testing and examination procedures are ef- In order to infer brain functioning based
ficient. School systems, which are where one on behavioral measures, it was necessary
finds children, do not often have the resourc- to validate these measures on children with
es for funding the types of diagnostic work- known brain damage (Nussbaum & Bigler,
ups neuropsychologists prefer. Therefore, 1989).
when one is consulting with a school system, The Halstead–Reitan Neuropsychologi-
it is necessary to be succinct and efficient in cal Test Battery for Older Children (for ages
planning a neuropsychological evaluation. If 9–14; see Table 2.1) was adapted from the
the school can provide the results of a very original Halstead–Reitan Neuropsycho-
recent intellectual and academic assessment, logical Test Battery, which was designed for
as well as of a behavioral assessment, this adults. The two batteries share much of the
can be then integrated into the neuropsycho- same equipment and many of the same tests;
logical assessment. If a recent intellectual however, there are some changes in the chil-
and academic assessment has not been com- dren’s battery. The Tactual Performance Test
pleted, it may be cost-efficient for qualified uses a 6-hole board instead of the 10-hole
school district personnel to complete this board. On the Speech Sounds Perception
portion of the assessment for later integra- Test, the child underlines the correct sound
tion with other data obtained and inter- from three alternatives instead of four. The
preted by the neuropsychologist. For chil- Category Test has been reduced from 208
dren in intensive rehabilitation facilities or slides to 168 slides. Likewise, Parts A and
medical settings, it may be appropriate for B of the Trail Making Test (Trails A and B)
school personnel to participate in the evalu- have been reduced in length.
ation prior to discharge. This collaborative The Trail Making Test is one of the most
involvement can facilitate program planning sensitive of all these tasks to the presence
with the receiving school district and is pref- of CNS dysfunction, but did not localize
erable to eliminating needed components of dysfunction as well as was previously be-
the neuropsychological evaluation. lieved. Subsequently, Reynolds (2002) devel-
TABLE 2.1. Halstead–Reitan Neuropsychological Test Battery for Older Children

(Ages 9–14)
Test administered Function or skills assessed Hypothesized localization
Lateral Dominance Aphasia Language Language items relate to left
Screening Test hemisphere; constructional items relate
to right hemisphere
Finger Tapping Test Motor Frontal lobe
Grip Strength Motor Frontal lobe
Sensory-Perceptual Examination Sensory-perceptual
Tactile Perception Test Contralateral parietal lobe
Auditory Perception Test Temporal lobe
Visual Perception Test Visual pathway; visual fields
Tactile Form Recognition Parietal lobe
Fingertip Writing Perception Test Peripheral nervous system; parietal lobe
Finger Localization Test Unilateral errors implicate contralateral
parietal lobe—can also occur with
bilateral errors
Rhythm Test Alertness and concentration Global
Speech Sounds Perception Test Alertness and concentration Global; anterior left hemisphere
Trail Making Test
Part A Visual–spatial Global
Part B Reasoning Global
Tactual Performance Test
Total Time Motor Frontal lobe
Memory Immediate memory Global
Localization Immediate memory Global
Category Test Reasoning Global; sensitive to right frontal lobe
dysfunction in older children
Note. Data from Reitan and Wolfson (1985).
oped the Comprehensive Trail-Making Test and letters in an alternating sequence (simi-
(CTMT), which contains five trails. The lar to Trails B of the TMT), while also being
CTMT has enhanced features to make the presented with empty distractor circles. The
tasks even more sensitive to frontal and ex- CTMT meets rigorous standards in the
ecutive deficits in particular, and is normed areas of reliability and validity. All internal-
for ages 8 years, 0 months to 74 years, 11 consistency values of the five CTMT trails
months. Trail 1 of the CTMT is similar to meet or exceed a value of .70, and the reli-
that of Trails A of the original Trail Making ability value of the Composite Index score
Test, as the examinee must connect numbers is .92 (Reynolds, 2002). A recent study by
circles in numerical order. This task assesses Armstrong, Allen, Donohue, and Mayfield
sustained attention, as well as basic sequenc- (2008) provided support for the CTMT’s
ing and visual–spatial scanning skills. Trails utility in assessment of TBI.
2 requires the examinee to connect numbers Further modifications have been made
in ascending order while ignoring simple with the Reitan–I ndiana Neuropsychologi-
distractors (empty circles). Trails 3 builds cal Test Battery (for ages 5–8; see Table 2.2).
on Trails 2 by including simple distractors Trails A and B, Speech Sounds Perception
(empty circles), as well as complex distrac- Test, and Rhythms have been omitted. Nu-
tors (circles with line drawings inside). merous tests have been added: Matching
Trails 4 and 5 require cognitive flexibility. Pictures, Matching V’s and Figures, Star
On Trails 4, the examinee is required to Drawing, Concentric Square, Target Test,
connect numbers and number words. Trails Marching Test, Color Form Test, and Pro-
5 requires the examinee to connect numbers gressive Figures. On the Category Test, the
16 BACKGROUND
TABLE 2.2. Reitan–Indiana Neuropsychological Test Battery for Children (Ages 5–8)

Test administered Function or skill assessed Hypothesized localization
Lateral Dominance Aphasia Language Language items relate to left
Screening Test hemisphere; constructional items relate
to right hemisphere
Finger Tapping Test Motor Frontal lobe
Grip Strength Motor Frontal lobe
Matching Pictures Visual–spatial Global right hemisphere
Matching V’s and Figures Visual–spatial Association areas
Concentric Square and Star Visual–spatial Global right hemisphere
Drawing
Target Test Visual–spatial Association areas
Marching Test Motor Global
Color Form Test
Reasoning Global Global
Progressive Figures Alertness and concentration Global
Sensory-Perceptual Examination Sensory-perceptual
Tactile Perception Test Contralateral parietal lobe
Auditory Perception Test Temporal lobe
Visual Perception Test Visual pathway; visual fields
Tactile Form Recognition Parietal lobe
Fingertip Writing Perception Test Peripheral nervous system; parietal lobe
Finger Localization Test Unilateral error implicate contralateral
parietal lobe—can also occur with
bilateral errors
Tactual Performance Test
Total Time Motor Frontal lobe
Memory Immediate memory Global
Localization Immediate memory Global
Category Test Reasoning Global; sensitive to right frontal lobe
dysfunction in older children
Note. Data from Reitan and Wolfson (1985).
number of items has been further reduced to to determine the score on the Neuropsycho-
80, and the number caps have been replaced logical Deficit Scale, which is the child’s level
with color caps. The same 6-hole board is of performance. Based on normative com-
used for the Tactual Performance Test as parisons, raw scores are weighted as “per-
that used for the Halstead–Reitan version; fectly normal” (score = 0), “normal” (score =
however, the board is placed horizontally 1), “mildly impaired” (score = 2), or “signifi-
rather than vertically. The Aphasia Screen- cantly impaired” (score = 3). Separate tables
ing Test uses the same booklet, but some of are available for the test results of older chil-
the items have been omitted and replaced dren and younger children.
with more age-appropriate items. Because In contrast to the use of standard batteries,
young children have difficulty manipulating the process approach uses a flexible battery
the manual finger tapper, an electric tapper of developmental and psychological tests,
was developed for the Finger Tapping Test. which permits the clinician to select tasks
Right–left differences, dysphasia and re- appropriate to the specific referral question,
lated deficits, and cutoff scores that differ- functioning levels, and response limitations
entiate nondisabled children from children of the child. Client variables such as “age,
with brain damage for each battery are used gender, handedness, familial handedness,
educational and occupational background, chologist seeks to discover the cause of the
premorbid talents, patient’s and family’s inattentiveness—whether it is truly ADHD
medical, neurological, and psychiatric his- or a learning disability, developmental delay,
tory, drug or alcohol abuse, use of medica- or psychiatric problem that is causing the be-
tions (past and present), etiology of the cen- havior problems exhibited by the child.
tral nervous system (CNS) dysfunction, and A child who has experienced a TBI is fre-
laterality and focus of the lesion” (Kaplan, quently referred for a neuropsychological
1990, p. 72) all provide valuable informa- evaluation to determine the extent of the
tion in developing the assessment. Further- brain injury in terms of the child’s cogni-
more, this process provides an analysis of tive strengths, weaknesses, and reentry into
the child’s neuropsychological assets, rather the school environment. On the basis of this
than focusing on a diagnosis or a specific evaluation, the neuropsychologist makes ap-
localization of brain impairment, for which propriate recommendations to the parents
the standardized batteries have been noted. and school.
The flexible-battery approach purportedly Even when the parents are unable to define
translates more directly into educational specific referral questions, the driving forces
and vocational interventions, and a major behind the majority of neuropsychological
goal of conducting a neuropsychological referrals are problems in the educational
assessment is to aid in the planning of such setting. Teachers are often unprepared to
interventions. Finally, since this method address these difficulties and do not under-
uses more traditional educational and psy- stand the specific learning problems of chil-
chological tests that are more familiar to dren with brain dysfunction. No two brain
school personnel, this assessment is more di- dysfunctions or injuries are the same. Two
rectly applicable to school settings. Schools children can experience the same type of in-
provide the most affordable and available jury and still require different modifications
habilitation and rehabilitation opportuni- in the classroom. Parents as well as teachers
ties for children with neuropsychological are looking for answers—ways to teach their
impairment; therefore, it is imperative that children and to provide appropriate educa-
the assessment data be transferred into these tional opportunities. A neuropsychological
settings (Telzrow, 1989). A major concern evaluation helps to furnish that information;
about the process approach is the difficulty it provides data for answering the question
in establishing validity for the innumerable “So what do we do now?” after a diagnosis
versions of batteries used, as interpretations has been made. The information gained from
may not be uniform or reliable. This issue a neuropsychological evaluation enables the
has been addressed inadequately thus far. neuropsychologist to make recommenda-
tions concerning attention, learning and
memory, intellectual functioning, cognitive
Reason for Referral strengths and weaknesses, problem-solving
abilities, and so forth to the parents and the
Children are initially referred to neuropsy- educators.
chologists for a variety of reasons. If a child
has a congenital brain defect, the child is
frequently brought to a neuropsychologist Teaching to the Child’s Strengths
early in his or her development, particularly
if developmental delays, language deficits, or One of the primary reasons for conducting
behavioral problems are observed. Depend- a neuropsychological evaluation is not to
ing on the results of the neuropsychological determine “what has been impaired,” but
evaluation, the child may qualify for early rather to determine “what has been spared.”
intervention programs or other special pro- Educators and parents supply numerous ex-
grams through the public school system. amples of what a child is unable to do: “He
In other cases, as a child grows, parents cannot follow instructions,” “She can’t re-
may seek a diagnosis of ADHD as they cope member anything,” “He cannot read.” Very
with the child’s problems at home and at seldom does a referral source approach an
school because of “hyperness” or “inabil- evaluation with a list of the activities or
ity to sit still.” At this time the neuropsy- skills that the child is able to accomplish
18 BACKGROUND
with ease and proficiency. But whether or A child’s school history provides invalu-
not the source realizes it at the time of the able information as well. The child’s grades
referral, such a list contains the very infor- and other school records allow the neuropsy-
mation that is urgently needed for the child chologist to look at trends in the student’s ed-
to move forward in the educational process. ucational process, and they provide a means
It is essential that we teach to the child’s of comparing the student’s abilities with
strengths instead of his or her weaknesses. those of peers. School transcripts may also
As pointed out by Reynolds (1981b), teach- be helpful in evaluating individual motiva-
ing to a child’s weaknesses focuses on brain tional factors, study habits, and daily class-
areas that are damaged or dysfunctional. room performance. IQ tests or other stan-
When teaching methods focus on cortical dardized academic tests (e.g., the most recent
areas that are not intact, the child’s poten- editions of the Woodcock–Johnson battery,
tial for failure is increased, and this is harm- the Wide Range Achievement Test, and the
ful to the child. Reynolds has also pointed Wechsler Individualized Achievement Test)
out that research on these remedial practices provide standardized scores, which give fur-
(referred to as deficit-centered models of re- ther information about a child’s cognitive
mediation) has found them to be ineffective. and academic strengths and weaknesses. If
In contrast, teaching to a child’s strengths a student has been receiving special services,
has a number of advantages. This method may one cannot assume that the existing services
be especially helpful for children who are re- will meet the child’s present needs; these ser-
sistant to focused remediation of weaknesses vices may need to be expanded or modified
(Rourke et al., 1983). When self-confidence is to meet the actual needs of the child.
low or when a failure syndrome emerges as a On the basis of the historical informa-
result of frustration, a strength-centered ap- tion obtained, the trained neuropsycholo-
proach should be adopted. Second, teaching gist conducts a structured interview, which
to the child’s strengths may reduce the possi- culminates in a list of referral questions and
bility of the child’s falling farther and farther specific concerns about the child.
below peers in academic areas. Finally, Luria
(1966) suggested that recovery of function
following cortical damage can be achieved Habilitation and Rehabilitation
“by the replacement of the lost cerebral link Considerations
by another which is still intact” (p. 55). “For
example, a child with an impaired auditory When one is making recommendations
system could be taught to differentiate sim- for rehabilitation of the child with a focal
ple sounds using visual or nonverbal images” injury or TBI, several additional consider-
(Teeter & Semrud-Clikeman, 1997, p. 364). ations are evident. It is important to deter-
More details on strength-centered models of mine what type of functional system is im-
remediation may be found in Reynolds and paired. Impaired systems may, for example,
Hickman (1987). be modality-specific or process-specific. The
nature or characteristics of the impairments
must be elucidated before an intelligent re-
Other Information Needed medial plan can be devised.
for Assessment The number of systems impaired should
be determined. In addition, because children
When a child is initially referred to a neu- may not be able to work on everything at
ropsychologist, the child’s history is the once, a system of priorities should be de-
first critical piece of information. This his- vised so that the impairments with the most
tory should include prenatal, perinatal, de- important impact on overall recovery are
velopmental, and medical history. It is also the first and most intensely addressed. The
important to include familial information degree of impairment, a normative ques-
about educational or learning problems, dis- tion, will be important to consider in this
cipline, and family structure. If the child has regard as well. At times this will require the
had a TBI or illness, age of onset, duration neuropsychologist to reflect on the indirect
of illness of injury, and time since illness or effects of a child’s disorder or injury, as an
trauma all provide important information. impaired or dysfunctional system may ad-
versely affect other systems that are without clude a lighter course load or special tutorial
true direct organic compromise. sessions; a collapsed or half-day schedule;
As noted earlier, the quality of the neu- or special education services ranging from
ropsychological strengths that exist will also part-time to full-time. Class size may also be
be important; this tends to be more of an ip- a consideration. Homebound or residential
sative than a normative determination. Cer- education programming may be yet another
tain strengths are more useful than others option. Fatigue is common during recovery
as well. Preserved language and speech are from a head injury or stroke, and a schedule
of great importance, for example, whereas that allows for a structured rest time may
an intact sense of smell (an ability often also be a needed option (Cohen, 1991).
impaired in TBI) is of less importance in Educational support materials, such as
designing treatment plans and outcome re- computers, calculators, audio recorders,
search. Even more important to long-term writing aids, positioning equipment, or aug-
recovery are intact planning and concept mentative communication devices, may be
formation skills. The executive functioning essential equipment in providing an appro-
skills of the frontal lobes take on greater and priate educational environment. The use of
greater importance with age, and strengths such classroom aids should be implemented
in these areas are crucial to long-term plan- in consultation with the occupational thera-
ning (as are weaknesses). These will change pist, physical therapist, and neuropsycholo-
with age, however, as the frontal lobes be- gist, and should be included on the IEP.
come increasingly prominent in behavioral Throughout this process, school person-
control after age 9 years, again through pu- nel must collaborate with the child’s parents.
berty, and continuing into the 20s. Open communication and cooperation be-
tween the parents and the school will assure
the parents that their requests, apprehen-
Bases for Educational sions, and concerns will be addressed, and
Modifications that their child will be provided with the
most appropriate education. The neurop-
After the neuropsychologist makes his or sychologist and school personnel can also
her assessment and recommendations, the make appropriate recommendations for the
school personnel and the parents hold a parents. With this information, the parents
multidisciplinary team meeting. The pur- are able to formulate appropriate guidelines
poses of this meeting are to make appropri- for behaviors and expectations for their
ate modifications in the classroom that will child’s educational potential.
enable the child to reach his or her academic
potential, and to develop an individualized
education program (IEP) for the child. In Memory and Learning
many cases, educational modifications that
teachers are currently using in their regu- In cases of TBI, including closed head inju-
lar classrooms (e.g., small groups, modified ry, problems with memory and attention are
assignments, individualized instruction) the most common, frequent complaints at all
are the only modifications needed. Cohen age levels. However, memory and learning
(1991) suggests developing active learning problems seem to characterize nearly any
situations, slowing down, assuring that les- CNS disorders in which higher cortical sys-
son tasks address the appropriate deficits, tems are involved (e.g., see Gillberg, 1995;
teaching the process of the activity, teach- Knight, 1992; Reynolds & Bigler, 1997).
ing students to become more independent, Table 2.3 provides a listing of the primary
and developing strategies that can be used in neurodevelopmental disorders in which the
various situations. In other cases, the needed clinician can anticipate memory and learn-
modifications include scheduling or place- ing deficits. The approach to assessment
ment issues that involve much more than proffered herein would seem to require an
the regular classroom setting. Placement assessment of children’s memory and imme-
options include the regular classroom, with diate learning skills. The neuropsychologi-
no provision or support in the classroom; cal batteries primarily in use with children,
modified regular education, which could in- even when accompanied by a thorough as-
20 BACKGROUND
TABLE 2.3. Primary Neurodevelopmental Disorders in Which Memory and Learning

Are Likely to Be Compromised
Attention-deficit/hyperactivity In utero toxic exposure (e.g., Neurofibromatosis

disorder (ADHD) neonatal cocaine addiction, fetal Prader–Willi syndrome
Autism alcohol syndrome) Rett syndrome
Cerebral palsy Juvenile Huntington disease Schizophrenia
Down syndrome Juvenile parkinsonism Seizure disorders
Endocrine disorders Learning disability Tourette syndrome
Extremely low birthweight Lesch–Nyhan syndrome Turner syndrome
Fragile X syndrome Mental retardation Williams syndrome
Hydrocephalus Myotonic dystrophy XXY syndrome
Hypoxic–ischemic injury Neurodevelopmental abnormalities XYY syndrome
Inborn errors of metabolism affecting brain development
(e.g., phenylketonuria [PKU], (e.g., anencephaly, microcephaly,
galactosemia) callosal dysgenesis)
Note. Based on Reynolds and Bigler (1997).
sessment of intellect (as they should be), pro- At the systemic level, there exists a divi-
vide only a brief screening of memory and sion of sorts in the formation of memory
learning skills. Comprehensive assessment and memory storage. There is considerable
of children’s memory and learning skills is a evidence for distributed storage of associa-
relatively recent phenomenon: The first com- tive memory throughout the cortex, which
prehensive batteries for evaluating memory may even occur as a statistical function
in children were not published until the (Cohen, 1993). At the same time, evidence
1990s (Reynolds & Bigler, 1994; Sheslow indicates more localized storage of certain
& Adams, 1990). By contrast, adult bat- memories and localized centers for memory
teries, notably the Wechsler Memory Scale, formation and for classical and operant con-
have been available since the 1930s. Never- ditioning.
theless, memory assessment in children was The medial aspect of the temporal lobe—
seen as important in evaluating children’s particularly the hippocampus and its con-
skills at least as early as the work of Binet in necting fibers within the other limbic and
the 1890s, and at least one measure of short- paralimbic structures—is particularly im-
term memory appears in every Wechsler portant in the development of associative
scale and most other major intelligence tests memory. The limbic system (with emphasis
(e.g., the various Kaufman batteries, the on the posterior hippocampal regions) also
McCarthy scales, and the various versions mediates the development of conditioned
of the Detroit Tests of Learning Aptitude). A responses, and some patients with posterior
brief review of the neurobiology of memory hippocampal lesions may not respond to
shows why it is so crucial to assess memory operant paradigms in the absence of one-to-
when organic deficiencies are suspected. one reinforcement schedules. Damage to or
anomalous development of either the medial
temporal lobe and its connecting fibers, or
Basic Neurobiology of Memory
the midline structures of the diencephalon,
Attention leaves tracks or traces within typically results in the difficulties in forma-
the brain that become memory. Memory, tion of new memories (anterograde amnesia);
as commonly conceived of, is the ability to however, it may also disrupt recently formed
recall some event or information of various memories preceding the time of injury (ret-
types and forms. Biologically, memory func- rograde amnesia). Various regions within the
tions at two broad levels: the level of the in- limbic and paralimbic structures have stron-
dividual cell and a systemic level. With the ger roles in formation of certain types of
creation of memories, changes occur in indi- memory, and simple conditioned memories
vidual cells (e.g., see Cohen, 1993; Diamond, may occur at a subcortical level. Through
1990; Scheibel, 1990), including alterations all the interactions of these systems, related
in cell membranes and synaptic physiology. mechanisms of attention, particularly in the
brainstem and the frontal lobes, are brought 1990, but it still provided a somewhat lim-
to bear and will influence memory formation ited scope of assessment. To increase the
directly and indirectly. Memory is a complex breadth and depth of assessment of memory
function of the interaction of brain systems and learning functions in children with a
(with unequal contributions), and damage to coordinated battery of diverse tasks, Reyn-
one or more of many structures may impair olds and Bigler (1994) developed the origi-
the ability to form new memories. nal TOMAL. The TOMAL-2 continues to
In right-handed individuals, there is a provide professionals with a standardized
tendency for damage to, or abnormal devel- measure of different memory functions of
opmental patterns within, the left temporal children and adolescents from the age of 5.
lobe and adjacent structures to affect verbal The many well-normed, reliable subtests of
and sequential memory more strongly. Dam- the TOMAL-2 provide examiners with the
age to the cognate areas of the right hemi- maximum flexibility in evaluating various
sphere affects visual and spatial memory referral questions and the choice of the most
more adversely. comprehensive assessments available. The
Through distributive storage of memo- individual subtests also have good reliability
ry, the entire brain participates in memory and specificity of measurement.
functioning. The recall of well-established
memories tends to be one of the most robust
Test of Memory and Learning—
of neural functions, whereas the formation
Second Edition
of new memories, sustained attention, and
concentration tend to be the most fragile The TOMAL-2 is a comprehensive battery
of neural functions. Neurological dysfunc- of memory and learning tasks normed for
tion of most types is associated with a non- used with children, adolescents, and adults
specific lessening of memory performance, from the age of 5 years, 0 months through 59
along with disruptions of attention and years. The TOMAL-2 has the broadest range
concentration; this is of greater consequence of memory tasks available in a standardized
when temporolimbic, brainstem, or frontal memory battery (Hartman, 2007). The core
lobe involvement occurs. However, a variety battery consists of eight subtests (four verbal
of psychiatric disturbances, especially de- and four nonverbal), whose scores contribute
pression, may also suppress fragile antero- to the Verbal Memory Index and Nonverbal
grade memory systems. A careful analysis of Memory Index, which can be combined to
memory, forgetting, affective states, history, derive a Composite Memory Index. A De-
and comprehensive neuropsychological test layed Verbal Recall Index is also available;
results may be necessary before one can con- this requires a repeat recall from two subtests
clude that memory disturbances are organic of the core battery administered 30 minutes
in origin, especially in the complex case of after the first administration. Six supple-
neurodevelopmental disorders. mentary subtests (four verbal, two nonver-
bal) can be used to provide a broader, even
more comprehensive assessment of memory.
Assessing Memory
A supplementary subtest may be substituted
The two most widely regarded and recom- for a core subtest when a core subtest cannot
mended memory batteries for children are be given, is spoiled, or is inappropriate for a
the Wide Range Assessment of Memory and particular examinee.
Learning (WRAML2; Sheslow & Adams, As noted above, memory may behave in
2003) and the Test of Memory and Learn- unusual ways in an impaired brain, and tra-
ing (TOMAL-2; Reynolds & Voress, 2007). ditional content approaches to memory may
The WRAML2 consists of nine subtests not be useful. The TOMAL-2 thus provides
divided equally into three scales, Verbal alternative groupings of the subtests into five
Memory, Visual Memory, and Learning, supplementary indexes: Attention/Concen-
followed by brief delayed-recall tasks to as- tration, Sequential Recall, Free Recall, As-
sess rapidity of the decay of memory. The sociative Recall, and Learning (Reynolds &
original WRAML represented a substan- Voress, 2007).
tial improvement over existing measures Table 2.4 gives the names of the subtests
of memory in children when it appeared in and summary scores, along with their met-
22 BACKGROUND
TABLE 2.4. Core and Supplementary Subtests and Indexes Available for the Test
of Memory and Learning—Second Edition (TOMAL-2)
Index Subtests M SD
Core composite indexesa
Verbal Memory 100 15
Memory for Stories 10 3
Word Selective Reminding 10 3
Object Recall 10 3
Paired Recall 10 3
Nonverbal Memory 100 15
Facial Memory 10 3
Abstract Visual Memory 10 3
Visual Sequential Memory 10 3
Memory for Locations 10 3
Supplementary composite indexes

Verbal Delayed Recall 100 15
Memory for Stories Delayed 10 3
Word Selective Reminding Delayed 10 3
Attention/Concentrationb 100 15
Digits Forward 10 3
Letters Forward 10 3
Manual Imitation 10 3
Digits Backward 10 3
Letters Backward 10 3
Sequential Recallb 100 15
Visual Sequential Memory 10 3
Digits Forward 10 3
Letters Forward 10 3
Manual Imitation 10 3
Free Recallc 100 15
Facial Memory 10 3
Abstract Visual Memory 10 3
Memory for Location 10 3
Associative Recallc 100 15
Memory for Stories 10 3
Paired Recall 10 3
Learningb 100 15
Word Selective Reminding 10 3
Object Recall 10 3
Paired Recall 10 3
Visual Selective Reminding 10 3
aThe eight Verbal Memory and Nonverbal Memory subtests make up the Composite Memory Index.
bRequires at least one supplementary subtest.
c Is derived entirely from core subtests.
rics. The TOMAL-2 subtests are scaled to A skilled examiner can administer the
the familiar metric of a mean of 10 and a core TOMAL-2 battery in less than 30 min-
standard deviation of 3 (range = 1–20). utes. However, the learning curve is quite
Composite or summary scores are scaled to steep, and it is not unusual for an examiner
a mean of 100 and a standard deviation of to require 60 minutes to complete the entire
15. All scaling was done using the method assessment during the first two to three ad-
of continuous norming and is described in ministrations. After that, most examiners
detail in Reynolds and Voress (2007). can complete the core battery in 30–35 min-
utes. Another 25–35 minutes are required to motoric modalities and combinations of
administer all of the supplementary subtests these. Multiple trials to a criterion are pro-
once the examiner has mastered administer- vided on several subtests, including the Selec-
ing the tasks. The subtests are briefly de- tive Reminding subtests, so that learning or
scribed in Table 2.5. acquisition curves may be derived. Multiple
The TOMAL-2 subtests systematically trials (at least five are necessary, according
vary the format of both presentation and re- to Kaplan [1996], and the TOMAL-2 pro-
sponse, so as to sample verbal, visual, and vides up to eight) are provided on the Selec-
TABLE 2.5. Description of TOMAL-2 Subtests
Core
•• Memory for Stories. A verbal subtest requiring recall of a short story read to the examinee. Provides a
measure of meaningful and semantic recall, and is also related to sequential recall in some instances.
•• Facial Memory. A nonverbal subtest requiring recognition and identification from a set of distractors:
black-and-white photos of various ages, both genders, and various ethnic backgrounds. Assesses
nonverbal meaningful memory in a practical fashion and has been extensively researched. Sequencing of
responses is unimportant.
•• Word Selective Reminding. A verbal free-recall task in which the examinee learns a word list and
repeats it; the examinee is only reminded of words left out in each trial. Tests learning and immediate
recall functions in verbal memory. Trials continue until mastery is achieved or until six trials have been
attempted. Sequence of recall is unimportant.
•• Abstract Visual Memory. A nonverbal task assessing immediate recall for meaningless figures where
order is unimportant. The examinee is presented with a standard stimulus and is required to recognize
the standard from any of six distractors.
•• Object Recall. The examiner presents a series of pictures, names them, has the examinee recall them,
and repeats this process until mastery is achieved or until five trials have been attempted. Verbal and
nonverbal stimuli are thus paired, and recall is entirely verbal, creating a situation found to interfere
with recall for many individuals with learning disabilities but to be neutral or facilitative for individuals
without disabilities.
•• Visual Sequential Memory. A nonverbal task requiring recall of the sequence of a series of meaningless
geometric designs. The ordered designs are shown, followed by a presentation of a standard order of the
stimuli, and the examinee indicates the order in which they originally appeared.
•• Paired Recall. A verbal paired-associates task on which the examinee is required to recall a list of word
pairs when the first word of each pair is provided by the examiner. Both easy and hard pairs are used.
•• Memory for Location. A nonverbal task that assesses spatial memory. The examinee is presented with a
set of large dots distributed on a page and is asked to recall the locations of the dots in any order.
Supplementary
•• Digits Forward. A standard verbal number recall task. Measures low-level rote recall of a sequence of
numbers.
•• Visual Selective Reminding. A nonverbal analogue to Word Selective Reminding, where examinees point
to specified dots on a card, following a demonstration by the examiner, and are reminded only of dots
recalled incorrectly. Trials continue until mastery is achieved or until five trials have been attempted.
•• Letters Forward. A language-related analogue to common digit span tasks, using letters as the stimuli in
place of numbers.
•• Manual Imitation. A psychomotor, visually based assessment of sequential memory. The examinee
is required to reproduce a set of ordered hand movements in the same sequence as presented by the
examiner.
•• Digits Backward. This is the same basic task as Digits Forward, except that the examinee recalls the
numbers in reverse order.
•• Letters Backward. A language-related analogue to the Digits Backward task, using letters as the stimuli
instead of numbers.

24 BACKGROUND
tive Reminding subtests to allow an analysis Assessment of Brain –Behavior

of the depth of processing. In the Selective Relationships through Lurian
Reminding format (wherein examinees are Processing Models
reminded only of stimuli “forgotten” or
unrecalled), when items once recalled are The previously reviewed approaches to as-
unrecalled by an examinee on later trials, sessing brain–behavior relationships focus
problems are revealed in the transference on specificity of aptitudes or mental skills
of stimuli from working memory and im- (i.e., their relative distinctiveness from one
mediate memory to more long-term storage. another) as a model for their assessment.
Cueing is also provided at the end of certain Processing models of brain function focus
subtests, to add to the examiner’s ability to more heavily on the manipulative demands
probe depth of processing. of a mental task than on the content de-
Subtests are included that sample se- mands. Cognitive tasks can thus be grouped
quential recall (which tends strongly to be according to these processing demands for
mediated by the left hemisphere, especially more reliable and detailed assessment, lead-
temporal regions; e.g., see Lezak, 1995) and ing to conclusions about brain function with
free recall in both verbal and visual formats direct implications for intervention (e.g., see
to allow localization. To assess more purely Hartlage & Reynolds, 1981; Kamphaus &
right-hemisphere functions, tests of pure Reynolds, 1987; Reynolds, 1981a, 1981b).
spatial memory are included; these are very
difficult to confound via verbal mediation.
Lurian Theories
Well-established memory tasks (e.g., re-
calling stories) that correlate well with school From a clinical perspective, the neuropsy-
learning are also included, along with tasks chological models of information processing
more common to experimental neuropsy- espoused by Luria are of the greatest utility.
chology that have high (e.g., Facial Memory) “Alexander R. Luria’s theory of higher cor-
and low (e.g., Visual Selective Reminding) tical function has received international ac-
ecological salience. Some subtests employ claim. His conceptual schemes of the func-
highly meaningful material (e.g., Memory for tional organization of the brain are probably
Stories), whereas others use highly abstract the most comprehensive currently available”
stimuli (e.g., Abstract Visual Memory). (Adams, 1985, p. 878). Much of Luria’s work
Aside from allowing a comprehensive re- elaborated and extended the earlier work of
view of memory function, the purpose of Sechenov (1863/1965) and Vygotsky (1978).
such a factorial array of tasks across mul- Luria defined mental processes in terms of
tiple dimensions is to allow a thorough, de- two sharply delineated groups, simultaneous
tailed analysis of memory function and of and successive, following Sechenov’s sugges-
the sources of any memory deficits that may tions. The first process involves the integra-
be discovered. The task of the neuropsy- tion of elements into simultaneous groups.
chologist demands subtests that have great Luria further qualified Sechenov’s original
specificity and variability of presentation meaning, indicating that simultaneous pro-
and response, and that sample all relevant cessing means the synthesis of successive
brain functions, in order to solve the com- elements (arriving one after the other) into
plex puzzle of dysfunctional brain–behavior simultaneous spatial schemes, whereas suc-
relationships. Kaufman (1979) first present- cessive processing means the synthesis of
ed a detailed model for analyzing test data separate elements into successive series.
in a comprehensive format (later elaborat- Luria (1966) divided the brain into three
ed; Kaufman, 1994), which likens the task blocks. Block One consists of the brainstem
of the clinician to that of a detective. The and reticular system and is responsible prin-
thoroughness, breadth, and variability of cipally for regulating level of consciousness,
the TOMAL-2 subtests, coupled with their arousal, and the overall tone of the cortex.
excellent psychometric properties, make Block Two consists of the parietal, occipital,
the TOMAL-2 ideal for use in a model of and temporal lobes of the brain (the lobes
“intelligent testing” and particularly in the posterior to the central sulcus) and is re-
analysis of brain–behavior relationships as- sponsible for receiving and encoding sensory
sociated with memory function. input. Block Three consists of those regions
of the brain anterior to the central sulcus (1987), Reynolds and Kamphaus (1997),
(the frontal lobes and the prefrontal regions) and Reynolds, Kamphaus, Rosenthal, and
and is responsible for the self-regulation of Hiemenz (1997). The KABC-II (Kaufman
behavior, including such variables as atten- & Kaufman, 2004), normed for ages 3 years
tion, planning and execution of behavior, through 18 years, maintains this utility and
and other tasks generally referred to as ex- expands its assessment as a function of the
ecutive functions. In Luria’s model, various Luria model, with the addition of a Planning
zones and regions of the brain interact in a Ability Scale.
transactional manner to produce complex In both the K-ABC and the KABC-II,
behavior; thus the functional localization the Kaufmans define mental processes in
of complex mental tasks is seen as dynamic, a manner similar to Luria’s and provide a
defying efforts at highly specific anatomical standardized assessment of these functions.
localization. Luria’s approach lends itself Simultaneous processing here refers to the
to strength-centered intervention models, mental ability to integrate input simultane-
wherein the clinician actively seeks intact ously in order to solve a problem correctly.
complex functional systems within the brain Simultaneous processing frequently involves
that can be used to habilitate and facilitate spatial, analogical, or organizational abili-
learning, rather than to models focusing on ties (Kaufman & Kaufman, 1983, 2004), as
remediating dysfunctional or damaged brain well as problems solved through the applica-
systems (e.g., see Reynolds, 1981b, 1997; tion of visual imagery. The Gestalt Closure
Riccio & Reynolds, 1998). and the Triangles (an analogue of Wechsler’s
Two neuropsychological batteries for chil- Block Design task) subtests of the KABC-II
dren are based primarily on Luria’s theory of are prototypical measures of simultaneous
brain function. The first to be published was processing. To solve these items correctly,
the Kaufman Assessment Battery for Chil- one must mentally integrate the components
dren (K-ABC; Kaufman & Kaufman, 1983), of the design to “see” the whole. Such a
followed soon thereafter by the Luria– task seems to match up nicely with Luria’s
Nebraska Neuropsychological Battery— qualifying statement about the synthesis of
Children’s Revision (LNNB-CR; Golden, separate elements into spatial schemes (e.g.,
1986). A second edition of the K-ABC is in Triangles, the larger pattern of triangles,
now available (the KABC-II; Kaufman & which may form squares, rectangles, or larg-
Kaufman, 2004). Each of these batteries has er triangles). Whether the tasks are spatial
a stronger focus on process than the typi- or analogical in nature, the unifying char-
cal neuropsychological test per se, with the acteristic of simultaneous processing is the
possible exception of the TOMAL-2, but the mental synthesis of the stimuli to solve the
TOMAL-2 focuses on memory processes problem, independent of the sensory modal-
more specifically. ity of the input or the output.
Sequential processing, on the other hand,
emphasizes the arrangement of stimuli in se-
Kaufman Assessment Battery
quential or serial order for successful prob-
for Children, Second Edition
lem solving. In every instance, each stimu-
The original K-ABC was designed and stan- lus is linearly or temporally related to the
dardized for use with children ages 2½ previous one (Kaufman & Kaufman, 1983,
years through 12½ years and was divided 2004), creating a form of serial interdepen-
into three scales, closely following a Lurian dence within the stimulus. The KABC-II in-
model: the Sequential Processing Scale, the cludes subtests that tap various modalities
Simultaneous Processing Scale (these two of sequential processing. Hand Movements
were summed to provide a global score, involves visual input and a motor response;
the Mental Processing Composite), and the Number Recall involves auditory input with
Achievement Scale (a measure of previously a response involving the auditory output
acquired information). The K-ABC was a channel only; and Word Order involves the
useful scale for applications in the neurop- visual channel for input and an auditory
sychological evaluation of children. Detailed response. Therefore, the mode of presenta-
discussions of its use in neuropsychology tion or mode of response is not what deter-
are provided in Kamphaus and Reynolds mines the scale placement of a task; rather,
26 BACKGROUND
the mental processing demands of the task interpretation of KABC-II test results; ob-
are important (Kaufman & Kaufman, 1983, servation in many cases will be a primary
2004). By providing systematic variation of source of information regarding which men-
modality of input and modality of response, tal processes a child has invoked on any
the KABC-II provides a clinical vehicle for given task, regardless of its scale.
locating intact complex functional systems, An equally important component of the
as well as for specifying where any potential KABC-II is the Knowledge Scale (formerly
breakdown may have occurred in a faulty the Achievement Scale, with a few changes).
functional system. Qualitative evaluation of This scale measures abilities that serve to
a child’s performance on the KABC-II can complement the mental processing scales.
be most useful in such instances and can Performance on the KABC-II Knowledge
lead to more effective rehabilitation plans. Scale, like that on the K-ABC Achievement
New to the KABC-II is the Planning Abil- Scale, is viewed as an estimate of children’s
ity Scale. This scale consists of two subtests, success in the application of their men-
Pattern Reasoning and Story Completion, tal processing skills to the acquisition of
wherein the examinee has to use inductive knowledge from the environment (Kauf-
reasoning to determine the plan of a series man, Kamphaus, & Kaufman, 1985). This
of either abstract/geometric shapes or mean- scale contains measures of what have been
ingless pictures (Pattern Reasoning) or to identified traditionally as verbal intelligence,
determine the missing elements in a set of general information, and acquired school
pictures that tell a story (Story Completion). skills. Keeping in mind that it is not possible
The plan must be deduced, and the examinee to separate entirely what individuals know
then completes the premeditated sequence. (achievement) from how well they think (in-
Although these subtests are strong measures telligence), the Kaufmans have attempted to
of overall cognitive function, it is not yet differentiate the two variables more clearly
clear from data in the KABC-II manual that than traditional measures of intelligence gen-
they differentiate Planning Ability as a sepa- erally do. From a clinical-neuropsychological
rate construct. However, the Sequential and standpoint, the KABC-II allows one to as-
the Simultaneous Processing Scales are very sess information-processing skills without
useful from a Lurian perspective. as much contamination from prior learning.
No one with an intact brain uses only a Measurement of children’s academic skills,
single type of information processing to however, is a traditional component of the
solve problems. These two methods of infor- comprehensive neuropsychological assess-
mation processing are constantly interacting ment. The inclusion of the Knowledge Scale
(even in the so-called “split brain” following in the KABC-II affords the opportunity to
commissurotomy), although one approach observe the application of processing skills
will often take a lead role in processing. to complex learning tasks, to assess func-
Which method of processing takes the lead tional academic levels, and to estimate long-
role can change according to the demands term memory ability.
of the problem or (as is the case with some Majovski (1984) noted the high degree of
individuals) can persist across problem type, fit between Luria’s theory and the original
forming habitual modes of processing. In K-ABC, and recommended that the test be
fact, any problem can be solved through ei- used as an integral part of a neuropsycho-
ther method of processing, but in most cases logical battery for children (see also Spreen
one method is clearly superior to another. & Strauss, 1991). It is a good complement
What makes the KABC-II a valuable tool to nearly any choice of neuropsychological
is that the two mental processing scales are instruments. Majovski found the K-ABC
primarily, not exclusively, measures of se- particularly useful in contrasting problem-
quential or simultaneous processing. “Pure” solving skills with acquisition of facts and
scales (i.e., scales measuring only one pro- in evaluating how a child solves a particular
cess) do not exist. Careful observation of problem.
a child’s performance, which should be the When young children (below age 6) are
order of the day during any evaluation, will being assessed, the KABC-II should be the
be particularly important to any neuropsy- neuropsychologist’s test of choice for mea-
chological assessment or neuropsychological suring intellectual skill. The KABC-II men-
tal processing subtests are child-oriented and and analytic tasks, and the right hemisphere
much briefer than (but with comparable reli- for more nonverbal, oppositional, synthetic,
ability to) those of its major competitor, the and holistic tasks. The literature includes a
Wechsler Preschool and Primary Scale of In- large number of studies of hemispheric spe-
telligence—Third Edition (Wechsler, 2002). cialization that have attempted to provide
For assessing mental processes, the KABC-II anatomical localization of performance on
model seems far superior to other measures specific, yet higher-order, complex tasks.
of intelligence, since it is far less dependent Much of the confusion in the literature
on prior learning and exposure to the main- stems from the apparently conflicting data
stream Anglo culture (e.g., see Kamphaus & in many of these studies. However, Luria’s
Reynolds, 1987). When one is assessing the principle of dynamic functional localization,
intellectual processes of non-native English and the knowledge that any specific task can
speakers, the independence of the KABC- potentially be performed through any of the
II mental processing scales is particularly brain’s processing modes, should give some
important, so as not to confound cultural insight into the conflicting results that ap-
experiences and cultural dependence of test pear in the literature. In this regard, it is most
items with neuropsychological processing important to remember that cerebral hemi-
(e.g., see Ardila, Roselli, & Puente, 1994). spheric asymmetries of function are process-
A growing body of literature shows the ap- specific and not stimulus-specific. Shure and
propriateness of the KABC-II across a broad Halstead (1959) noted early in this line of re-
range of U.S. ethnic minorities. search that manipulation of stimuli is at the
Support for use of the KABC-II model in root of hemispheric differences—a notion
the context of neuropsychological assess- that is well supported by subsequent empiri-
ment also comes from a variety of sources cal research (e.g., Ornstein, Johnstone, Her-
in cerebral specialization research. In a com- ron, & Swencionis, 1980) and thought (e.g.,
prehensive review of research concerning Reynolds, 1981a, 1981b). The confusion of
the lateralization of human brain functions, the content and sensory modality through
Dean (1984) concluded that the original which stimuli are presented with the process
K-ABC is well suited to clinical use and in by which they are manipulated, particularly
research with children. in the secondary and tertiary regions of each
It has been proposed that sequential pro- lobe of the neocortex, seems to be at the root
cessing and simultaneous processing are lat- of the chaos. How information is manipulat-
eralized to the left and right hemispheres, ed while in the brain is not dependent on its
respectively (e.g., Reynolds, 1981b). Many modality of presentation and not necessarily
other dichotomies have been suggested. Some dependent on its content, though the latter
find the research on cerebral specialization may certainly be influential. The variations
difficult to coalesce. Indeed, the many seem- in content and in method of presentation
ing contradictions in the results of cerebral of the tasks that make up the scales of the
specialization studies have prompted at least KABC-II allow one to tease out any modal-
one pair of leading researchers to remark ity or content effects that may nevertheless
some decades ago: “[To] say that the field occur for a specific child, though clearly the
of hemispheric specialization is in a state of emphasis of the KABC-II is on process, not
disarray and that the results are difficult to content.
interpret is an understatement. The field can We think that a process-oriented explana-
best be characterized as chaotic” (Tomlinson- tion provides a better organizing principle
Keasey & Clarkson-Smith, 1980, p. 1). On than does a focus on content. The “content-
the other hand, reviews by Dean (1984) and driven” attempts at explaining hemispheric
Reynolds (1981a) noted some consisten- differences fail to recognize the possibilities
cies, especially when one focuses on process for processing any given set of stimuli or
specificity and not the content of the task particular content in a variety of processing
stimulus, consistencies upheld by research of modes. Bever (1975) emphasized this point
subsequent decades. and elaborated on two modes of informa-
For the vast majority of individuals, the tion processing that are of interest here be-
left cerebral hemisphere appears to be spe- cause of their similarity to simultaneous and
cialized for linguistic, propositional, serial, sequential cognitive processes.
28 BACKGROUND
The KABC-II also taps most of the func- ropsychological Battery for adults. Original-
tions identified by Dean (1984) in his review ly, in its research form, it was administered
of the literature on cerebral specialization, down to age 5, but reliable performance
with the exceptions of depth, haptic, and could only be obtained beginning at age 8
melodic perceptions. These skills are as- (Golden, 1997). After age 12, the adult bat-
sessed by other traditional neuropsychologi- tery is used.
cal batteries, although such tasks are virtu- There are 11 scales on the LNNB-CR,
ally nonexistent for the very young child. and each is listed and described in Table 2.6.
Careful observation may still provide insight As Golden (1997) describes, the LNNB-CR
into neuropsychological processing deficits, lends itself to three levels of interpretation:
especially if one pays particular attention to scale, item, and qualitative. Each of the 11
the manner in which errors are made. Quali- scales yields a T-score, and the resulting
tative and quantitative data are complemen- profile has been the subject of significant
tary, not interchangeable; Kaufman’s (1994) empirical work. However, the items with-
philosophy of “intelligent testing” is just as in these scales vary in modality and other
crucial to neuropsychological assessment as demand characteristics, and an analysis of
to any other area of clinical evaluation. item scores is also used. Finally, Luria was a
Finally, the KABC-II offers, with a variety renowned clinician and approached patients
of supplementary subtests, assessment ac- individually; Golden (1986) thus designed
cording to the Cattell–Horn–Carroll model the LNNB-CR to allow qualitative analysis
of intelligence. This will be of less interest as a supplement to the typical Western psy-
to the neuropsychologist, but it broadens the chological approach of quantitative analy-
appeal of the KABC-II in a variety of cir- sis of performance on the various scales.
cumstances. As Table 2.6 indicates, the LNNB-CR has
some scales and items where process is the
dominant feature, but others where content
Luria–Nebraska Neuropsychological
and learned behavior predominate. Care-
Battery—Children’s Revision
ful review of LNNB-CR performance at all
The LNNB-CR (Golden, 1986) is a down- three levels (scale, item, and qualitative) is
ward extension of the Luria–Nebraska Neu- not just possible but necessary. In a qualita-
TABLE 2.6. Scales of Luria–Nebraska Neuropsychological Battery—Children’s Revision

(Ages 8–12)
Scales Description of abilities assessed
Motor Skills Motor speed, complex coordination, imitation of motor movements, constructural
praxis
Rhythm Attention, perceiving and repeating rhythmic patterns, analyzing groups of tones
Tactile Finger localization, arm localization, two-point discrimination, movement
discrimination, shape discrimination, stereognosis, verbal–tactile integration
Visual Visual recognition, visual discrimination, spatial perception
Receptive Speech Following simple commands, comprehending verbal directions, decoding
phonemes, naming
Expressive Language Reading and repeating words and simple sentences, naming object from
description, using automated speech, discerning missing words
Writing Analyzing letter sequences, spelling, writing from dictation, copying
Reading Letter and word calling, sentence and paragraph reading, nonsense syllable reading
Arithmetic Simple calculation, number writing, number recognition (Arabic and Roman)
Memory Verbal and visual memory, some interference tasks
Intelligence Vocabulary, verbal reasoning, picture interpretation, social reasoning, deduction,
scanning
tive analysis, an examiner is more concerned to tailor the assessment to the referred prob-
with wrong answers than with correct ones lem. There is quite a bit of research on indi-
and analyzes the nature of the errors com- vidual aspects of the BPA (e.g., see White &
mitted by the examinee. For example, was Rose, 1997), but research on the BPA as a
the inability to write to dictation caused by whole is lacking. The modifications made to
a visual–motor problem; a visual-perceptive well-designed, carefully standardized tests
deficit; a failure of comprehension; or a plan- such as the Wechsler scales also have unpre-
ning, attention, or execution problem? Only dictable and at times counterintuitive out-
through careful observation and a review of comes in patient examination (e.g., Slick et
successful tasks can these questions be anal., 1996). Slick and colleagues (1996) found
swered. Examiners must have extensive ex- that changes made to the BPA version of the
perience with normal individuals, however, Wechsler Adult Intelligence Scale—Revised
to avoid overinterpretation. This process of caused a substantial number of individuals to
interpretation at multiple levels continues to earn lower scores on the modified items than
be consistent with Kaufman’s (1979, 1994) on the corresponding standardized versions
philosophy of “intelligent testing” and is ad- of the items, even though the intent of the
visable for use with all assessment devices modification was in part to make the items
discussed herein. However, the LNNB-CR easier. This could easily draw a clinician
was devised with these approaches in mind, into overinterpretation and overdiagnosis
making it more amenable to multilevel of pathology. Slick and colleagues correctly
analysis. A revision of the LNNB-CR is un- conclude that whenever changes are made
derway that is intended to expand the scale to standardized instruments, comprehensive
from its currently very limited age range, norms are required under the new testing
extending it downward to age 5 years. This conditions. They also conclude that clinical
will certainly make the battery more useful interpretation of such modified procedures
for children with various neurodevelopmen- prior to the development and purveyance of
tal disorders. the norms is questionable from an ethical
standpoint.
The lack of good normative or reference
Boston Process Approach
data has been a long-term problem for neu-
Another, newer effort at evaluating process ropsychological assessment (e.g., see Reyn-
in neuropsychological assessment is known olds, 1997). This causes a variety of prob-
as the Boston Process Approach (BPA) and is lems related to test interpretation, not the
described in detail in Kaplan (1988, 1990). least of which involve understanding the
This model also tries to integrate quantita- relationship of status variables such as gen-
tive and qualitative approaches to interpreta- der, ethnicity, and socioeconomic status to
tion and analysis of performance on various test performance. The BPA, because of its
cognitive tasks. The BPA alters the format principal strengths, also makes inordinate
of items on traditional tests such as the vari- cognitive demands on the examiner. Until
ous Wechsler scales, and BPA versions of the the BPA’s normative and data integration
Wechsler Intelligence Scale for Children— problems are solved, it is recommended here
Third Edition and the Wechsler Adult Intel- primarily only as a research approach (albeit
ligence Scale—Third Edition are available. a most promising one). It may be useful now,
Additional, supplementary tests have been but only to a small group of clinicians with
devised specifically for the BPA over many extensive, supervised training in its use from
years, including the Boston Naming Test, one of its progenitors.
the Boston Diagnostic Aphasia Examina-
tion, and the California Verbal Learning
Test, along with others. As with other meth- Concluding Remarks
ods of assessment, examiners are advised
to use BPA assessments in conjunction with There are many methods and models of neu-
history and interview data and observations ropsychological assessment. The field of pe-
of the patient. diatric neuropsychology is young as clinical
The strength of the BPA lies in its flex- disciplines go. Controversies continue over
ibility, which enables a neuropsychologist the training and credentialing of neuropsy-
30 BACKGROUND
chologists as well. However, the field has nations. Neuropsychological results may in-
proven itself to be of value in contributing dicate a need for specific interventions (e.g.,
to patient care, and thereby it will continue neurocognitive therapy, speech therapy) or
to grow and even thrive. Clinicians must for specific methods of intervention within
recognize that patient care is the ultimate a known class (e.g., reading instruction via
goal and must provide carefully integrated, phonics vs. whole language; inefficacy of
treatment-relevant data. A clinician writing certain behavior therapies in the face of par-
a report on a child’s neuropsychological ex- ticular neuropsychological findings).
amination should pay particular attention to
the following suggestions: Neuropsychologists have much of value to
offer in the care of children with neurodevel-
1. Write reports that go beyond a simple opmental disorders. Data and recommenda-
descriptive presentation of test data and tions related to symptom expressivity, new
findings. A clinician should integrate data problems, effectiveness of treatment, and
across the history and across data sources. possible behavioral interventions are some
Data should be interpreted for the reader. of their most valuable offerings. In this age
2. Write professionally. A clinician should of cost containment, it is crucial to provide
use proper grammar and formal language useful, scientifically supported conclusions
structures in presenting reports. that contribute to treatment and other facets
3. Use language that is easily understood. of patient care, and to maximize the benefit
Reports on children will be used in many of the neuropsychological examination for
arenas, and writing a child’s neuropsycho- the child.
logical report in such a way as to be inter-
pretable only by a physician or another neu-
ropsychologist does not facilitate treatment. References
The report of the neuropsychologist is of no
value if it cannot be understood. Reports Adams, K. (1985). Review of the Luria–Nebraska
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therapists, physical therapists), and parents, Neuropsychological evaluation of the Spanish-
in addition to referring physicians. speaker. New York: Plenum Press.
4. Write reports about children, not Armstrong, C. M., Allen, D, N., Donohud, B., &
about tests. Too often the neuropsycho- Mayfield, J. (2008). Sensitivity of the Compre-
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Bayley, N. (2005). Bayley Scales of Infant and Tod-
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to find contradictory statements in such rote TX: Harcourt Assessment.
reports. Parents often interpret such imper- Bever, T. G. (1975). Cerebral asymmetries in hu-
sonal reports as lacking in concern or inter- mans are due to the differentiation of two in-
est for their child. compatible processes: Holistic and analytic. In
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extent of their knowledge, treatment impli- for students with head injuries. Journal of Head
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Hartman, D. E. (2007). Test review: Wide Range As- ogy (pp. 181–192). New York: Plenum Press.
sessment of Memory and Learning–2 (WRAML- Ornstein, R., Johnstone, J., Herron, J., & Swien-
2). Wredesigned and weally improved. Applied cionis, C. (1980). Differential right hemisphere
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neuropsychology: The evolution of a specialty in Reitan, R. M., & Wolfson, D. (1974). Clinical neu-
school psychology. In R. C. D’Amato, E. Fletcher- ropsychology: Current status and applications.
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Wiley. Reitan Neuropsychological Battery: Theory and
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the school-aged child (pp. 87–124). New York: er cortical function. In A. Scheibel & A. Wechsler
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ogy (2nd ed., pp. 180–203). New York: Plenum Sheslow, D., & Adams, W. (1990). Wide Range As-
Press. sessment of Memory and Learning. Wilmington,
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M aking Test. Austin, TX: PRO-ED. Sheslow, D., & Adams, W. (2003). Wide Range
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Chapter 3
and Medical Genetics
An Overview
Bonnie J. Baty
John C. Carey
William M. McMahon
The entrance of the discipline of medical ge- ders presented in this book. The first section
netics into the care of persons with neurode- of the chapter provides an overview of basic
velopmental disorders is a relatively recent concepts in human genetics. The second sec-
but highly significant event. The application comprises a primer on the principles of
tion of the principles of genetics to medicine medical genetics. The chapter closes with a
is crucial because of the important role of brief discussion of the concept of behavioral
genes in the causation of human develop- phenotypes in dysmorphic syndromes and
mental disorders. In addition, a precise di- genetic conditions.
agnosis of a genetic condition or syndrome
is important to the person diagnosed, his or
her family, and the practitioner caring for Basic Concepts in Medical Genetics
the individual. Moreover, parents of indi-
Genomic Structure
viduals with disabilities and differences fre-
quently ask questions about the chance of a The influence of genetics as we currently
disorder’s occurring in future pregnancies. know it is primarily the result of research
Medical genetics has only recently accomplished during the last 50 years of
emerged as a bona fide specialty in orga- the 20th century. The basic foundation of
nized medicine. In the 1960s, the fields of the field of genetics is the understanding of
biochemical genetics, clinical cytogenetics, genomic structure. The genome is the term
and dysmorphology developed and paved applied to the total complement of deoxyri-
the way for the delineation of this discipline. bonucleic acid (DNA). DNA molecules are
Now, with the recently publicized advances organized into approximately 30,000 units
in the mapping and cloning of human dis- (genes). Alterations in these genes, either
ease genes, interest in genetics and its roles alone or in combination with alterations in
in human disorders is commonplace; indeed, other genes, can produce the diseases that
these have become topics of everyday con- we call genetic disorders. Genes are strips
versations. The purpose of this chapter is of DNA that are the functional and physical
to summarize the body of knowledge and units of heredity, passed from parent to off-
principles of medical genetics needed for the spring. Most genes contain the information
discussion of the neurodevelopmental disor- for making a specific protein product. They
33
34 BACKGROUND
are organized in a microscopically visible set 2. Monogenic (Mendelian) conditions.

of structures called chromosomes. The basic These are disorders in which a single gene
biology of DNA and chromosomes was es- or pair of genes contains a mutation (altera-
tablished in the 1950s and 1960s; thus most tion of DNA structure) that is the primary
of our knowledge of the molecular, chromo- cause of the disease. They are divided into
somal, and even biochemical bases of human autosomal dominant, autosomal recessive,
diseases has been acquired in just the past and X-linked conditions. The term Mende-
50–60 years. lian derives from Gregor Mendel, the 19th-
Each human cell—with the exception of century scientist who established the basic
a few cell types, notably the gametes (i.e., laws of heredity in his studies of plants.
sperm or egg cells)—contains 23 pairs of 3. Multifactorial or polygenic disorders.
different chromosomes for a total of 46 These are conditions caused by a combi-
chromosomes. One member of each pair is nation of multiple effects, either multiple
derived from an individual’s father, while genes (hence the term polygenic) or gene–
the other is derived from the mother. One environment interactions. Epidemiological
pair of chromosomes is designated as sex and family studies indicate that there is a
chromosomes, consisting of XX in a female genetic basis for these conditions, but the
and XY in a male. XX indicates that females conditions do not follow the simple, regular
have two sex chromosomes with the same rules of inheritance established for single-
sequence of genes, while XY indicates that gene disorders (Mendel’s laws). Many human
males have two sex chromosomes with a dif- diseases fall into this less well-defined cate-
ferent sequence of genes, forming the basis gory. These include neurodevelopmental dis-
for the unique features of X-linked inheri- orders such as attention-deficit/hyperactivity
tance. The remaining 22 pairs of chromo- disorder (ADHD) (Acosta, Arcos-Burgos, &
somes are called autosomes and are num- Muenke, 2004; Faraone, 2004) and learn-
bered from 1 to 22. A gamete or germ cell ing disabilities (Chapman, Raskind, Thom-
is different from a somatic cell, in that it son, Berninger, & Wijsman, 2003; Francks,
contains only one chromosome from each MacPhie, & Monaco, 2002; Plomin &
pair. The reader is referred to basic texts of Walker, 2003), as well as psychiatric disor-
biology and genetics that discuss cell divi- ders such as autism spectrum disorders and
sion and meiosis in more detail (e.g., Jorde, bipolar disorders (Fisch, 2008; Sherman et
Carey, & Bamshad, 2010). al., 1997; Smalley, 1997).
4. Mitochondrial disorders. This group of
disorders includes a relatively small number
Types of Genetic Disorders
of diseases caused by alterations of the small
Genetic disorders in humans are classified cytoplasmic mitochondrial chromosome.
into four major groups:
The chromosome, monogenic, and multi-
1. Chromosome disorders. In these con- factorial disorders, as well as their principles,
ditions, the entire chromosome or segments are reviewed in some detail in this chapter.
of a chromosome are missing or duplicated. Although a discussion of mitochondrial dis-
They are divided into conditions of abnor- orders is important in any review of genetic
mal number (aneuploidy) and conditions of diseases, these conditions are not covered in
abnormal structure. Human chromosome detail here. The reader is referred to recent
disorders are diagnosed by performing a texts on medical genetics for more detail on
karyotype (chromosome study) of a body mitochondrial disorders (Gelehrter, Collins,
tissue—usually blood, but almost any tissue & Ginsberg, 1998; Jorde et al., 2010; Nuss-
in which cells can grow can be utilized. The baum, McInnes, & Willard, 2007).
resulting chart of the chromosomes is called Table 3.1 summarizes the various types of
a karyogram. A number of disorders, such human genetic disorders defined above, with
as the Down, Klinefelter, and 22q11 deletion examples in each category. This table also
syndromes, have missing or extra chromo- lists three other features of inheritance—
somal material as their biological basis. Some mosaicism, genomic imprinting, and an-
of the important concepts that relate to chro- ticipation, which are defined and discussed
mosome syndromes are discussed below. later in this chapter. All of the concepts in
Neurodevelopmental Disorders and Medical Genetics 35
TABLE 3.1. Types of Human Genetic Disorders

Inheritance Exemplary disorders
Traditional
Chromosome Down syndrome, Klinefelter syndrome
Monogenic/Mendelian Neurofibromatosis type 1, fragile X syndrome
Multifactorial/polygenic Learning disabilities, autism spectrum disorders, schizophrenia
Nontraditional
Mitochondrial Kearns–Sayre syndrome, MELAS a
Mosaicism Turner syndrome, fragile X syndrome
Genomic imprinting Prader–Willi and Angelman syndromes
Anticipation Fragile X syndrome, Huntington disease
Note. a MELAS, mitochondrial encephalopathy and stroke-like episodes.
the table are also discussed in the chapters well-established genetic disorders during his
on individual conditions. or her lifetime. These figures, however, do
not include cases of common adult diseases
such as schizophrenia, diabetes mellitus,
Population Prevalence of Human
and cancer, all of which have some genetic
Genetic Disorders
basis (Jorde et al., 2010). Moreover, most
Although genetic disorders are often thought epidemiologists would not classify human
of as rare and exotic, these conditions con- disease as purely environmental/acquired or
stitute an important cause of human mortal- purely genetic. Rather, causation of human
ity and morbidity. The most common causes disease represents a continuum. At one end
of infant mortality as of the mid-1980s were of the spectrum are those disorders that are
congenital malformations, most of which strongly determined by genes, especially mo-
have some genetic basis. About one-third nogenic and chromosome disorders; at the
of children with developmental disabilities other end are those that are strongly deter-
have a congenital malformation or other ge- mined by environment. However, there is
netic condition as the primary etiology of the now increasing evidence that many infec-
problem. By the 1970s, 50% of all deaths in tious diseases or even types of resistance to
childhood were found to be attributable to infectious diseases (e.g., resistance to HIV)
genetic causes (Jorde et al., 2010). At least have a genetic basis (Cheung, Wynhoven, &
50% of sensory disabilities are caused by ge- Harrigan, 2004; Quirk, McLeod, & Pow-
netic mechanisms (Morton & Nance, 2006). derly, 2004), and thus most diseases are mul-
Twelve percent of adult hospital admissions tifactorial in the strict sense of the word.
are for genetic causes (Rimoin, Connor, Py-
eritz, & Korf, 2007) and 10% of the chronic
Types of Genetic Services
diseases (heart problems, diabetes, arthri-
tis) that occur in adult populations have a With the development of medical genetics as
significant genetic component (Weatherall, a specialty in mainstream medicine, clinical
1985). genetic services have become an integral part
The calculation of incidence and preva- of the health care delivery system in North
lence figures for genetic disorders is very America and Europe, where most university
complex. Difficulties in establishing disease medical centers have a program or clinic in
registries and standardization in diagno- genetics. In addition, medical genetics ser-
sis and recording practices make estimates vices are becoming more common in other
challenging. Various investigations that countries. The percentage of clinical genet-
have attempted to estimate the frequency ics posters presented at the American Soci-
of monogenic disorders, chromosome disor- ety of Human Genetics meetings from coun-
ders, and congenital malformations derive tries outside North America and Europe has
figures of about 3–7% for the likelihood increased remarkably from the 1990s to the
that an individual will develop one of these present. The major objective of clinical ge-
36 BACKGROUND
netic programs is to provide genetic diagno- of the tasks require strong communication
sis and counseling services for the referred skills to enable the family to understand and
patient population. process complicated medical and personal
The cornerstone of medical genetics is information and to utilize the information in
the art and science of genetic counseling. a way that enhances their health and quality
Although the term counseling implies that of life.
this service is in the domain of mental health The 1975 definition was drafted during an
or psychotherapy, genetic counseling in fact early period in the establishment of medical
is a marriage of human genetics and behav- genetics as a service. Because of this, the Na-
ioral science. In 1975, the American Society tional Society of Genetic Counselors (NSGC
of Human Genetics adopted a definition Definition Task Force, 2006) has published
that was proposed by an assigned working a more contemporary definition of genetic
group: counseling, which simplifies and broadens
the definition and addresses current practice:
Genetic counseling is a communication pro-
cess which deals with the human problems as- Genetic counseling is the process of helping
sociated with the occurrence, or the risk of oc- people understand and adapt to the medical,
currence, of a genetic disorder in a family. This psychological and familial implications of ge-
process involves an attempt by one or more ap- netic contributions to disease. This process in-
propriately trained persons to help the individ- tegrates the following:
ual or family to: (1) comprehend the medical
facts including the diagnosis, probable cause • Interpretation of family and medical histo-
of the disorder, and available management; (2) ries to assess the chance of disease occur-
appreciate the way heredity contributes to the rence or recurrence.
disorder and the risk of occurrence in specified • Education about inheritance, testing, man-
relatives; (3) understand alternatives for deal- agement, prevention, resources and re-
ing with the risk of reoccurrence; (4) choose search.
a course of action which seems to them ap- • Counseling to promote informed choices
propriate in the view of their risk, their family and adaptation to the risk or condition.
goals, and their ethical and religious standards (p. 79)
and act in accordance with that decision, and
(5) to make the best possible adjustment to the
disorder in the affected family member and/
The practice of clinical genetics involves
or to the risk of recurrence of that disorder. a diverse array of services. A genetics pro-
(Ad Hoc Committee on Genetic Counseling, gram or clinic provides diagnosis, manage-
1975, p. 241) ment, genetic counseling, and consultation.
These occur in a variety of settings, includ-
This definition illustrates the complex ing university outpatient clinics, community
tasks presented to the practitioner of medi- clinics, hospital wards, and specialty clin-
cal genetics. The first task involves establish- ics, often with a multidisciplinary team ap-
ing the diagnosis and discussing the natural proach. For example, medical geneticists are
history and management of the disorder in often involved in organizing or coordinating
question. The second task requires an un- team clinics for such disorders as Turner syn-
derstanding of the basic tenets of medical drome, neurofibromatosis type 1 (NF1), and
genetics. The third and fourth objectives of sickle cell disease. Multidisciplinary clinics
the genetic counseling process underlie the have improved medical care for individuals
primary differentiation between the genetic with genetic disorders and birth defects by
model suggested here and the traditional providing better access to services, greater
biomedical approach. Here the tasks involve likelihood of multidisciplinary consensus
a discussion of reproductive options and a in medical decision making, concentrated
facilitation of decision making, respectively. expertise among a group of practitioners,
Implicit in the definition is the notion of re- less redundancy of services, and the ability
spect for the family members’ autonomy and to offer unusual services (e.g., direct access
for their perception of the risk. The final task to research protocols, support groups and
of the genetic counseling process involves emergency coverage). Genetic services also
helping the family cope with the condition, include prenatal screening, which is present-
its impact, and its potential heritability. All ly done in conjunction with obstetricians and
perinatologists. Moreover, genetic practitio- clinical discussion of these genetic disorders

ners are closely involved with the develop- are emphasized throughout the discussion
ment, orchestration, and delivery of genetic (see also Jorde et al., 2010; Rimoin et al.,
screening programs, which serve prenatal, 2007).
neonatal, and general populations. Genetic
practitioners also provide presymptomatic
Chromosome Disorders
or predictive genetic testing, which enables
family members at risk for specific gene mu- Figure 3.1 is a standard karyogram, showing
tations in their family to learn whether or the chromosome arrangement of a normal
not they have a gene mutation that will pre- male. Note that the chromosomes are paired
dict or predispose them to genetic disease. and numbered from 1 to 22. There are dark
From this development, the specialty of and light areas (bands) on each chromosome.
cancer genetics emerged within the field in Each chromosome is lined up in a standard
the last decade. Traditionally, genetic condi- way, with the centromere (central constric-
tions have few treatment options available. tion) representing a landmark. The shorter
However, this is gradually changing with of the two longitudinal chromosome seg-
the advent of therapies involving enzyme re- ments is called the p arm, and the longer one
placement (e.g., for mucopolysaccharidoses) is called the q arm. The chromosomes are
and gene therapy (e.g., for severe combined grouped according to the size and location
immunodeficiency deficiency), in addition to of the centromere. Chromosomes 1 through
more traditional therapies such as pharma- 3 have a centrally placed centromere (meta-
cological treatment (e.g., growth hormone centric), while chromosomes 4 and 5 have
for Turner syndrome) and nutritional man- a submetacentric construction. Details of
agement (e.g., a special diet for Prader–Willi the standard banding/numbering system
syndrome). Genetic services are beginning to are available in many genetic texts. Figure
include treatment centers. The various types 3.2 shows two chromosome diagrams (idio-
of clinical genetic services are discussed in grams) and their designated bands.
detail elsewhere (Donnai, 2002; Read & Most chromosome studies done in a clini-
Donnai, 2007; Rimoin et al., 2007). cal setting utilize a Giemsa-banding (G-
An essential aspect of evaluation in a clin- banding) technique, which averages about
ical genetic setting is the documentation of 550 bands on all 23 pairs of chromosomes.
family history. It is now considered standard A more recently developed technique called
for practitioners evaluating a person with a high-resolution banding (HRB) stops the cell
potential genetic disorder to construct an ac- in an early part of the cell cycle and allows
curate family history (pedigree) and place it for more extended chromosomes, and thus
in the patient’s chart. The NSGC has devel- for more bands (average about 650). HRB
oped recommended standards for symbols techniques allow for the recognition of more
to be used in the construction of a pedigree subtle chromosome disorders. For example,
to document this important data set (Ben- research using HRB in the early 1980s demon-
nett, 1999; Bennett et al., 1995; see www. strated that some patients with Prader–Willi
nsgc.org/client_files/consumer/family_his- syndrome had a subtle but definite missing
tory_logos.pdf for family-friendly instruc- piece (deletion) of the uppermost band on the
tions). long arm of chromosome 15. However, HRB
was not sensitive enough to pick up the dele-
tion seen in individuals with Williams syn-
Principles of Medical Genetics : drome. In this situation, the diagnosis of the
A Primer characteristic deletion of Williams syndrome
requires a newer technique combining DNA
In this section, the basic principles of medi- fluorescent probes with HRB of chromo-
cal genetics required to understand the bio- somes. This technique, called fluorescent in
logical basis of the syndromes described in situ hybridization (FISH), is of significance
this book are summarized. Our goal here is because it is now the technique of choice for
not to provide a comprehensive summary of detecting the subtle deletions of Prader–Willi,
the science, but rather to highlight the im- Angelman, Williams, and 22q11.2 deletion
portant points. The key terms important in syndromes. Also, it is sometimes utilized to
38 BACKGROUND
FIGURE 3.1. G-banded karyogram from a normal male. Note that there are 23 pairs of chromosomes
arranged in a specific, orderly array. The autosomes are numbered from 1 through 22, and the sex chro-
mosomes are conventionally placed at the bottom right-hand portion of the karyotype. The individual
pattern of G-bands determines the chromosome. (Courtesy of Dr. Art Brothman, University of Utah
Health Sciences Center)
pick up more subtle submicroscopic deletions cations (but not rearrangements) throughout
in relatively well-known deletion syndromes, the genome. The technique uses an array of
such as 5p or 4p deletion syndrome. Figure small, regular-spaced, cloned segments of
3.3 is a black-and-white photograph of FISH DNA from all the chromosomes. CGH has
in a patient with the 22q11.2 deletion syn- become the principal approach in screen-
drome. This important condition is the most ing an individual with a neurodevelopmen-
common autosomal deletion syndrome in tal condition and no medical diagnosis for
humans. a subtle chromosome abnormality (such as
A special application of the FISH tech- small deletions or duplications) (Edelman
nique is called subtelomeric FISH analysis. & Hirschhorn, 2009). Figure 3.4 is a black-
The tips of chromosomes are called telom- and-white photograph of a microarray anal-
eres. It has been shown (de Vries, Winter, ysis. Laboratory tests have become clinically
Schinzel, & van Ravenswaaij-Arts, 2003; available that combine a microarray assay
Flint & Knight, 2003) that about 5–10% with a conventional karyotype, followed
of undiagnosed individuals with mental re- by confirmation of abnormal results using
tardation and other signs of multisystem in- FISH probes. Because the deletions and du-
volvement have a deletion close to the tip of a plications detected with these powerful new
chromosome (the subtelomeric region). Some tools are usually smaller than previously
of these deletions coincide with known dele- described imbalances, genotype–phenotype
tion syndromes (e.g., 4p deletion syndrome), data are needed to provide clinical predic-
and others are in regions without previ- tion. These techniques have enabled practi-
ously described syndrome associations. An tioners to diagnose a higher percentage of in-
even newer technique, called comparative dividuals with clinical symptoms suggesting
genomic hybridization (CGH) microarray a chromosomal condition, including many
analysis, detects small deletions and dupli- individuals whose tests were negative when
previous techniques were used (Edelman & and partial trisomy, respectively, are also
Hirschhorn, 2009). utilized. The most common deletion syn-
As mentioned above, chromosome disor- dromes include 5p deletion (also known as
ders can be divided into disorders of chro- cri du chat syndrome), 4p deletion (Wolf–
mosome number and structure. Disorders of Hirschhorn syndrome), and 18q deletion.
chromosome number are those conditions Although the letter p or q refers to the par-
in which there is either an entire extra chro- ticular chromosomal arm, that designation
mosome or a missing chromosome. Down does not tell one where the actual deletion
syndrome (trisomy 21) involves the presence is; the banding number is also needed. A
of an extra chromosome 21 (usually the en- more comprehensive discussion of chromo-
tire chromosome) and represents the proto- some biology is available in most textbooks
typical chromosome condition of abnormal of human and medical genetics.
number (see Hazlett, Hammer, Hooper, & In the 1980s, as noted above, a number of
Kamphaus, Chapter 19, this volume). Turn- chromosome deletion syndromes involving
er syndrome (monosomy X) and Klinefelter very subtle deletions were described. These
syndrome (47,XXY) represent other disor- have come to be known as the microdele-
ders of abnormal chromosomal number (see tion syndromes. Prader–Willi, Angelman,
Powell & Schulte, Chapter 13, and Hazlett, and Williams syndromes all fall into this cat-
De Alba, & Hooper, Chapter 20, this vol- egory. Because the deletions are subtle and
ume). are thought to affect a potentially definable
Disorders of abnormal structure involve cluster of neighboring genes, the microdele-
conditions where a segment of a chromo- tion syndromes are sometimes referred to as
some is either missing (deletion) or extra contiguous-gene syndromes. Prader–Willi
(duplication). The terms partial monosomy and Angelman syndromes are prototypical
FIGURE 3.2. Idiograms at the 550-band resolution for chromosomes 7 and 15, two important chro-
mosomes for neurobehavioral disorders. Chromosome 7 is a typical submetacentric chromosome (i.e.,
the centromere is off center). The part of the chromosome on the shorter side is called the short arm or
p arm; the part on the longer side is called the long arm or q arm. Chromosome 15 is called an acro-
centric chromosome; the centromere is near one end, and the short arm contains the satellite material.
Note that the band numbers move consecutively away from the centromere, and the chromosome arms
are divided broadly into segments and then into individual bands. Chromosomes are numbered by seg-
ment and then by band. The region that is deleted in the Prader–Willi syndrome is the 15q11–13 region.
The region that is deleted in Williams syndrome is the 7q11.2 region. (Courtesy of Dr. Art Brothman,
University of Utah Health Sciences Center)
40 BACKGROUND
FIGURE 3.3. An abnormal FISH study of an individual with a 22q11.2 deletion. The normal chromo-
some 22 shows two signals, while the other chromosome 22 (lower left) is missing a signal. Thus there
is a missing piece of DNA in the critical region consistent with this syndrome. (Courtesy of Dr. Art
Brothman, University of Utah Health Sciences Center)
FIGURE 3.4. Ratio plot of chromosome 22, showing deletion at the DiGeorge locus (22q11.2) on the
left of the plot where the two lines separate. Each clone is shown by a dot along the line and signifies
that the clone is deleted. (Courtesy of Dr. Art Brothman, University of Utah Health Sciences Center)
for the group and are discussed further in the imbalances, with correspondingly subtle
section below on nontraditional inheritance. physical features, most clinicians currently
From a clinical point of view, chromosome order microarray analysis for individuals
disorders are associated with characteristic with these “nondistinctive” findings. Many
syndromes. In each of these conditions there clinicians have also considered doing a kary-
is a recognizable and relatively reproducible otype for any individual with autism who
pattern of physical manifestations, minor has no associated medical diagnosis. This
anomalies, and sometimes major congenital is because of the recognition of the inverted
malformations, often consistent enough to duplication 15 syndrome, where the clinical
be recognized by the experienced clinician. signs are quite subtle (Battaglia et al., 1997).
The syndrome thus represents the manifes- The yield of chromosome studies looking
tations that we actually observe physically for this finding or for other chromosome
or clinically (phenotype). The concept of disorders in large populations of individuals
phenotype is contrasted with the term geno- with autism but with no medical diagnosis is
type, which refers to the individual’s genetic currently under investigation in the United
constitution. For example, the phenotype in States and Europe (Edelman & Hirschhorn,
Down syndrome is the constellation of physi- 2009), and this testing can be pursued on a
cal findings first described by Dr. J. Langdon case-by-case basis. It is important to order
Down; the genotype is the chromosomal both a high-resolution karyotype and FISH
constitution of 47,XY +21. (About 90–95% when one is considering one of the specific
of persons with Down syndrome have the microdeletion syndromes (i.e., Prader–Willi,
chromosomal finding of trisomy 21, while Angelman, Williams, or 22q11 deletion syn-
the remaining 5–10% have other structural drome).
changes; see Hazlett et al., Chapter 19, this Another reason for a chromosome study is
volume.) to study a parent when a child has a disorder
One of the clinical decisions that often of chromosome structure. Here one is look-
confronts the practitioner is when to order ing for a chromosome rearrangement (e.g.,
a chromosome analysis. The most common translocation, inversion). There are a num-
reason for such a study is to confirm the ber of other indications for performing chro-
presence of a well-established chromosome mosome studies that are not as relevant to
disorder, such as Down or Turner syndrome. the neurodevelopmental arena and are not
Since autosomal chromosome disorders pro- discussed in detail here; these include recur-
duce syndromic patterns of multiple anoma- rent miscarriages, an undiagnosed stillborn
lies, usually with intellectual disability, a infant, concern about one of the chromo-
karyotype is indicated in a person who has somal instability syndromes, and diagnosis
this type of clinical picture. Thus, in the eval- of certain malignancies. Comprehensive dis-
uation of an individual with developmental cussions of these indications are available in
delay or a neurodevelopmental disorder, a the texts cited earlier in the chapter.
chromosome study is obviously indicated
when a person has multiple major and minor
Monogenic Disorders
anomalies or features different from those of
his or her family background. The question Monogenic disorders are those conditions
of doing a karyotype in a person who has resulting from a mutation (change in a
an intellectual disability or developmental gene), either in a single allele or both alleles
delay without dysmorphic signs or minor of a gene. Prior to the 1980s, the notion of
anomalies is somewhat more controversial. a monogenic disorder was one that involved
However, since the dysmorphic features an assumption. Now that the genes for over
can often be quite subtle even in established 2,000 human disorders have been mapped
syndromes (e.g., 5p deletion/cri du chat syn- to a chromosomal location, or in many cases
drome and 17p deletion/Smith–Magenis identified (cloned) (see the Online Mende-
syndrome), most geneticists seriously con- lian Inheritance in Man [OMIM] website,
sider doing a karyotype for any individual discussed below), the notion of the gene is no
with developmental delay or intellectual dis- longer a theoretical construct.
ability (Curry et al., 1997). Since microarray Monogenic disorders, also known as Men-
analysis is capable of detecting very small delian conditions, can be divided into auto-
42 BACKGROUND
somal dominant, autosomal recessive, and father transmits his Y to a son and his X to
X-linked conditions. The determination of a daughter.) In many autosomal dominant
the inheritance pattern was known long be- traits, a condition starts off with a person
fore the new DNA technology became avail- called the progenitor. In that situation it is
able; it was based on interpretation of pedi- assumed that there is a de novo (new) muta-
gree structure. Thus, when a condition was tion in the gene. Thus, in many autosomal
recognized to occur through generations in a dominant conditions there will be no fam-
vertical fashion, the assumption was usually ily history because the particular person in
made that the condition was an autosomal question is the progenitor for the disorder.
dominant disorder. This was the logic that This is often the case in NF1, where in the
permitted the recognition of NF1 as an au- clinical setting about 50% of all patients
tosomal dominant condition long before the who present to a medical genetics clinic have
gene was identified in 1990. (NF1 is utilized their disorder because of a de novo mutation.
in this section to illustrate principles.) (The other 50% inherit the gene from one of
The concept of an autosomal dominant their parents.) This illustrates the point that
gene means that one allele in each gene pair the absence of any family history of a condi-
possesses a mutation, while the other is a tion by no means excludes genetic causation.
normal (wild-type) allele. In recent years In fact, in X-linked and autosomal recessive
many of these mutations have been deter- conditions (where there is often no family
mined at the molecular level for many con- history) as well, the belief that the lack of
ditions. When a person has an autosomal family history mitigates against a genetic
dominant mutation, the chance of transmit- disorder is inaccurate.
ting the mutation to offspring is one in two An autosomal recessive disorder is one in
(or 50%) with each pregnancy. The pedigree which both alleles in a gene pair have a mu-
structure will often be multigenerational be- tation. In an autosomal recessive pedigree,
cause inheriting the trait from one parent is each parent is assumed to carry a mutant
sufficient to cause the condition. Figure 3.5 copy of the gene, and thus the parents are
shows a typical autosomal dominant pedi- called carriers or heterozygotes. The term
gree in a family with NF1. Note that there homozygote is used when a person has two
is transmission in this particular family his- mutant alleles or two normal alleles. Because
tory from a father to a son (i.e., male-to- of the segregation pattern (the genotypes in-
male transmission), confirming that this is herited by the offspring) that occurs in re-
an autosomal trait and not an X-linked trait. cessive situations, the chance that a family
(In an X-linked trait, a male cannot trans- in which both parents are carriers will have
mit the trait to a male offspring because the a child with the recessive condition is one in
= NF1
• = NF1
FIGURE 3.5. This family pedigree illustrates the typical inheritance pattern of an autosomal domi-
nant trait, NF1. Note the transmissions from a father to a son.
four (25%) with each pregnancy. Most in- mutations), and in some cases can have mul-
born errors of metabolism, such as most of tiple modes of inheritance. For example, re-
the mucopolysaccharidoses (see M. Brown, tinitis pigmentosa mutations are associated
Chapter 15, this volume), are inherited in with both dominant and recessive modes of
an autosomal recessive fashion. These bio- inheritance in different families. Detailed
chemical conditions represent disorders of discussions of the evidence for inheritance
intermediary metabolism, and a homozy- patterns of human diseases and phenotypes
gous deficiency of an enzyme accounts for are available in the classic multivolume text
each such disorder. Moreover, the hemoglo- Mendelian Inheritance in Man. V. A. McK-
binopathies, including sickle cell anemia (see usick, the author, is regarded as the father of
Smith & Baker, Chapter 18, this volume), medical genetics, and has produced 12 edi-
are also inherited in an autosomal recessive tions of this seminal work. One is now able
fashion. A comprehensive discussion of the to look up conditions or phenotypes and
principles of population genetics that are discover key and recent citations on clini-
important in any discussion of autosomal cal and genetic aspects as well as molecular
recessive diseases can be found in the text- biology (McKusick, 1998). Moreover, this
books cited earlier. work is currently available online through
The third type of disorder transmitted in the World Wide Web (www.ncbi.nlm.nih.
a Mendelian fashion is an X-linked disorder. gov/omim) at no cost. This is an incompa-
The X-linked disorders are conditions that rable and invaluable resource for current
from pedigree structures (and now DNA knowledge about the genetic and molecu-
technology) are known to be mutations on lar basis of almost any condition. The 12th
the X chromosome. In this situation, a female print edition (McKusick, 1998) included
(who typically has two X chromosomes) will 8,587 entries; as of May 2009, the online
“carry” the gene for the condition and may version (OMIM) listed 12,777 loci. Another
or may not express it, while the male (who online resource that is especially useful for
only has a single X) will almost invariably clinical information—including differential
express the condition. Again, just as in auto- diagnosis, diagnostic tests, detailed genetic
somal dominant disorders, some individuals information, management, and family sup-
who have an X-linked disorder may have it port groups—is GeneTests (www.ncbi.nlm.
because of a new mutation of the gene on nih.gov/sites/GeneTests/?db=GeneTests).
the X chromosome. Figure 3.6 shows a typi-
cal X-linked pedigree of a family with frag-
Genotype–Phenotype Relationships:
ile X syndrome seen in a clinical setting (see
Basic Tenets
Hagerman, Chapter 14, this volume). Other
conditions of significance in the neurodevel- Although the discussion thus far seems to be
opmental arena with X-linked inheritance relatively straightforward, the actual evalu-
include Hunter syndrome (see M. Brown, ation of a patient with a potential genetic
Chapter 15, this volume), Lesch–Nyhan condition is not so clear-cut. As mentioned
syndrome (see Wodrich & Long, Chapter above, an abnormality of chromosome struc-
23, this volume), and X-linked aqueductal ture or a gene mutation produces a pheno-
stenosis/hydrocephalus. In addition to frag- type that is recognizable and often discrete.
ile X syndrome, several other X-linked con- However, the relationship between the gene
ditions can cause intellectual disability and alteration and the disease state is complex,
neurodevelopmental disorders (Stevenson, as there is marked variability in the clinical
Schwartz, & Schroer, 1999). picture, regardless of the genotype. Various
Decisions about patterns of inheritance conditions seem to have their own intrinsic
are complex and often controversial in the degree of variability. For these reasons, ge-
field of medical genetics. Knowledge of the neticists over the past century have devel-
genetic basis for many conditions is now oped concepts that explain the often fuzzy
being acquired through recent developments relationship between genotype and pheno-
in DNA technology. In some cases, this has type. These concepts are discussed in the
led us to recognize that a single clinical con- following paragraphs.
dition can be caused by multiple mutations Expressivity is a term utilized in genetics
(some genes have several hundred different to refer to the variability in clinical severity
44 BACKGROUND
•
70 y
•
28 y
• • •
= LD
8y 15 y 12 y
P • = DD
FIGURE 3.6. A typical family pedigree of an X-linked condition, fragile X syndrome. Note that one
female is mildly affected, and there is no male-to-male transmission. LD, learning disabilities; DD,
developmental delay.
seen in a given condition. Various members tion, while others with the same mutation
of the same family with a certain genetic will have clinical signs. Penetrance is usually
trait have exactly the same mutation, yet the expressed as the ratio of individuals with the
degree of involvement can range from mini- mutation and symptoms to all individuals
mal to severe. The study of the clinical as- with the mutation. The absence of any signs
pects of NF1 illustrates this point (see Payne of such a disorder will give the impression
& North, Chapter 17, this volume). About that the gene in question has skipped a gener-
50–70% of patients with NF1 only have café ation. The concept of incomplete penetrance
au lait spots or dermal neurofibromas, and or lack of penetrance is an attempt to ex-
their disorder is of mild significance. Ap- plain the clinical picture where the genotype
proximately 30–50% of patients have one and phenotype do not match, as one would
of the many listed serious manifestations of expect. All of the monogenic conditions de-
NF1, including optic pathway tumors, neu- scribed in this book essentially have 100%
rofibrosarcomas, or scoliosis. Even within penetrance. For example, in NF1, individu-
the same multigenerational kindred, there als who have the trait have some cutaneous
will be marked variability. This discussion or eye signs of NF1—usually by the age of 5,
also applies to Noonan syndrome (see Tee- but certainly by the age of 20 years. Some-
ter Ellison, Chapter 16, this volume). Again, times it may be difficult to exclude the pres-
even within the same pedigree, there will ence of the gene in a young child, but usually
be marked variability in the clinical signs by adulthood, the café au lait spots, dermal
(short stature, pulmonic stenosis, etc.), even neurofibromas, and Lisch nodules of the iris
though all patients will have at least the fa- have made their appearance. In examination
cial features. of NF1 pedigrees, one does not see examples
Penetrance is the frequency of expression of three-generation pedigrees where the gene
of a genotype. Some individuals who carry a mutation has skipped. On the other hand,
gene mutation in a Mendelian disorder will in tuberous sclerosis, there have been cases
have no observed clinical signs of the condi- reported in which there are two affected off-
spring of normal, unaffected parents. This heterogeneity has been proven. For example,
particular pedigree structure could be de- in tuberous sclerosis, some families with
scribed as incomplete penetrance; however, this autosomal dominant gene map to chro-
one does not see three generations of people mosome 16 and have a mutation of a cer-
with tuberous sclerosis where the person in tain tumor suppressor gene, whereas other
the middle generation lacks any signs. Most families map to chromosome 9 and have the
geneticists currently think that families with disorder because of mutations of a different
siblings affected with tuberous sclerosis and gene. This can be referred to as either locus
unaffected parents represent germ-line mo- heterogeneity or genetic heterogeneity. The
saicism (i.e., mutation occurring in multiple term is also used to refer to a mixture of phe-
gametes and not in somatic cells, putting notypes as well. For example, when it was
the parents at increased risk for recurrence). recognized in the 1980s that bilateral acous-
Mosaicism is now thought to occur more tic neuromas were not seen in classical NF,
often than previously recognized. In Table the notion of phenotypic heterogeneity of
3.1 it is listed as one of the nontraditional the NFs was proposed. Even before the two
modes of inheritance, and it is discussed fur- separate genes were mapped and cloned, cli-
ther below. nicians and scientists were referring to mul-
The concepts of expressivity and pene- tiple forms of NF. Now the terms NF1 and
trance are critical in the evaluation of family NF2 are used for the classic condition (NF1)
histories of complex diseases such as depres- and for bilateral acoustic neuromas (NF2).
sive disorders and learning disabilities. In The concept of pleiotropy refers to the
such kindreds, it is typical to have multiple idea that diverse manifestations in different
affected family members with intervening organs and systems can have a single-gene
relatives who do not express the condition cause. Again, NF1 illustrates this concept
(nonpenetrance) or express it partially (vari- nicely. In this syndrome one sees manifesta-
able expressivity). In these cases, we are not tions that at first glance do not seem to be
only dealing with variable expression of a tied together pathogenically (i.e., café au
single gene, but often multiple genes and/ lait spots, neurofibromas, optic pathway tu-
or environmental factors. We often think of mors, learning disabilities, skeletal findings,
these genes as conferring a susceptibility to etc.). The notion here is that a single gene has
the condition. multiple roles in development and cell biol-
Age is an important factor in the concepts ogy, and thus that a mutation in this gene
of both expressivity and penetrance. For has multiple effects. In the case of NF1, the
many conditions, symptoms are age-specific. common denominator is presumably in the
This means that the phenotype changes with control of cells derived from the developing
age and may be harder to recognize at some neural crest of the embryo. To give another
ages than others. Examples are coarsening example, the pleiotropic manifestations of
of facial features in mucopolysaccharidoses Noonan syndrome include the characteristic
as storage material accumulates in the body, face, short stature, pectus excavatum, and
the development of adrenal tumors in mul- pulmonic stenosis. Again, this diverse array
tiple endocrine neoplasia, and dilation of the of effects appears to be due to the single mu-
aortic root in Marfan syndrome. Thus symp- tation. The concept of pleiotropy is impor-
toms vary not only between family members, tant in understanding how a gene produces
but in individuals throughout the life cycle. the phenotype (i.e., its pathogenesis) and the
It also means that penetrance is sometimes idea of a syndrome.
calculated as an age-specific curve. As mentioned in various places in the
The concept of heterogeneity presently chapter, mutation refers to the specific al-
has a number of usages in medical genetics. teration of the DNA molecule in a particular
The traditional concept is genetic hetero- condition. In recent years, with the advances
geneity, in which a certain phenotype (e.g., in DNA technology, the specific mutations
retinitis pigmentosa or cataracts) is known that cause many disorders have been detect-
to be caused by different genetic alterations ed. For example, after the gene for NF1 was
(i.e., autosomal dominant, autosomal reces- identified in 1990, about 10% of individuals
sive, or X-linked). With the recent advances with NF1 had a detectable mutation. In the
in DNA technology, the existence of genetic other 90%, scientists were not technically
46 BACKGROUND
able to find the gene alteration, presumably are two cell lines—either one that is normal
because of the size of the NF1 gene. Since and one that contains a gene or chromosome
1990, because of new techniques, labora- mutation, or two that are abnormal. More
tory scientists have been able to detect the rarely, mosaic individuals have more than
disease-causing mutations in 95% of NF1 two cell lines. In many cases, a normal cell
patients (Messiaen et al., 2000). Of note is line makes the phenotype milder. Other con-
the fact that about 80% of the mutations cepts proposed in the 1990s include genomic
are ones in which the gene is basically in- imprinting and anticipation. These concepts
activated (i.e. there is simply one operating have altered thinking about the clinical and
gene, while the other is not operating). In genetic aspects of several important condi-
some cases the entire gene is deleted, while tions. These concepts are discussed below,
in others a small deletion of only a few nu- as they relate to two of the conditions de-
cleotides is present. Most cases are caused scribed in this text (i.e., Prader–Willi and
by a single nucleotide change that either re- fragile X syndromes), as well as to Angelman
sults in a shortened protein or affects func- syndrome.
tion of the protein. In other conditions, the The principle of genomic imprinting chal-
specific type and location of gene mutations lenged the central dogma of genetics that
affect the phenotype. For example, Apert arose from Mendel’s experiments with peas.
syndrome is due to relatively specific muta- Originally it was thought that a trait was in-
tions of a gene that encodes a protein called herited from a mother or a father, and that
fibroblast growth factor receptor 2 (Webster the parent of origin made no difference.
& Donoghue, 1997). This is a cell receptor However, it has become increasingly appar-
protein that sits on the outside of a cell and, ent that in some genes the parent of origin
when signaled by a growth factor, sends a does make a difference and has an effect
message to the nucleus of the cell. It is now on phenotype and disease manifestation. In
known that Apert syndrome is due to mu- imprinting, the expression of a gene is influ-
tations of the gene that alter the extracel- enced by the parental origin of the gene, and
lular portion of this growth factor receptor. the activity level depends on this origin. The
Mutations of other parts of this same gene concept of genomic imprinting in humans
produce different phenotypes and cause rec- is best illustrated by Prader–Willi and An-
ognized syndromes that have manifestations gelman syndromes. As mentioned earlier, it
overlapping with those of Apert syndrome, has been known since the early 1980s that
but are considered different and distinct clin- a microdeletion on chromosome 15 in the
ical syndromes (Reardon et al., 1994; Wilkie upper portion of the long arm could produce
et al., 1995). These other syndromes, which Prader–Willi syndrome (see Dykens, Cassi-
include Crouzon and Pfeiffer syndromes, are dy, & DeVries, Chapter 25, this volume). A
not discussed here in detail. similar deletion was recognized in some pa-
In summary, the area of genotype– tients with Angelman syndrome. (Angelman
phenotype correlation is a timely topic. Ide- syndrome is a condition of profound devel-
ally, better understanding of how mutations opmental disability, seizure disorder, muscle
in specific genes produce specific phenotypes tone abnormalities, small head size, and a
will clarify the pathogenesis of human dis- characteristic face.) If a deletion arises on
eases of this nature. the paternal chromosome 15, the offspring
will develop Prader–Willi syndrome; if the
deletion arises on the maternal chromosome
Recently Delineated Concepts:
15, the offspring will develop Angelman
Nontraditional Inheritance
syndrome. Thus there is a definite parent-of-
As mentioned above, the concepts of vari- origin effect. It is now clear that a gene (or
ability, pleiotropy, and heterogeneity were genes) within the crucial segment of chromo-
created to explain observed relationships some 15 is normally only active on the pater-
between genotypes and phenotypes. In the nal chromosome and not the maternal one
1980s and 1990s, a number of newer, non- (the maternal copy is said to be imprinted).
traditional categories of inheritance were In a case when the critical gene (or genes)
recognized. One of these, mosaicism, has is deleted on the paternal chromosome and
been mentioned above. In mosaicism, there thus inactivated, this deletion results in Prad-
er–Willi syndrome. Conversely, the gene for DNA Technology and Linkage
Angelman syndrome has also been identi-
The tools and strategies to localize a particu-
fied, and the logic is the reverse. Although
lar gene for a Mendelian disorder to its par-
most cases of Prader–Willi syndrome and
ticular chromosome (or chromosomes) arose
Angelman syndrome are sporadic (i.e., with-
in the late 1970s and early 1980s. The com-
out a family history), this parent-of-origin
effect results in some unusual pedigrees that bination of the development of DNA probes,
would not at first glance fit any of the sim- complicated computer programs, and re-
ple rules of single-gene disorders discussed striction endonucleases laid the groundwork
above (see Jorde et al., 2010). for the application of this technology. Before
Another concept that is classified as non- this, the biological bases for the overwhelm-
traditional is anticipation. Since the early ing majority of genetic disorders (except the
part of the 20th century, it has been observed biochemical disorders) were almost entirely
that some genetic diseases display an earlier unknown. One could speculate that a condi-
age of onset and have more severe expres- tion like NF1 was due to some disorder of
sion in later generations of the family tree. neural crest biology, or that Apert syndrome
Such disorders are said to exhibit anticipa- was due to a developmental disorder of the
tion. Until recently, most investigators felt skeleton, but the real basis of the pleiotropy
that this was probably a bias of ascertain- in each case was unclear. For this reason,
ment and not a real biological phenomenon. the concept that one can map a gene by uti-
In the early 1990s, the genes for a number lizing the incredible and well-known varia-
of conditions were identified through the tion in DNA structure arose. The concept
positional cloning approach. These included of linkage analysis is based on the idea that
fragile X syndrome (see Hagerman, Chapter an individual’s normal DNA variations co-
14, this volume), myotonic dystrophy, and segregate with the disease genes in question.
Huntington disease. These conditions share By using complicated computer programs
a unique mutation mechanism, that of the and previously linked DNA probes, one can
expanded DNA repeat; they have thus been map a gene. Once a disease gene is mapped,
labeled the trinucleotide repeat-expansion the first step toward being able to isolate the
disorders. There are repeat sequences of causative gene is accomplished. The isola-
DNA nucleotides that are normally pres- tion of the gene for a condition is referred to
ent in all individuals; persons with repeat- as gene identification or cloning. If the basic
expansion disorders have an increased structure of the DNA is known, one can
number of these nucleotide repeat sequenc- then derive the amino acid sequence and the
es. Such an expansion affects the way the peptide structure. The strategy, once called
DNA works, or the amount or function of reverse genetics and now referred to as po-
the protein, and therefore it produces the sitional cloning, has been highly successful
disease. There is also a correlation with re- since the 1980s in identifying important
peat size and phenotype: Larger repeat sizes disease genes. The first gene mapped by this
are associated with more severe symptoms approach was the gene for Huntington dis-
and/or earlier onset. Repeats in the ex- ease. In the late 1980s, the genes for cystic
panded range are unstable and tend to get fibrosis, Duchenne muscular dystrophy, and
larger in offspring. For example, in fragile NF1 were mapped and then cloned. Another
X syndrome, expanded cytosine–guanine– important refinement of linkage analysis in-
guanine repeats are associated with methy- troduced in the 1990s is the use of single-
lation of a cytosine–guanine dinucleotide) nucleotide polymorphisms. This type of
island, which appears to “turn off” the DNA variation is ubiquitous in the genome
gene. Thus for these conditions triplet re- and enabled mapping at much smaller inter-
peat expansions explain the phenomenon vals of DNA, thus enabling more rapid local-
of anticipation and give it a biological basis. ization of genes. The process of identifying
Like genomic imprinting, this phenomenon human genes has been aided by the Human
provides the biological and molecular basis Genome Project, a massive, government-
for observations in family histories that were funded biological project that succeeded in
discrepant with the known rules of Mende- mapping the entire human genome between
lian inheritance. 1990 and 2003 (see the National Human
48 BACKGROUND
Genome Research Institute website, www. receptor 2, mutations were detected in pa-
nhgri.nih.gov). Correlation of the detected tients with Crouzon syndrome. The logical
mutations with specific phenotypes is now hypothesis was that perhaps different muta-
ongoing for all conditions in which there has tions of the same gene cause related disor-
been gene identification. ders, including Apert syndrome. This turned
Figure 3.7 illustrates this paradigm. First, out to be the case, and it is now known that
families with a particular dominant or re- the gene for fibroblast growth factor recep-
cessive condition are collected. If, by chance, tor 2 is the causative gene in Apert syndrome
some patients have an associated chromo- (Webster & Donoghue, 1997). As mentioned
somal rearrangement that suggests a gene lo- above, this paradigm was also successful in
cation, the success rate in mapping the gene mapping and cloning the important gene in
is improved. Once a gene is mapped, linkage fragile X syndrome. At present, if a person is
testing in the clinical arena is available. For recognized to have fragile X syndrome and
example, in familial cases of NF1, the fami- this is confirmed on a molecular basis, DNA
lies that are interested in prenatal diagnosis testing can be offered to other members of
or early-infancy diagnosis (often before any the family who are at risk. Direct mutation
café au lait spots have developed) now have testing for the expanded repeat of fragile X
this option. Once a gene has been mapped or syndrome is currently available in most clini-
localized, perusal of the existing gene map cal molecular laboratories in North America
may show candidate genes in the same re- (see Hagerman, Chapter 14, this volume).
gion that may be the basis for the disorder in With the increased use of faster technology
question. This approach was used to clone the that shortens the time between mapping and
gene responsible for Apert syndrome. Once cloning a gene, direct mutation testing has
the gene for a related but different condition become the norm for clinical testing. Inter-
called Crouzon syndrome (referred to above) estingly, although new techniques have rev-
was mapped to chromosome 10, and a can- olutionized the availability of clinical tests
didate gene on chromosome 10 was discov- once biological samples are available, the
ered that encodes fibroblast growth factor process is still just as dependent on astute
Accurate diagnosis Collection of families

Clinical delineation
Chromosomal
Gene mapping rearrangements
Animal models
Candidate genes Linkage testing
Molecular biology
Gene identification
Genetic counseling Animal models
Genotype–phenotype Pathogenesis
Treatment
correlation
FIGURE 3.7. The gene-cloning paradigm: The chronology of the mapping and identifying of a disease
gene, with its resulting consequences. Note that mapping a gene results in the possibility that linkage
testing can be used in the clinical arena. Cloning a gene creates the potential for understanding patho-
genesis and perhaps orchestrating strategies for treatment and prevention.
clinicians’ reporting and collecting blood which symptoms are expressed (penetrance
samples from families affected with genetic of the condition is the percentage above the
disorders. threshold). This threshold may be different
The ultimate aim of this strategy is to for males and females. Figure 3.8 shows a
understand the molecular pathogenesis of liability distribution for a multifactorial dis-
these single-gene conditions. If the protein ease in a population. These conditions are
is detected and its role in cell biology is usually common, and often are mixtures of
sorted out, then investigators can begin to multiple conditions with similar or identical
propose treatments that can alter or modify phenotypes (genetic heterogeneity). In many
the sequence of events in the cell pathway in cases, Mendelian conditions have been iden-
question. For example, the gene for NF1 is tified and “pulled out” of the more general
a tumor suppressor gene that is involved in category (e.g., fragile X and Rett syndromes
signal transduction within the cell. The en- are subsets of autism; fragile X, Turner,
coded protein, neurofibromin, is known to Noonan, and Williams syndromes, as well
slow down growth within the cell. Thus, if a as NF1 and sickle cell anemia, are subsets
mutation occurs, the expected brakes on cell of ADHD).
growth will not be present and will predis- The analytical tools that have been most
pose a person to develop benign or malignant useful in the analysis of multifactorial con-
tumors. If one could figure out how to alter ditions are twin concordance studies (mea-
some of the elements of the pathway, then suring the frequency of the condition in
perhaps one could prevent the occurrence of identical and fraternal twins); large-scale
benign or malignant tumors in NF1. family studies with linkage analysis (match-
ing disease status to known DNA markers)
and segregation analysis (observation of
Multifactorial Inheritance
proportion of affected offspring); and the
Multifactorial inheritance refers to the im- use of computer models to compute herita-
portant group of disorders that have an in- bility (estimate of the proportion of cases
herited component involving more than one attributed to genetic factors) and the likeli-
gene and/or gene–environment interactions. hood of major-gene and other models. For
These include such important neurodevel- most multifactorial conditions, we have not
opmental disorders as learning disabilities, delineated models that provide risk figures
Tourette syndrome, mood disorders, and au- for families; therefore, recurrence risks are
tism spectrum disorders (see the appropriate generally derived from empirical data from
chapters of this volume). It has been chal- family studies, taking into account gender
lenging to delineate the genetic components of the proband and degree of relationship.
of these conditions because of the difficulty Since most of these conditions also have en-
in describing discrete phenotypes, unravel- vironmental triggers, it will be important to
ing the effects of multiple genes and envi- study these factors as well.
ronmental factors, and determining genetic
heterogeneity. Genes influencing these condi-
Diagnostic Principles
tions may operate by any of the mechanisms
described for Mendelian (single-gene) con- For many of the genetic disorders described
ditions, and a given condition may involve in this chapter and in this text, clinicians
genes with different modes of inheritance. and investigators have set forth criteria that
Because of the complexity of these condi- allow a practitioner to arrive at a secure di-
tions, geneticists have developed mathemati- agnosis. The idea of developing these criteria
cal models to study genetic effects in these arose in the 1980s as gene linkage studies
disorders. Some of the important concepts progressed. It became clear to both clini-
related to multifactorial inheritance are dis- cians and scientists that in order for anyone
cussed in the following paragraphs. to attempt to map a gene, there had to be
Multifactorial conditions are often a consensus on who was affected and who
thought of in the context of a normal curve was not. The diagnostic criteria for NF1
of susceptibility, with both genes and the illustrate this principle. In 1987, at a Na-
environment capable of contributing sus- tional Institutes of Health (NIH) conference
ceptibility. There may be a threshold above on NF1 and NF2, criteria were proposed
50 BACKGROUND
FIGURE 3.8. A liability distribution for a multifactorial disease in a population. To be affected with
the disease, an individual must exceed the threshold on the liability distribution. This figure shows
two thresholds, a lower one for males and a higher one for females. From Jorde, Carey, Bamshad, and
White (2003). Copyright 2003 by C.V. Mosby, Inc. Reprinted by permission.
for making the diagnosis of this condition. needs to be evaluated. The concept of diag-
Table 3.2 presents these criteria. The basic nostic criteria is emphasized here simply to
premise is that if a patient’s manifestations underscore the subjective nature and occa-
fulfill the required items, a clinician can sional difficulty of arriving at the diagnosis
settle upon a highly secure diagnosis of the of a genetic disorder or syndrome. This con-
condition (NIH Consensus Development cept is further discussed below in regard to
Conference, 1988). Diagnostic criteria are syndromes (and, later, to behavioral pheno-
not widely available or established for many types). Diagnosis is often considerably more
other genetic conditions. However, in certain difficult for multifactorial conditions (e.g.,
circumstances (e.g., Apert syndrome) diag- see discussion in Goldstein, Schwebach, &
nostic criteria are not really necessary, since Cunningham, Chapter 6, this volume).
the distinctiveness of the pattern is clear-cut.
For conditions in which the diagnosis can be
Syndrome Diagnosis
made on a molecular basis (e.g., Prader–Wil-
li syndrome), diagnostic checklists or crite- The term syndrome is utilized in a specific
ria are not needed as much for diagnosis, but way in the field of medical genetics. It re-
are still useful to help a clinician decide who fers to a recognizable and consistent pat-
TABLE 3.2. NIH Consensus Statement: the clinician has the appropriate index of
Diagnostic Criteria for NF1 suspicion; ordering the chromosome study
The diagnostic criteria for NF1 are met in an confirms the diagnosis. As mentioned earli-
individual if two or more of the following are er, if one is considering a microdeletion syn-
found: drome, the appropriate chromosome study
•• Six or more café au lait macules of over (including FISH) needs to be performed. By
5 mm in greatest diameter in prepubertal contrast, if the condition in question pos-
individuals and over 15 mm in greatest sesses relatively consistent features (e.g., as
diameter in postpubertal individuals. the multiple café au lait spots of NF1), and
•• Two or more neurofibromas of any type or diagnostic criteria are available to establish
one plexiform neurofibroma. the diagnosis, the diagnostic reasoning pro-
•• Freckling in the axillary or inguinal regions.
•• Optic glioma.
cess can be fairly straightforward. Condi-
•• Two or more Lisch nodules (iris hamartomas). tions familiar in childhood may be harder
•• A distinctive osseous lesion such as sphenoid to recognize in adulthood, as the typical
dysplasia or thinning of the long bone cortex features may change with age; thus it is im-
with or without pseudoarthrosis. portant to obtain information about how
•• A first-degree relative (parent, sibling or phenotype changes with age.
offspring) with NF1 by the above criteria. One of the important points in this dis-

Note. From NIH Consensus Development Conference cussion is that the concept of a syndrome
(1988). encompasses a multiplicity of manifesta-
tions, most of which are variable within the
constellation. In chromosome syndromes
tern of multiple manifestations known to in general, and in the syndromes discussed
have a specific etiology. The cause is usually in this book in particular, some disorder of
a mutation of a single gene, a chromosome development is likely to be present. In that
alteration, or an environmental agent. In sense, intellectual disability (mental retar-
other words, a syndrome is a specific com- dation) is accepted widely as a component
plex phenotype that has a single cause. The manifestation of many of these syndromes.
notion of syndrome is related closely to the In the same sense, alterations in cognition,
concept of pleiotropy, described earlier. The personality, and behavior can be variable
diagnosis of malformation or developmental manifestations in many of these syndromes,
syndromes in general is a challenge, as over just like the more clearly defined manifesta-
1,000 syndromes involving multiple congen- tion of intellectual disability. This point is
ital anomalies are listed in catalogs and diag- the essence of the concept of behavioral phe-
nostic computer programs (see Jones, 2006; notype, which is discussed below.
Hennekam, Allanson, & Krantz, 2009).
In addition to knowledge of the more com-
mon disorders, the clinician who approaches Environmental Syndromes
the area of syndromology needs knowledge In addition to syndromes of single-gene or
and skill in the recognition of minor anoma- chromosome etiology, there exist several
lies of structure, which often provide phe- syndromes caused by teratogenic agents. A
notypic clues for a diagnosis. Thus, for ex- teratogen is an agent external to the fetus
ample, diagnosing Williams syndrome can that induces structural malformations,
be difficult in early childhood or infancy growth deficiency, or functional alterations
unless one is familiar with the physical char- during prenatal development. Although
acteristics of the face in the context of the teratogens cause only a small percentage of
developmental condition. Even such signs as developmental disabilities and birth defects,
curly hair and characteristic voice are part they are an important group because of the
of the component manifestations that are potential for prevention. In the neurobehav-
helpful in diagnosis. Since no individual fea- ioral arena, the most important and common
ture or manifestation is obligatory in almost condition is fetal alcohol syndrome (FAS).
any syndrome, one has to be familiar with This condition has a recognizable pattern of
the clinical variability in order to secure the malformation consisting of prenatal growth
diagnosis. The diagnosis of a chromosome deficiency (low birthweight and birth length),
syndrome can often be straightforward if postnatal growth deficiency (short stature,
52 BACKGROUND
failure to thrive), microcephaly, and a char- study on the learning profile is also needed.
acteristic pattern of minor facial anoma- Little is known about the adult phenotypes
lies (Streissguth, Clarren, & Jones, 1985; in the teratogenic syndromes.
Thackray & Tifft, 2001). Although at first
glance the facial anomalies may seem non-
Benefits of Diagnosis
specific, taken together they are diagnostic
of FAS. These facial alterations include short Often the diagnosis of a neurodevelopmen-
palpebral fissures (small eyelids on horizontal disorder or dysmorphic syndrome is rel-
tal measurement), short upturned nose, long egated to the area of the exotic. However, as
philtrum (distance from nasal septum to has been emphasized throughout this chap-
upper lip), and relatively thin upper lip. The ter, diagnosis is important for the individual,
facial gestalt of older children with FAS is the family, and their medical practitioners.
quite characteristic, and a clinician who has Table 3.3 summarizes the benefits of mak-
experience with the disorder can make a se- ing the diagnosis of a genetic condition or
cure clinical diagnosis in the context of ma- syndrome. These can be illustrated in the di-
ternal alcohol abuse. The full syndrome oc- agnosis of Williams syndrome. Once a diag-
curs in 10–40% (depending on the study) of nosis has been established, and the deletion
infants whose mothers drink excessively and of the elastin gene has been confirmed with
abuse alcohol (Stratton, Howe, & Battaglia, FISH, recurrence risk counseling can occur;
1996). While the issue of whether moderate if a parent does not have Williams syndrome
or less frequently used amounts of alcohol (which is usually the case), the deletion is
cause adverse effects is controversial and not certainly de novo, and the recurrence risk
clear-cut, there is no question that maternal approaches that of the background risk. Pre-
alcoholism is a significant risk factor for this natal diagnosis with the FISH technique is
recognizable syndrome. possible in future pregnancies but is prob-
One of the component manifestations
of FAS is neurodevelopmental difficulty. A
majority of children with FAS have learning TABLE 3.3. Benefits of Diagnosis
disabilities, but some have enough develop- in a Genetic Condition or Syndrome
mental delay to be diagnosed as having in- •• Recurrence chance in genetic counseling.
tellectual disability/mental retardation. In The recognition of an established disorder of
addition to this, a behavioral phenotype has known etiology provides information on cause
been proposed in the literature (Mattson & and genetic aspects of the condition, including
Riley, 1998; Stratton et al., 1996). This par- chance of recurrence, reproductive options, and
ticular behavioral profile includes attention identification of at-risk relatives.
deficits, hyperactivity, an unusual degree of •• Prediction of prognosis. Each disorder has its
memory loss, and conduct problems (a de- own particular natural history and outcome.
ficiency in a person’s awareness of the con- Knowledge of the degree of disability that
occurs on average is often helpful to families.
sequences of his or her actions). Although
none of these components of the behavioral •• Appropriate laboratory testing and screening.
profile are specific, when taken together in Precise diagnosis can eliminate the need
the context of full FAS they appear to repre- for many tests frequently considered in the
evaluation of an individual with a developmental
sent a consistent manifestation of the overall disorder. Appropriate screening can be planned
pattern. according to natural history.
Some of the other teratogenic syndromes
•• Guidelines for management. Knowledge of
are known to involve developmental difficul- the natural history of a syndrome allows for
ties, but all require additional investigation the establishment of guidelines for routine
before any firm conclusions can be drawn. care, including suggestions for educational and
For instance, some children with the fetal vocational interventions.
valproate syndrome have been said to have •• Family support. In some families, the
autism (Christianson, Chesler, & Kromberg, knowledge of a condition helps in dealing with
1994), but this requires further investigation. the uncertainty of the situation. A diagnosis
Children with fetal hydantoin and isotretin- provides a biological basis for a condition, as
oin syndromes have also been recognized to well as an entrée to support groups, specialty
clinics, and other services.
have developmental disabilities, but further
ably not necessary, given the low recurrence culties. For many families, the diagnosis is
risk in sporadic cases. An individual with the entrée to a support group and specialty
Williams syndrome has a 50% risk of hav- clinics with concentrated expertise (e.g.,
ing a child with Williams syndrome with for Williams syndrome, a support group’s
each pregnancy and can consider a range website is www.williams-syndrome.org).
of reproductive options, including prenatal When families participate in support groups
diagnosis. Depending on the individual’s and specialty clinics, this provides pools of
developmental status, parenting skills must patients who often volunteer for studies of
also be considered. When other relatives are genotype–phenotype correlations, which in
at increased risk for the condition, it is also turn improves patient care. Also, although it
important to recommend genetic counseling seems self-evident that individuals with spe-
for other at-risk family members to preserve cial needs should be able to obtain services
their reproductive choices. based on those needs, in practice a diagnosis
In addition, the diagnosis helps the cli- often entitles these persons and their care-
nician in stating some predictions about givers to services previously denied without
prognosis—especially the neurodevelop- a diagnosis.
mental outcome, but also the natural history One important new area of diagnosis is
of the condition. Individuals with Williams predictive or presymptomatic diagnosis. Pre-
syndrome need a cardiac evaluation, due to symptomatic diagnosis is a diagnosis based
a 60% occurrence of heart defects (espe- on DNA testing before symptoms are pres-
cially supravalvular aortic stenosis). In addi- ent. An example of presymptomatic diagno-
tion, a higher index of suspicion for hearing sis is testing for Huntington disease (HD).
loss, visual difficulties, urinary tract infec- The genetic test is fairly straightforward,
tions, and hypertension should occur, and using a polymerase chain reaction assay to
this should further modify the primary care determine the number of cytosine–adenine–
practitioner’s health supervision plan. Cli- guanine repeats in the HTT gene. Individu-
nicians have developed management guide- als with 40 or more CAG repeats develop
lines, also referred to as anticipatory guid- the symptoms of HD. The disease typically
ance, for common genetic conditions (e.g., manifests itself in a person’s 30s or 40s, and
Cassidy & Allanson, 2010). These guide- includes progressive chorea and dementia,
lines are usually organized by the age of the with death typically occurring 10–15 years
individual. A diagnosis makes it possible to after diagnosis. It is an autosomal dominant
avoid unnecessary laboratory testing. A per- condition, so children of a gene mutation
son with Williams syndrome who has devel- carrier have a 50% risk of developing the
opmental delay should not require any meta- condition, with age-specific penetrance that
bolic testing or neuroimaging—tests that are reaches 100% by late adulthood. Testing
frequently done in the diagnostic evaluation is generally only done in centers that offer
of a individual with this presentation. More- a protocol including genetic counseling,
over, knowledge of the natural history of neurological examination, and psychiatric
the developmental profile in Williams syn- evaluation and support. There are complex
drome at least allows for some initial steps psychosocial and ethical issues involved in
in planning educational and vocational in- presymptomatic testing for HD. Psychoso-
terventions. Although it is certainly true that cial issues include the availability of life-
a “cookbook”-type plan cannot be laid out, altering testing when no effective treatments
there is a profile of strengths and weaknesses are currently available; complex family is-
in individuals with Williams syndrome that sues, including survivor guilt; and the risk
can help the educator or therapist. Finally, of adverse psychological reactions in both
making a diagnosis of a specific condition counselees who test positive and those who
often helps a family with the experience of test negative. Ethical issues include the no-
uncertainty, as often a general diagnosis of a navailability of testing without counseling,
developmental disability conveys a sense of the possibility of insurance discrimination,
meaninglessness and confusion. A diagnosis testing in minors, and testing in situations
of a particular syndrome, even an uncom- where one family member’s results reveal
mon one, gives a biological basis for (and those of another family member. Testing in
often credibility to) the individual’s diffi- childhood is not recommended unless the
54 BACKGROUND
child has definite neurological symptoms concept then, we propose, should hold true
such as chorea or rigidity. for behavioral components.
Predictive diagnosis is similar to presymp- In the literature, the term behavioral phe-
tomatic diagnosis, but in this case the test notype is used without necessarily clarify-
predicts a susceptibility rather than certain- ing whether it refers to a psychological/
ty of symptoms. An example of predictive cognitive profile, a behavioral disorder, or
diagnosis is testing for multiple endocrine a personality trait (Turk & Hill, 1995). In
neoplasia, type 2. This condition poses a this context, we propose a modification of
risk in childhood for adrenal malignancies, the definition of the term suggested by Turk
and screening and treatment are available. and Hill. We posit that a behavioral phe-
Thus childhood testing is recommended. notype is a profile of behavior, cognition,
or personality that represents a component
of the overall pattern seen in many or most
Behavioral Phenotypes individuals with a particular condition or
in Medical Genetics syndrome. Although the profile may not be
specific, it is consistent in the syndromic pat-
The term behavioral phenotype has been tern. The challenge for the next decades (as
used for the last 20 years in the fields of child stated in many of the chapters in this book)
psychiatry and medical genetics to refer to is continued documentation of these param-
the neurobehavioral aspects of a condition. eters with state-of-the-art tools. The diag-
There is no consensus on its definition, and nosis of a dysmorphic syndrome needs to be
it is used by different people to mean dif- rigorous and clear-cut, and the documenta-
ferent things. Turk and Hill (1995) provide tion of the neurodevelopmental and neurop-
an excellent summary of the issues in their sychological profile demands the same cur-
review. These authors assert that “a num- rent strategies. At present, a glance through
ber of conditions, recognizable by a com- review papers, like those of Turk and Hill
mon physical phenotype, single gene defect (1995) and Flint and Yule (1994), gives one
or chromosomal abnormality, seem also to the impression that there is not much speci-
have a constellation of behaviors or cognitive ficity to the behavioral patterns described
anomalies which are characteristic” (p. 105). in the literature reviewed. However, this
Flint and Yule (1994) take a stricter view of perusal is not very different from one’s first
this concept and require that before the term glance through a catalog of listed facial fea-
is used, there must be a distinctive behavior tures and minor anomalies in chromosome
that occurs in almost every case and rarely syndromes. Yet the consistency in the facial
in other conditions. However, we agree with features of individuals of the same age with
Turk and Hill that this more restrictive view chromosome disorders illustrates the repro-
is not applicable to the inclusion of nonbe- ducibility of these syndromes. Recognition
havioral manifestations in the definition of of facial features and documentation of their
syndromes. For example, the atrioventricular pattern are often difficult without tools for
canal defect seen in 20–30% of individuals quantification. These same kinds of issues
with Down syndrome is relatively character- apply to documentation in the neurobe-
istic, as almost two-thirds of individuals with havioral realm, especially in the profiles of
this defect have Down syndrome. However, behavioral disorders and personality traits.
there are clearly other causes of this defect The principles are the same; just as the fa-
other than trisomy 21, and not all patients cial features differ from those of the family
with Down syndrome have it. Similarly, only background in such conditions as Williams
about 20% of individuals with Turner syn- syndrome and Down syndrome, there is an
drome have a left-sided obstructive lesion of alteration of the biological basis of behav-
the heart, and the overwhelming majority of ior and personality beyond the family back-
cases who have this heart lesion do not have ground in these conditions. Shalev and Hall
Turner syndrome. Thus, as illustrated here, (2004) have recently proposed a behavioral
most clinicians would not require the physi- pattern profile. This tool consists of 12 cate-
cal defects of the heart to occur completely gories of behavioral features and is intended
consistently and specifically before includ- to facilitate a standardized collection of be-
ing them as part of the syndrome. The same havioral data in a clinical setting.
Table 3.4 lists dysmorphic syndromes that ics to dissect this complex phenotype first re-
have been found to have a relatively specif- quired careful study of the reading disability
ic or characteristic behavioral profile. The phenotype through state-of-the-art cognitive
chromosomal location or identified gene is science (Pennington, 1997). Future prog-
listed as well. The reader is referred to the ress in understanding genotype–phenotype
above-cited review papers. Moreover, the relationships in neurobehavioral disorders
chapters in this text summarize the behav- such as autism (Fisch, 2008) or Tourette
ioral profiles of several of these syndromes. syndrome is likely to rely on an interplay of
A behavioral phenotype is generally de- approaches from psychology, genetics, neu-
fined by beginning with a sample of subjects roimaging, and other disciplines.
with a specific dysmorphic syndrome and
then studying specific cognitive, affective, or
behavioral characteristics, as compared to Conclusion
those of a relevant control group. Some syn-
dromes, such as Williams and Prader–Willi The field of medical and molecular genetics
syndromes, have been associated with chro- has blossomed in the last two decades, with
mosomal regions as well as with behavioral a concomitant interest in genetics among
patterns. A complementary approach has primary care practitioners and specialists
made use of several large affected families, in other fields. The basic paradigm provides
extensive cognitive testing, and DNA mark- the potential for a newer understanding of
ers to find linkages for components of a com- human disease pathogenesis, similar to the
plex cognitive phenotype—developmental advances made in infectious diseases and
dyslexia. In six large families containing immunology in the early 20th century. The
94 adults affected with reading disability principles necessary to apply this approach
(documented in childhood), defective pho- in the clinical setting can be mastered with
nological awareness was linked to markers some effort and are valuable in the care of
on chromosome 6, and defective single-word patients with neurodevelopmental disor-
reading was linked to chromosome 15 (Grig- ders. The diagnosis of genetic disorders
orenko et al., 1997). Success in using genet- and syndromes is of vital importance to
TABLE 3.4. Dysmorphic Syndromes Thought to Have a Characteristic

Behavioral Phenotype
Syndrome Cause
Chromosome
Williams syndrome 7q1 microdeletion
Velocardiofacial/DiGeorge syndrome 22q11 deletion
Prader–Willi syndrome 15q11–13 microdeletion a
Angelman syndrome 15q11–13 microdeletion a
Smith–Magenis syndrome 17p11 microdeletion
Down syndrome Trisomy 21
Klinefelter syndrome 47,XXY
Monogenic
Neurofibromatosis type 1 (NF1) Mutation in NF1 gene at 17q11.2
Noonan syndrome Mutation in PTPN11 gene at 12q24.1 (plus at least
four other genes—genetically heterogeneous)
Fragile X syndrome Mutation in FMR1 gene at Xq27.3
Rett syndrome Mutation in MECP2 gene on Xq28
de Lange syndrome Mutation in NIPBL gene on 5p13.1
Environmental
Fetal alcohol syndrome (FAS) Maternal alcohol abuse
Fetal valproate syndrome Maternal use of valproate
a Imprintable genes (see text). See also Dykens, Cassidy, and DeVries (Chapter 25, this volume).
56 BACKGROUND
patients, their families, and care providers. ton, D., Byrne, J., Carey, J. C., et al. (1997). Eval-
The relatively recently proposed concept of uation of mental retardation: Recommendations
behavioral phenotype fits quite well into of a consensus conference. American Journal of
the paradigm of medical genetics. Ongoing Human Genetics, 72, 468–477.
de Vries, B. B. A., Winter, R., Schinzel, A., & van
work utilizing current techniques in pheno-
Ravenswaaij-Arts, C. (2003). Telomeres: A diag-
type analysis, medical genetics, and neurop- nosis at the end of the chromosomes. Journal of
sychology will be necessary to delineate the Medical Genetics, 40, 385–398.
behavioral profiles, specific or nonspecific, Donnai, D. (2002). Genetic services. Clinical Ge-
of various syndromes. An understanding of netics, 61(1), 1–6.
the biological basis of the neurodevelopmen- Edelman, L., & Hirschhorn, K. (2009). Clinical
tal aspects in these genetic conditions can utility of array CGH for detection of chromo-
provide fresh insight into well-known and some imbalances associated with mental retarda-
common symptomatic disorders, such as tion and multiple congenital anomalies. Annals
learning disabilities and autism. of the New York Academy of Sciences, 1151,
157–166.
Faraone, S. V. (2004). Genetics of adult attention-
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Chapter 4
Neuroimaging and Genetic Disorders
Shelli R. Kesler
Elizabeth Wilde
Jennifer L. Bruno
Erin D. Bigler
Neuroimaging methods allow safe and ef- ment of brain function by detecting blood
fective measurement of in vivo neurobio- flow differences (Logothetis, 2008), but it
logical status and are widely used to study can be challenging in children with genetic
brain–behavior relationships in children, as disorders that are associated with significant
well as adults. Neuroimaging studies can intellectual disability, due to the increased
provide insight regarding the specific neural cognitive-behavioral demands of fMRI ac-
systems that subserve the cognitive deficits quisition. White matter pathway coherence
associated with various syndromes and pa- and fiber tracking are made possible by dif-
thologies, including genetic disorders. Since fusion tensor imaging (DTI), which relies
the first edition of this volume was pub- on water diffusion near myelinated axons
lished, there have been significant advances (Hua et al., 2009) and provides measures
in neuroimaging technology, stimulating a of microstructural integrity (e.g., frac-
substantial increase in gene–brain–behavior tional anisotropy [FA]). MR susceptibility-
research. Whereas previously we were only weighted imaging (SWI) uses both phase
able to include neuroanatomical or brain and magnitude images to provide increased
morphological information associated with visualization of brain tumors, microbleeds,
various childhood genetic syndromes, there and other vascular abnormalities, as well as
have since been multiple studies involving diffuse axonal injury associated with trauma
measurements of functional brain activa- and neurodegenerative pathologies (Sehgal
tion, white matter pathway coherence, and et al., 2006; Thomas et al., 2008). MR spec-
neurometabolites. troscopy (MRS) can detect neurometabolite
Structural or volumetric magnetic reso- levels, which putatively provide metrics of
nance imaging (MRI) can provide three- neuronal and axonal integrity, membrane
dimensional, high-resolution images for turnover, and neurotransmitter function
qualitatively identifying gross pathology, as (Gujar, Maheshwari, Bjorkman-Burtscher,
well as quantitative, tissue-specific (white & Sundgren, 2005). It is now even possible
matter, gray matter, and cerebrospinal fluid to use functional neuroimaging techniques,
[CSF]) brain volume measurements (Kenne- including fMRI, to measure brain activation
dy, Haselgrove, & McInerney, 2003). Func- in real time (deCharms, 2008). All of these
tional MRI (fMRI) allows in vivo assess- MR methods significantly improve the sen-
58
Neuroimaging and Genetic Disorders 59
sitivity and specificity with which research- tabase, developed by scientists at Johns Hop-
ers can identify neurodevelopmental mecha- kins University School of Medicine. Despite
nisms and trajectories associated with the the growing number of genetic syndromes
cognitive-behavioral phenotypes of various that are being identified, this chapter fo-
genetic disorders. These data are vital for cuses on the most common genetic disorders
guiding, developing, and even implementing affecting children. The chapter also briefly
syndrome-specific treatments and interven- discusses neuroimaging findings from cer-
tions. tain multifactorial syndromes that may have
The above-mentioned neuroimaging genetic underpinnings resulting in inherited
methods all rely on MR physics and prin- vulnerability for the syndrome. These syn-
ciples. They are implemented by using pow- dromes include attention-deficit/hyperactiv-
erful magnetic fields and radiofrequency ity disorder (ADHD) and pervasive devel-
pulses to manipulate the nuclear magnetic opmental disorders (PDDs), such as autism.
resonances of hydrogen atoms, which are OMIM numbers for individual syndromes
abundant in human tissue. MR techniques are included when applicable.
are noninvasive, though some involve the in-
jection of contrast agents to enhance certain
image targets. Unlike computed tomography Craniofacial Syndromes
(CT), MRI does not use radiation and is
Apert Syndrome (OMIM #101200)
therefore a very low-risk procedure. How-
ever, patients with ferrous metal implants Apert syndrome is characterized by cranio-
or biomedical devices cannot undergo MR synostosis, which causes facial abnormalities
techniques. Several sources are available and can affect the development of the brain,
that describe the details of MR neuroim- leading to cognitive impairments. Imaging
aging techniques such as fMRI, DTI, and studies of children with Apert syndrome
MRS, including works by Huettel, Song, suggest an increased incidence of ventriculo-
and McCarthy (2008), Filippi (2009), Jez- megaly, hypoplasia of the corpus callosum,
zard, Matthews, and Smith (2003), Mori cavum vergae, hypoplasia of the septum pel-
(2007), and Gujar and colleagues (2005). lucidum, arachnoid cysts, and hydrocepha-
Other neuroimaging techniques, including lus (Collmann, Sorensen, & Krauss, 2005;
single-photon emission computed tomogra- Quintero-R ivera et al., 2006; Yacubian-
phy, positron emission tomography (PET), Fernandes et al., 2004, 2005) (Figure 4.1).
and near-infrared spectroscopy, have also
been utilized to provide valuable informa-
Down Syndrome (OMIM #190685)
tion regarding neurobiological status in
various populations. These are described Resulting from trisomy of chromosome 21,
in Huettel and colleagues (2008) and Jez- Down syndrome is the most common cause
zard and colleagues (2003). Although these of intellectual impairment. Children with
other imaging methods are sometimes used Down syndrome are at increased risk for
to assess children with genetic disorders, reduced total brain volumes (Pinter, Eliez,
the primary imaging tool for this purpose is Schmitt, Capone, & Reiss, 2001b) and for
MR, and thus MR-based techniques are the smaller regional volumes, including those
focus of this chapter. Only the most recent of the hippocampus and cerebellum (Pinter,
neuroimaging findings from studies of child- Brown, et al., 2001; Pinter, Eliez, et al.,
hood genetic disorders that involve pediatric 2001). Subcortical gray matter volumes may
human participants are discussed. be enlarged (Pinter, Eliez, et al., 2001). At-
Genetic technologies have also advanced rophy of the corpus callosum has also been
significantly in the past 10-plus years, al- noted (Kieslich, Fuchs, Vlaho, Maisch, &
lowing identification of new syndromes and Boehles, 2002; Murphy, Brenner, & Ann
further specification of gene products and Lynch, 2006) (Figure 4.2). An MRS study
their functions in the brain and other or- of children with Down syndrome demon-
gans. Comprehensive information regarding strated decreased levels of N-acetylaspar-
human genes and their phenotypes is avail- tate (NAA) and glutamine/glutamate in the
able on the World Wide Web via the Online frontal lobes (Smigielska-Kuzia & Sobaniec,
Mendelian Inheritance in Man (OMIM) da- 2007).
60 BACKGROUND
Velocardiofacial Syndrome
(OMIM #192430)
Velocardiofacial syndrome (VCFS) is a rela-
tively common congenital disorder associat-
ed with cardiac and facial abnormalities, as
well as learning disabilities and significant
risk for serious neuropsychiatric disorders,
including schizophrenia (Gothelf, 2007).
Neuroimaging studies have demonstrated
reduced total brain volumes (Bird & Scam-
bler, 2000; Eliez, Antonarakis, Morris, Da-
houn, & Reiss, 2001; Eliez, Schmitt, White,
FIGURE 4.1. Apert syndrome: Ventriculomega- & Reiss, 2000) and reduced regional brain
ly and corpus callosum hypoplasia—MRI sagit- volumes, including those of the thalamus
tal plane and T1 acquisition (A), and axial plane (Bish, Nguyen, Ding, Ferrante, & Simon,
and T1–inversion recovery (IR) acquisition (B). 2004), hippocampus (Debbane, Schaer,
Cavum vergae and arachnoid cyst in the posterior Farhoumand, Glaser, & Eliez, 2006; De-
fossa—MRI in sagittal plane and T1 acquisition
(C), and axial plane and T1-IR acquisition (D).
boer, Wu, Lee, & Simon, 2007; Kates et
Septum pellucidum hypoplasia—MRI in coronal al., 2006), cerebellum (Bish et al., 2006;
plane and T2 acquisition (E). Arachnoid cyst in Eliez, Schmitt, White, Wellis, & Reiss,
posterior fossa—MRI in axial plane and T1-IR 2001), superior temporal gyrus (Eliez, Bla-
acquisition (F). From Yacubian-Fernandes et al. sey, Schmitt, et al., 2001), parieto-occipital
(2005). Copyright 2005 by Arquivos de Neuro- region (Campbell et al., 2006), corpus cal-
Psiquiatria. Reprinted by permission. losum (Machado et al., 2007; Shashi et al.,
2004), and posterior fusiform gyrus (Gla-
ser et al., 2007). Caudate asymmetry and
enlargement have been repeatedly observed
in children with VCFS (Campbell et al.,
2006; Eliez, Barnea-G oraly, Schmitt, Liu,
& Reiss, 2002; Kates et al., 2004; Sugama
et al., 2000). Kates and colleages (2006)
also demonstrated amygdalar enlargement.
Simon and colleagues (2005) found a pro-
file of reduced and enlarged regional gray
matter, CSF, and white matter volumes, as
well as increased and decreased white mat-
ter FA, using voxel-based morphometry
and DTI. Kates and colleagues also dem-
onstrated reduced white matter volumes in
parietal and temporal regions associated
with VCFS (Kates et al., 2001), as well as
in frontal regions (Kates et al., 2004). Cor-
tical thickness and shape abnormalities
have been consistently noted in children
with VCFS (Bearden et al., 2007; Gothelf,
Schaer, & Eliez, 2008). fMRI studies sug-
gest an altered pattern of frontal and
parieto-occipital activation during working
FIGURE 4.2. Down syndrome: General brain
atrophy, callosal dysplasia, cerebellar hypopla- memory (Kates et al., 2007) (Plate 4.1), as
sia (sagittal T2-weighted MRI). From Kieslich, well as altered activation of the left parietal
Fuchs, Vlaho, Maisch, and Boehles (2002). regions during arithmetic (Eliez, Blasey,
Copyright 2002 by Sage Publications. Reprinted Menon, et al., 2001) and response inhibi-
by permission. tion tasks (Gothelf et al., 2007).
Williams Syndrome disorder (usually ataxia of gait and/or trem-

(OMIM #194050) ulous movement of limbs); and behavioral
uniqueness, including any combination of
Williams syndrome (WS) is a neurogenetic
frequent laughter/smiling, apparent happy
disorder characterized by facial, cardiac,
demeanor, and easily excitable personality.
and other physical abnormalities as well as
In addition, there is often delayed, dispro-
neurocognitive impairments, particularly portionate growth in head circumference,
in visual–spatial skills (Reiss et al., 2004). usually resulting in microcephaly (≤ 2 stan-
WS has been associated with a reduction in dard deviations of normal fronto-occipital
brain volume (Faravelli et al., 2003; Reiss et circumference by age 2 years), which is more
al., 2004) and with regional abnormalities pronounced in individuals with 15q11.2–13
in the parietal lobe volumes (Boddaert et al., deletions. Seizures, usually with an onset
2006; Campbell et al., 2009) (see Paterson before 3 years of age, are common. Char-
& Schultz, 2007, for a review). In addition to acteristic abnormal electroencephalographic
parieto-occipital volume reductions, Camp- patterns are also often evident in the first 2
bell and colleagues (2009) demonstrated years of life.
decreased basal ganglia, left putamen/glo- Individuals with AS are generally thought
bus pallidus, thalamus, and right posterior to have normal brain imaging studies, al-
cingulate gyrus volumes. They also noted though occasional abnormalities have been
significantly increased gray matter in the reported. The most common conventional
frontal lobes, anterior cingulate gyrus, left MRI or CT change, when any is detected,
temporal lobe, and bilateral anterior cingu- is mild cortical atrophy and/or mildly de-
late white matter (Plate 4.2). Reiss and col- layed myelination of cerebral white matter
leagues (2004) also demonstrated enlarged (Harting et al., 2009; Leonard et al., 1993).
volumes in amygdala, superior temporal Several studies using more advanced imag-
gyrus, orbital prefrontal cortex, and dorsal ing applications such as PET have reported
anterior cingulate. Cerebellar enlargement developmental dysregulation of gamma-
may be present very early in children with aminobutyric acid type A (GABA(A)) in the
WS (Jones et al., 2002). WS may be asso- cerebellar cortex and cerebellum of patients
ciated with reductions in corpus callosum with various genotypic expressions of AS,
thickness (Luders et al., 2007) and volume but these studies are limited by small sample
(Tomaiuolo et al., 2002) as well as abnor- sizes, given the uncommon nature of the dis-
malities in gyrification and sulcal morphom- order (Asahina et al., 2008; Holopainen et
etry (Faravelli et al., 2003; Gaser et al., al., 2001).
2006; Van Essen et al., 2006) (Plate 4.3). Recent studies using additional advanced
fMRI studies of children with WS indicate neuroimaging techniques, including DTI,
reduced prefrontal–striatal activation during quantitative MRI, and magnetization trans-
response inhibition (Mobbs, Eckert, Mills, fer imaging, have revealed abnormalities in
et al., 2007), reduced temporal lobe and in- deletion-positive individuals with AS (Peters
creased right amygdala activation during au- et al., 2008). Despite apparently normal im-
ditory processing of music and noise (Levitin aging on conventional sequences, DTI re-
et al., 2003), and significantly reduced visual vealed reduced FA and increased apparent
and parietal cortex activation during global diffusion coefficient (ADC) in white matter
visual processing (Mobbs, Eckert, Menon, pathways involving the frontal, temporal,
et al., 2007). parietal, and limbic areas in patients with
AS relative to control children (Peters et al.,
2008). Plate 4.4 illustrates DTI tractography
Imprinting Disorders of the corpus callosum in a group of children
and adolescents with AS in contrast to a typ-
Angelman Syndrome
ically developing adolescent, highlighting
(OMIM #105830)
aberrant fiber patterns or paucity of fibers
Symptoms associated with Angelman syn- in the individuals with AS. The arucate and
drome (AS) include functionally severe de- uncinate fasciculi reveal additional notable
velopmental delay; movement or balance differences (Plate 4.5 and 4.6) that may re-
62 BACKGROUND
late to deficits in language, cognition, and demonstrated in the posterior limb of the
behavior. Quantitative MRI has also high- internal capsule bilaterally, the right frontal
lighted reduced volumes in several regions, white matter, and the splenium of the corpus
including the cerebellum, cerebrum, basal callosum (Yamada, Matsuzawa, Uchiyama,
ganglia, and corpus callosum, in individuals Kwee, & Nakada, 2006).
with AS in comparison to age- and gender- PET studies have revealed altered GABA(A)
comparable typically developing children receptor number or composition, predomi-
(Plate 4.7), as well as subtle cortical thin- nantly in the cingulate, frontal, and temporal
ning in temporal, frontal, and occipital re- neocortices and insula, in a small sample of
gions, primarily in the left hemisphere (Plate patients with PWS as compared to a control
4.8) (Peters et al., 2009). It has not yet been sample (Lucignani et al., 2004). PET stud-
determined whether these abnormalities are ies using [18F]fluorodeoxyglucose in children
present in other molecular subtypes of AS. with PWS have revealed decreased glucose
metabolism in the right superior temporal
gyrus and left cerebellar vermis—regions
Prader–Willi Syndome
that are associated with taste perception/
(OMIM #176270)
food reward and cognitive and emotional
Patients with Prader–Willi syndrome (PWS) function, respectively. Increased metabolism
have a deletion in an imprinted region on was observed in the right orbitofrontal, bi-
paternal chromosome 15 (15q11–13), a ma- lateral middle frontal, right inferior frontal,
ternal disomy for this segment, or (rarely) a left superior frontal, and bilateral anterior
chromosomal imprinting center deletion that cingulate gyri, right temporal pole, and left
gives rise to suppression of the equivalent pa- uncus—regions that are involved in cogni-
ternal genes. It is characterized by a complex tive functions related to eating or obsessive–
clinical picture that involves cognitive im- compulsive behavior (Kim et al., 2006).
pairment; behavioral abnormalities such as Finally, fMRI studies have demonstrated in-
hyperphagia, seeking and hoarding food, and creased activation in the hypothalamus and
eating of nonfood substances; poor impulse orbitofrontal cortex—components of neu-
control; impaired responses to somatic pain; ral circuits known to be involved in hunger
and physical manifestations including short and motivation—in response to high- ver-
stature, obesity, and hypogonadism. Studies sus low-calorie foods and in comparison to
of patients with PWS have highlighted pitu- controls (Dimitropoulos & Schultz, 2008).
itary abnormalities, including a reduction In another study, individuals with PWS had
in pituitary height or a complete absence of an increased blood-oxygen-level-dependent
the posterior pituitary bright spot in some response in the ventromedial prefrontal cor-
patients, implicating central hypothalamic– tex compared with normal-weight controls
pituitary dysfunction that may be related to when viewing pictures of food; this finding
the clinical phenotype (Iughetti et al., 2008; supports the possibility that an increased re-
Miller et al., 2008). In addition, convention- ward value for food may underlie the exces-
al MRI studies have revealed intracranial sive hunger in PWS, and also supports the
abnormalities in individuals with PWS, in- significance of the frontal cortex in modu-
cluding ventriculomegaly, decreased volume lating the response to food (Miller et al.,
of brain tissue in the parieto-occipital lobe, 2007).
Sylvian fissure polymicrogyria, incomplete
insular closure (Miller et al., 2007), and
white matter lesions (Miller et al., 2006). Inherited Metabolic Disorders
Quantitative MRI studies have additionally
Phenylketonuria (OMIM #261600)
demonstrated smaller cerebellar volumes in
patients with PWS than in sibling controls Phenylketonuria (PKU) is an autosomal re-
(Miller et al., 2009). cessive disorder caused by a multiplicity of
Advanced imaging studies utilizing DTI mutations mapped to chromosome 12q22–
in small samples of patients with PWS have 24.1. Most cases of PKU are caused by a defi-
demonstrated higher diffusivity in the left ciency of phenylalanine hydroxylase (classic
frontal white matter and the left dorsome- type), but a deficiency of dihydropteridine
dial thalamus, whereas reduced FA was reductase may also be implicated more rarely
(malignant type). These deficiencies result in

the production of compounds that are toxic
to the developing brain. PKU may present in
the first year of life with insufficient growth,
retarded development, irritability, vomiting,
eczema, musty urine, and body odor.
Upon conventional imaging, diffuse signal
irregularites including white matter abnor-
malities (particularly on T2-weighted and
fluid-attenuated inversion recovery [FLAIR]
imaging) suggestive of delayed or defective
myelination are often reported in patients
with PKU, particularly in the parietal peria-
trial or periventricular white matter (Leuzzi
et al., 2007), though lesions extending to
frontal or subcortical white matter may be
apparent in more severely affected patients.
Subcortical cyst-like lesions may also be ap-
parent. Calcification in the basal ganglia,
including the globi pallidi, and frontal sub-
cortical regions may appear on CT or T1-
weighted MRI. Adherence to a strict diet
may lead to resolution of these abnormalities
to varying degrees in some patients after a
few months on MRI (Cleary et al., 1995).
FIGURE 4.3. Conventional imaging (top, T1-
MRS findings may hold particular clini- weighted; middle, T2-weighted; bottom, FLAIR)
cal value in the diagnosis and therapeutic demonstrating the classic pattern of parieto-
monitoring of PKU, as MRS is able to detect occipital abnormalities in an adolescent with
elevated brain concentrations of phenyla- ALD. The progression of the disease is evident
lanine in the affected white matter (Leuzzi within a 1-year span of time, such that the T2-
et al., 2000). Given the involvement of my- weighted and FLAIR images demonstrate involve-
elin, diffusion-weighted imaging and DTI ment of the frontal lobes, in addition to more ex-
may contribute additional information to tensive involvement in the parieto-occipital areas
assessing and monitoring the white matter by the second time point.
changes in patients with PKU (Ding et al.,
2008; Kono et al., 2005; Peng, Tseng, Chien,
Hwu, & Liu, 2004; Vermathen et al., 2007), years after onset of symptoms), and because
particularly in patients whose white matter treatments such as hematopoietic stem cell
appears normal on conventional imaging or transplantation (HSCT) may lead to stabi-
whose abnormalities are not as obvious. lization or reversal of clinical and MRI ab-
normalities (see Figure 4.4) if performed at
an early stage of the disease (Aubourg et al.,
Adrenoleukodystrophy
1990; Baumann et al., 2003; Shapiro et al.,
(OMIM #300100)
2000), advanced imaging modalities such
Adrenoleukodystrophy (ALD) is a disorder as MRS and DTI have recently been inves-
characterized by adrenal insufficiency and tigated to provide information for decision
rapid demyelination of cerebral white matter making with respect to HSCT and other
and is caused by mutation in the ALD gene potential treatments. For example, MRS
on chromosome Xq28. Parieto-occipital has been shown to be more sensitive than
white matter is the most commonly affect- MRI in detecting metabolic abnormalities,
ed area of brain tissue, but damage may be axonal damage or loss, and incipient demy-
present or progress into other white matter elination, even in normal-appearing white
regions as well (Figure 4.3). matter (Kruse et al., 1994; Pouwels et al.,
Because the course of this disease is par- 1998; Salvan et al., 1999), and has been used
ticularly aggressive (death may ensue in 3–5 to predict lesion progression (Eichler et al.,
64 BACKGROUND
FIGURE 4.4. Conventional serial imaging (top, T2-weighted; bottom, FLAIR) from a child with ALD
who is a sibling of the adolescent represented in Figure 4.3. This child was diagnosed much earlier in
the course of his disease than his sibling and received HSCT just after the initial imaging. Although
subtle progression of the disease is evident over time in both the T2-weighted and FLAIR images in the
splenium of the corpus callosum, the relative lack of progression of the disease is evident in this child,
as compared to the more typical course represented in Figure 4.3.
2002). In addition, DTI may assist in defin-

ing the extent of white matter involvement,
predicting disease activity and progression,
and characterizing affected white matter
areas. Initial observations suggest that re-
duced ADC values at the leading edge of a
white matter lesion may predict rapid pro-
gression of the disease (Melham & Golay,
2005).
Neuronal Ceroid Lipofuscinosis

(OMIM #256730 and Others)
Neuronal ceroid lipofuscinosis (NCL) is in-
herited as an autosomal recessive trait, and
is a progressive and fatal lysosomal storage
disease characterized by the accumulation of FIGURE 4.5. MR images of a patient with ju-
ceroid lipofuscin in neuronal and extraneu- venile NCL (NCL3) show visually detectable
ronal cells. Clinical features include mental progressive cerebral and cerebellar atrophy. T2-
and motor deterioration, loss of vision, sei- weighted axial image (a) and T1-weighted sagit-
zures, ataxia, and myoclonus. There are sev- tal image (d) at the age of 12 years show nor-
eral variants, but the infantile type (NCL1) mal CSF spaces. T2-weighted axial images (b, c)
may be particularly aggressive in the early and T1-weighted sagittal image (e) at the age of
years. 17 years demonstrate enlarged lateral and third
Conventional MRI in several variants of ventricles as well as enlarged cerebral sulci (b, c).
NCL commonly demonstrates diffuse cere- Note that the corpus callosum is very thin and
the vermis is reduced (e). Note also that the sig-
bral and cerebellar atrophy, T2-hyperinten- nal intensity of the thalamus is inhomogeneous
sity of the lobar white matter, and thinning (b). From Autti, Hämäläinen, Mannerkoski, Van
of the cerebral cortex (Autti, Raininko, Van- Leemput, and Aberg (2008). Copyright 2008 by
hanen, & Santavuori, 1996; D’Incerti, 2000; Springer. Reprinted by permission.
Sayit et al., 2002; Seitz et al., 1998) (Figure
4.5). Hypointensity in the thalamus has also
been reported (Autti et al., 1996, 1997; Seitz ease produces increased vascular flow on the
et al., 1998; Vanhanen, Raininko, Autti, luminal wall; this may in turn create a hy-
& Santavuori, 1995), though not consis- perplasia due to noninflammatory response.
tently (Petersen, Handwerker, & Huppertz, This thickening produces a stenosis, which
1996). increases the velocity of flow through the
Advanced imaging in combination with stenosis until thrombosis or embolus leads
conventional MR may again play a role in to occlusion. These infarctions are classi-
monitoring and therapeutic intervention, as cially located deep within the white matter
MRS has detected abnormal findings before of the centrum ovale and are seen as a series
clinical manifestations of the disease and of bright areas on T2-weighted and FLAIR
also has shown progressive deterioration of imaging (Zimmerman, 2005). Other factors
neurometabolism after onset (Vanhanen et contributing to the pathogenesis of SCD-
al., 2004). In addition, it may help to dif- related imaging abnormalities include severe
ferentiate NCL from other neurometabolic anemia, hypoxia, and acute medical events
disorders (Seitz et al., 1998). (Debaun, Derdeyn, & McKinstry, 2006).
Medium- or small-vessel disease may result
from these mechanisms, and the resulting
Sickle Cell Disease (OMIM #603903)
vascular lesions may be clinically significant
Sickle cell disease (SCD) is a recessive ge- or “silent.” When severe occlusive disease oc-
netic disorder, which is caused by a point curs, collateral blood vessels may arise from
mutation resulting in the substitution of the posterior circulation’s posterior cerebral
valine for glutamic acid at the sixth posi- artery branches, creating a moyamoya-like
tion in the beta chain of hemoglobin. Ce- condition on arteriography.
rebral ischemic injury is perhaps the most In addition to MRI, diffusion-weighted
devastating cerebral complication of SCD, imaging has become widely used clinically,
though significant complications can occur due to its sensitivity in demonstrating acute
in many organs. Neuroimaging abnormali- infarction (Zimmerman, 2005). Transcra-
ties in SCD are related to the greater like- nial Doppler has also been used to examine
lihood of vascular lesions and strokes in changes in blood flow, which has therefore
these patients, most prominently involving rendered this technique an important initial
the periventricular regions of the brain (see step in screening patients at risk for SCD-
Figure 4.6). The majority of children with related cerebrovascular disease (Abboud et
SCD who develop stroke have arteriopa- al., 2004; Kwiatkowski et al., 2009). MR
thy affecting the terminal internal carotid angiography has also been employed rou-
artery or proximal middle cerebral artery. tinely at some institutions in the evaluation
The mechanism of stenosis is purportedly as of cerebral vessel stensosis in patients with
follows. The anemia resulting from the dis- SCD (Kwiatkowski et al., 2009; Silva et al.,
FIGURE 4.6. Conventional imaging (T1-weighted, T2-weighted, FLAIR) representing two classic
patterns of cerebrovascular disease in a 10-year-old child with SCD. A medium-vessel infarct is evident
in the right parietal area, resulting in atrophy and increased CSF. Classic small-vessel disease is also
evident in the right and left frontal areas.
66 BACKGROUND
2009; Zimmerman, 2005). Additional ad- and affects both sexes, though males have
vanced imaging techniques such as arterial significantly worse outcome (Reiss & Dant,
spin labeling have been used with varying 2003). Neuroimaging findings have demon-
levels of success in monitoring cerebrovas- strated reduced volumes in the prefrontal,
cular disease and evaluating novel treatment anterior cingulate, superior temporal, in-
strategies in SCD (Helton et al., 2009). sular, posterior cerebellum, amygdala, and
hippocampal regions, as well as increased
volumes in caudate, hypothalamic, and fusi-
Tay–Sachs Disease (OMIM #272800)
form areas, when compared with findings
Tay–Sachs disease is a variant of juvenile for controls (Gothelf, Furfaro, 2008; Hoeft
GM2 gangliosidosis, a group of autosomal et al., 2008; A. D. Lee et al., 2007) (Plate
recessive inherited neurodegenerative dis- 4.9). A DTI study in females with FXS re-
eases caused by deficiency of lysosomal beta- ported lower FA values in frontostriatal and
hexosaminidase, resulting in GM2 ganglio- parietal sensory–motor white matter path-
side accumulation in the brain. Tay–Sachs ways (Barnea-Goraly et al., 2003). Haas
classically presents with progressive neu- and colleagues (2009) demonstrated similar
rological deterioration that initially affects white matter anomalies in males with FXS
motor and spinocerebellar functioning; it by showing greater relative white matter
commonly includes gait disturbance, speech fiber density in the left ventral frontostriatal
problems, and incoordination, and may also pathway than that of controls. In addition,
include muscle wasting, weakness, seizures, lower dorsolateral prefrontal cortex cho-
behavioral and psychiatric disturbances, and line/creatine levels have been demonstrated
dysphagia (Maegawa et al., 2006). in males with FXS than in controls (Kesler,
The most consistent imaging finding for Lightbody, & Reiss, 2009). fMRI studies
individuals with Tay–Sachs disease on con- highlight aberrant neurofunction in left orb-
ventional imaging is moderate to severe cer- itofrontal cortex (Tamm, Menon, Johnston,
ebellar atrophy (Maegawa et al., 2006; Neu- Hessl, & Reiss, 2002), ventrolateral prefron-
dorfer et al., 2005). Mild generalized atrophy tal cortex (Hoeft, Hernandez, et al., 2007),
and subcortical white matter changes have cingulate, basal ganglia, and hippocampus
also been reported, which may precede cer- (Menon, Leroux, White, & Reiss, 2004)
ebellar atrophy (Maegawa et al., 2006; Neu- during various response inhibition tasks; in
dorfer et al., 2005). Though MRS studies right middle frontal gyrus and left cerebel-
have only been performed in small samples lum during a math task (Rivera, Menon,
of individuals with Tay–Sachs disease, there White, Glaser, & Reiss, 2002); in hippocam-
are reports that changes in metabolites on pus and basal forebrain during a memory
MRS were closely linked to clinical features task (Greicius, Boyett-A nderson, Menon,
and may prove useful for the evaluation of & Reiss, 2004); in fusiform gyrus and left
neuronal changes in children with this dis- superior temporal gyrus during a face and
ease (Aydin, Bakir, Tatli, Terzibasioglu, & gaze discrimination task (Garrett, Menon,
Ozmen, 2005; Imamura, Miyajima, Ito, & MacKenzie, & Reiss, 2004); in the anterior
Orii, 2008; Maegawa et al., 2006). cingulate cortex and caudate nucleus during
an emotion recognition task (Hagan, Hoeft,
Mackey, Mobbs, & Reiss, 2008); and in the
X-Linked Syndromes left insula, left amygdala, and bilateral pre-
frontal cortices during an eye gaze discrimi-
Fragile X Syndrome
nation task (Watson, Hoeft, Garrett, Hall,
(OMIM #300624)
& Reiss, 2008).
Fragile X syndrome (FXS) is caused by an
expansion of repeated trinucleotides within
Klinefelter Syndrome
the FMR1 gene on the X chromosome, re-
sulting in disrupted production of the fragile Klinefelter syndrome (KS) is a disorder char-
X mental retardation protein (FMRP). The acterized by sex chromosome aneuploidy
syndrome is associated with cognitive, emo- (47,XXY) that affects males. It is associated
tional, social, and behavioral dysfunction with language-based learning disorders and
with executive, social, and motor planning er et al., 2008). Many of the recent neuroim-
difficulties, but spatial abilities are preserved aging studies have focused on neurochemi-
(Giedd et al., 2007). Individuals with KS were cal changes using MRS and have consistently
found to have smaller total cerebral volumes demonstrated decreased NAA and increased
than those of age-matched male controls, as choline on average throughout the brain
well as smaller lobar volumes in all lobes ex- (Gokcay, Kitis, Ekmekci, Karasoy, & Sener,
cept parietal white matter. In contrast, the 2002; Horska et al., 2000, 2009; Naidu et
lateral ventricles in individuals with KS were al., 2001). Others have noted specific regional
shown to be significantly larger than those vulnerabilities, including decreased NAA in
of age-matched male controls (Giedd et al., the frontal lobe (Horska et al., 2000; Khong,
2007). More localized gray matter volume Lam, Ooi, Ko, & Wong, 2002; Naidu et al.,
reductions have been observed in the insula, 2001); decreased NAA in the insula, hip-
amygdala, hippocampus, cingulate, tempo- pocampus (Horska et al., 2000; Naidu et
ral, and occipital gyri in KS (Giedd et al., al., 2001), and cingulate gyrus white matter
2006; Rose et al., 2004; Shen et al., 2004). (Pan, Lane, Hetherington, & Percy, 1999);
KS is associated with thinner cortex in the and increased glutamate in cingulate gray
left inferior frontal, left motor, left infe- matter (Pan et al., 1999) and left frontal
rior parietal, and bilateral temporal regions white matter (Horska et al., 2009).
(Giedd et al., 2007). MR case reports of in-
dividuals with a more severe variant of the
Turner Syndrome
syndrome (49,XXXXY) demonstrate some
of the findings listed above, in addition to the Turner syndrome (TS) results from complete
presence of white matter disease (Hoffman, or partial X monosomy in females and is as-
Vossough, Ficicioglu, & Visootsak, 2008). sociated with short stature, gonadal dysgen-
esis, and other physical features, as well as
executive and visual–spatial function defi-
Rett Syndrome (OMIM 312750)
cits (Kesler, 2007). Volumetric MR studies
Children with Rett syndrome typically dem- have consistently indicated parietal lobe ab-
onstrate normal early development, followed normalities in children and adolescents with
by severe neurodevelopmental decline, aprax- TS (Brown et al., 2002, 2004). In addition,
ia, and autistic-like behaviors (Chahrour & TS has been associated with abnormalities
Zoghbi, 2007). Rett syndrome primarily oc- of occipital lobe and cerebellar morphology
curs in females, although certain mutations (Brown et al., 2002; Fryer, Kwon, Eliez, &
of the associated X-linked MECP2 gene are Reiss, 2003). Amygdala, superior temporal
believed to cause syndromic features in boys gyrus, and orbitofrontal volumes may be en-
(Kankirawatana et al., 2006; Leonard et al., larged compared to those of controls (Good
2001). The first morphometric MR studies et al., 2003; Kesler et al., 2003; Kesler, Gar-
showed significantly reduced cerebral vol- rett, et al., 2004; Rae et al., 2004), while
umes with a greater decrease of gray matter hippocampal and corpus callosum volumes
in comparison to white matter, particularly are reduced (Fryer et al., 2003; Kesler, Gar-
in the frontal regions, and disproportion- rett, et al., 2004). Several fMRI studies have
ally reduced caudate and midbrain volumes demonstrated frontoparietal deficits associ-
(Chang, Huang, & Huang, 1998; Reiss et ated with spatial orientation (Kesler et al.,
al., 1993; Subramaniam, Naidu, & Reiss, 2004b), working memory (Haberecht et al.,
1997). Dunn and colleagues (2002) also 2001; Hart, Davenport, Hooper, & Belger,
demonstrated reduced basal ganglia volumes 2006), arithmetic (Kesler, Menon, & Reiss,
including caudate and thalamus. A more re- 2006), and response inhibition (Tamm,
cent study utilizing multimodal volumetric Menon, & Reiss, 2003). A recent DTI study
MR techniques showed reduced total brain illustrated significantly reduced structural
volumes affecting both gray and white mat- connectivity (e.g., FA) among frontal, stri-
ter, as well as decreased gray matter volumes atal, and parietal regions, whereas pari-
in the bilateral parietal lobe, right cingulate, etotemporal connectivity was enhanced
right middle occipital, left middle frontal, (Holzapfel, Barnea-Goraly, Eckert, Kesler,
and bilateral pre- and postcentral gyri (Cart- & Reiss, 2006) (Plate 4.10).
68 BACKGROUND
Inherited Ataxias 2009; Ergun, Okten, Gezercan, & Gezici,

2007; Hu et al., 2008). Gray and white mat-
Friedreich Ataxia (OMIM #229300)
ter volumes may be reduced in the brain re-
Friedreich ataxia is the most common of the gions surrounding angiomas, with frontal
inherited ataxias and the most consistently and temporal white matter volumes being
diagnosed during childhood. Symptoms in- particularly vulnerable (Pfund et al., 2003).
clude gait ataxia and speech impairments. MRS studies suggest abnormal NAA and
Studies utilizing qualitative MRI methods choline levels in frontal tissue, despite nor-
have indicated atrophy of the cerebellum mal DTI and qualitative MRI findings (Ba-
(Mantovan et al., 2006; Mateo et al., 2004), tista et al., 2008; Sijens et al., 2006). A study
subcortical regions, and frontal lobe (Man- including DTI revealed abnormal FA in left
tovan et al., 2006). A quantitative regional parietal white matter (Juhasz et al., 2007),
MRI study demonstrated reduced volume, and MR SWI studies have demonstrated
altered shape, and iron accumulation in the abnormalities in gyrification patterns and
dentate nuclei of the cerebellum (Boddaert gray–white matter junction (Hu et al., 2008;
et al., 2007). An fMRI study indicated an Juhasz et al., 2007).
abnormal pattern of cortical activation as-
sociated with finger movements (Mantovan
Tuberous Sclerosis Complex
et al., 2006).
(OMIM #191100)
Tuberous sclerosis complex (TSC) is a mul-
Neurocutaneous Syndromes tisystem genetic disorder characterized by
skin abnormalities (e.g., hypomelanotic ma-
Sturge–Weber Syndrome
cules), seizures, and intellectual disability.
(OMIM #185300)
MRI findings frequently include cortical
Sturge–Weber syndrome, also referred to as tubers, transmantle dysplasia, subependy-
encephalotrigeminal angiomatosis, is char- mal nodules, giant cell astrocytomas, white
acterized by skin abnormalities (e.g., port matter anomalies, hemimegalencephaly, cor-
wine marks), meningeal angiomas, seizures, tical dysplasia, and schizencephaly (Arca,
developmental delays, and calcification of ce- Pacheco, Alfonso, Duchowny, & Melnick,
rebral tissue (Pascual-Castroviejo, Pascual- 2006; Christophe et al., 2000; O’Callaghan
Pascual, Velazquez-Fragua, & Viano, 2008). et al., 2008) (Figure 4.7). Eluvathingal and
Diffuse cerebral atrophy is a common MRI colleagues (2006) also noted a high incidence
finding (Adams, Aylett, Squier, & Chong, of cerebellar lesions in children with TSC.
FIGURE 4.7. MRI scans of a 17-year-old male with TSC, showing numerous cortical tubers (stars),
infolded cortical dysplasia (as deep distortion of the normal cortical architecture) (thin arrows), and
dystrophic calcification as signal void in b (thick arrow). From Christophe et al. (2000). Copyright
2000 by Elsevier. Reprinted by permission.
Neurofibromatosis (OMIM #162200, genetics and etiology; hence we use the term

Type 1; OMIM #101000, Type 2) multifactorial syndromes in this section.
For example, the Diagnostic and Statistical
Neurofibromatosis (NF) is an autosomal
Manual of Mental Disorders, fourth edi-
dominant disorder in which tumors grow
tion (DSM-IV; American Psychiatric Asso-
in nerve tissues of the brain as well as cells
ciation, 1994) lists pervasive developmental
under the skin. MRI studies reveal multiple disorders (PDDs) as a general category en-
hyperintensities, or unidentified bright ob- compassing a broad spectrum of disorders
jects (UBOs), corresponding to lesions in first diagnosed in infancy, childhood, or ad-
the basal ganglia, thalamus, brainstem, hip- olescence, including autistic disorder, Rett’s
pocampus, cerebellum (Lopes Ferraz Filho, disorder (although more is known about the
et al., 2008), and corpus callosum (Mimou- genetics of this disorder than when DSM-IV
ni-Bloch, Kornreich, Kaadan, Steinberg, came out in 1994; see Matijevic, Knezevic,
& Shuper, 2008), as well as optic gliomas Slavica, & Pavelic, 2009), childhood disin-
(Hsieh, Wu, Wang, Chin, & Chen, 2007). tegrative disorder, Asperger’s disorder, and
Using DTI, Alkan and colleagues (2005) the catch-all diagnosis of PDD not otherwise
demonstrated significantly increased ADC specified (PDD-NOS). For each of these dis-
values within UBOs in the frontal lobe, orders, although the phenotypic behaviors
parieto-occipital region, cerebellar white may be specific enough to identify and label
matter, globus pallidus, hippocampus, thal- with behavioral characteristics (as has been
amus, and midbrain in children with NF1; done in the DSM-IV classifications), specific
ADC values were also significantly increased etiologies are not well understood and are
even in normal-appearing hippocampal and assumed to be multiple.
thalamic tissues. ADC is another index of
microstructural integrity in brain tissues.
fMRI studies of children with NF1 have Pervasive Developmental Disorders
indicated significantly altered patterns of The multifactorial nature of the PDDs is
prefrontal, temporal, parietal, and occipital exemplified by autism and can be readily
activation associated with phonological and appreciated by viewing Figure 4.8, taken
visual–spatial processing (Billingsley et al., from Geschwind and Levitt (2007). There
2003, 2004). An MRS study demonstrated is no single path that consistently leads to
significantly increased choline and myo- autism, and without a specified etiology,
inositol levels in normal-appearing frontal understanding this disorder (or any PDD)
and parietal white matter, as well as signifi- from a neurobiological perspective is chal-
cantly decreased NAA in normal-appearing lenging. However, recent genetic studies are
frontal white matter (Alkan et al., 2003). beginning to demonstrate genes that may be
participating in this complex disorder (see
Bayou, M’Rad, Ahlem, Bechir Helayem, &
Multifactorial Syndromes Chaabouni, 2008; Bishop, 2009; Levitt &
Campbell, 2009). Because nearly two-thirds
In the nosology of childhood neuropsychi- of the genes in the human genome are re-
atric disorders, problems of diagnostic clas- lated to brain function in some fashion (Pe-
sification and specificity exist for complex trella, Mattay, & Doraiswamy, 2008), it be-
disorders with potential multiple etiologies comes obvious why the neurodevelopmental
and overlap in symptoms and behaviors, processes that lead to any of the multifac-
especially in terms of their genetics and the torial disorders are exceedingly complex;
role that neuroimaging may play in defin- nonetheless, the search for candidate genes
ing each disorder. In contrast to disorders for autism has revealed some most interest-
discussed elsewhere in this chapter (e.g., ing findings. For example, Glessner and col-
X-linked syndromes, where distinct genetic leagues (2009) recently observed that genes
bases for the behavioral and neuropsycho- that potentially regulate synaptic function
logical phenotype of each disorder are well and neuronal connectivity among diverse
known), complex neuropsychiatric disorders brain regions may play a role in autism. This
are much more ambiguous with respect to observation has direct implications for how
70 BACKGROUND
Developmental regression
Seizures
Language delay
Big brain
Gastrointestinal complains
or immunological dysfunction
“The Autisms” Maleness

Neurogenesis
Neuronal migration
Asperger syndrome? Axon pathfinding
Synaptogenesis
Neuronal or glial structure
Regionalization
Epigenetic Common alleles
modifications
Environmental Nonsyndromic
Rare or private copy number variation
Duplication
mutations (deletions or duplications)
of 15q11–13
Fragile X Rett
syndrome Other known single-gene
disorders/syndromes:
Sex chromosome
Chr 22q u Joubert syndrome
aneuploidy
u Tuberous sclerosis
FIGURE 4.8. This diagram shows the multifactorial nature of what may be the basis for the autism
spectrum disorders. Such complexity makes it impossible to focus on a single factor in the study of
autism, and underscores the need to consider such complexities in neuroimaging and neuropsychologi-
cal outcome studies of this disorder. From Geschwind and Levitt (2007). Copyright 2007 by Elsevier.
Adapted by permission.
neuroimaging should be used to examine po- out the scan image in the middle as that of
tential anomalies in attempting to improve the child who suffered a severe TBI because
our understanding of autism. there are clearly noticeable differences: The
Indeed, from a neuroimaging standpoint, ventricles are dilated, prominent cortical
the role that connectivity plays appears to sulci are visible, and the hippocampi are
be critical in understanding all of the mul- withered. However, which of the other two
tifactorial syndromes, not just autism. scan images is that of the child with autism?
However, there are two core features of It is impossible to tell simply by viewing the
autism—impairment in communication and images. The typical image of the brain of the
social behavior—that can be the target of child with autism appears normal (Bigler et
neuroimaging investigations of connectivity. al., 2003). So if gross appearance reveals no
Figure 4.9 shows three coronal views of the universally distinguishing feature that iden-
brain, all at approximately the same level, in tifies a child with autism, the abnormalities
three different subjects, all males and about of autism must be found within the neural
14 years of age: one with autism, one with organization of the brain—its microanato-
traumatic brain injury (TBI), and one age- my and neural integrity.
matched, healthy, typically developing con- Currently the best method to noninva-
trol. The reader is asked to view these brains sively assess the microanatomy of the liv-
and decide which one is the brain of the ing brain is DTI (Lainhart, Lazar, Bigler, &
child with autism. It is relatively easy to pick Alexander, 2006), which has been used in
FIGURE 4.9. Three coronal MRI sections are depicted, all from males approximately 14 years of age.
The middle one is obviously abnormal, with dilated ventricles and with cortical and hippocampal atro-
phy. The one on the viewer’s right is from a child with autism, and the control child is on the viewer’s
left. These comparisons are shown merely to demonstrate that the typical MRI findings in children
with autism reflect no gross abnormality and cannot be distinguished from those of typically develop-
ing controls simply through visual inspection. This indicates that more refined neuroimaging analyses,
such as DTI, are necessary to uncover the complex neural aberrations that may underlie autism.
several investigations of autism (see reviews 2009). This probably disrupts the integra-
by Muller, 2007; White, Nelson, & Lim, tion between the two hemispheres, which is
2008). This research has focused on connec- also necessary for normal social-emotional
tivity within the brains of individuals with functioning and the integration of verbal
autism versus typically developing controls. and nonverbal information.
Among many candidate areas to investigate, Using DTI, an example of these abnormal
there are two logical places to begin exam- areas of white matter development in autism
ining brain connectivity in individuals with is given in Plate 4.11 (Petrella et al., 2008),
autism—the corpus callosum (CC) and the which shows the relationship of scores on the
superior temporal gyrus (STG). The CC is Social Responsiveness Scale (SRS; Constan-
used since it is the largest brain commissure tino, 2005)—an index of social interactive
and houses the major white matter pathways behavior, reciprocity, and reactivity—to dif-
that integrate the two cerebral hemispheres ferences in the CC and white matter of the
(Sullivan & Pfefferbaum, 2006); the STG is temporal lobe, including the STG and tempo-
used because it not only is involved in com- ral stem. Notice in this illustration that SRS
munication (i.e., auditory processing and re- scores differentiate individuals with autism
ceptive language), but participates in social from typically developing individuals, and
cognition and human behavioral interaction that increased problems with social respon-
(Paul et al., 2007; Pelphrey & Carter, 2008). siveness relate to DTI-detected white matter
Several studies that have used DTI to exam- differences. Also note in this illustration how
ine these brain regions have found significant widespread the white matter differences are.
differences in these regions between subjects Interestingly, disorders in the PDD cate-
with autism and typically developing con- gory are associated with another multifacto-
trols. Firsts, these studies have suggested a rial set of disorders classified by DSM-IV as
significant difference in the organization of attention-deficit and disruptive behavior dis-
white matter within the STG (Bigler et al., orders. ADHD is the most common of these
2007; J. E. Lee et al., 2007). This has im- and is often a component of PDDs (Sinzig,
plications for disorganization of language Walter, & Doepfner, 2009) and many other
function: The normal language circuitry is neuropsychiatric disorders (Galanter &
not properly in place in individuals with au- Leibenluft, 2008; Nijmeijer et al., 2008).
tism, and this also likely disrupts the nor- Gogtay, Giedd, and Rapaport (2002) have
mal integration of information necessary for shown a number of neuroanatomical differ-
social-emotional processing. Furthermore, ences in brain size and structure in children
DTI studies specific to the CC show that with ADHD, particularly in frontal lobe de-
it may be slightly smaller in autism, with velopment (see also Castellanos et al., 2002;
potentially disorganized white matter con- Kelly, Margulies, & Castellanos, 2007). A
nectivity (Alexander et al., 2007; Lee et al., summary of these findings is provided in
72 BACKGROUND
Plate 4.12, which shows different develop- long been assumed that environmental stres-
mental trajectories among typically devel- sors during childhood adversely affect brain
oping children, children with ADHD, and development and predispose individuals
children with childhood-onset schizophre- to develop neuropsychiatric disorders (van
nia. These and similar studies suggest that Winkel, Stefanis, & Myin-G ermeys, 2008).
there are likely to be critical stages in these A host of unknown genetic and environ-
disorders where brain development, connec- mental factors are probably involved in all
tivity, and/or cellular pruning are disrupted, disorders that can be categorized as multi-
and that these disruptions probably relate to factorial syndromes. One of the early mod-
the behavioral phenotypic expression of the els for gene–environment interaction dealt
disorders. with alcoholism and other substance abuse
(see Alterman & Tarter, 1983). This type of
outcome was relatively easy to understand
Tourette Syndrome
within these rather blatant models of de-
Another multifactorial disorder is Tourette velopmental psychopathology because chil-
syndrome, characterized by the occurrence dren being raised by parents with addiction
of irresistible, stereotyped, unwanted, and problems experience multiple sets of adverse
unplanned movements and/or vocalizations circumstances: heritability of the disorder,
(tics). Symptoms frequently begin as early as potential gestational effects of substance
6–7 years of age, often peaking in intensity abuse during conception and pregnancy,
in adolescence (Swain, Scahill, Lombroso, and the adverse effects on parenting result-
King, & Leckman, 2007). From a neurop- ing directly or indirectly from the parents’
sychiatric perspective, obsessive–compulsive alcoholism/drug addiction. However, neu-
disorder (OCD) and ADHD have a very high roimaging has opened entirely new avenues
comorbidity with Tourette syndrome (Pless- of investigation that are becoming incredibly
en, Royal, & Peterson, 2007; Singer, 2005) informative about how dynamic the relation-
and probably share aberrant neural sytems ship among heritability, brain development,
associated with impulse control, motor con- and parental psychopathology may be, and
trol, and executive functioning. Because how this extends beyond the older models
the presence of tics is central to Tourette of substance-abusing parents and dysfunc-
syndrome, but it also shares features with tional environment. For example, a recent
ADHD and OCD, various theories about study by Choi, Jeong, Rohan, Polcari, and
dysfunctional frontostriatal pathways have Teicher (2009) used DTI to examine white
been proposed; contemporary neuroimag- matter integrity in young adults exposed to
ing studies support such dysfunction for all parental verbal abuse. In the group exposed
of these disorders (MacMaster, O’Neill, & to such abuse, there were changes in white
Rosenberg, 2008). For example, Church and matter connectivity in several limbic regions
colleagues (2009) have shown by using fMRI of the brain, compared to matched typically
methods that regulatory or control networks developed young adults. Such findings sug-
are different in persons with Tourette syn- gest that adverse environmental effects may
drome compared to typically developing disrupt normal neural development in brain
controls. Neuroimaging has also shown the areas associated with emotional health and
expected involvement of dopaminergic nu- well-being. It is likely that such disruption
clei (including the substantia nigra and ven- of normal brain development in childhood
tral tegmental areas) in Tourette syndrome, results in greater susceptibility to the devel-
in association with the abnormal tic behav- opment of later psychiatric disorder, par-
ior (Gilbert et al., 2006; Wong et al., 2008). ticularly if there is already increased genetic
It has long been assumed that inherited susceptibility.
vulnerabilities predispose individuals to de-
velop neuropsychiatric disorders, and that
Personality Disorders
when such inherited vulnerabilities interact
with particular adverse environmental cir- Another multifactorial disorder with com-
cumstances or stressors, the neuropsychi- plex genetic and environmental influences
atric disorders emerge (State, Lombroso, occurs within the spectrum of difficulties
Pauls, & Leckman, 2000). Likewise, it has defined in DSM-IV as personality disor-
ders (Goodman, New, & Siever, 2004; Mc- 2005). These are just a few examples. The
Closkey et al., 2009). These disorders were use of such neuroimaging predictors in mul-
originally assumed to be the quintessential, tivariate models can significantly improve
prototypical disorders illustrating psycho- the accuracy of prognosis. Studies attempt-
dynamic influences in the emergence of psy- ing to predict outcomes in various popula-
chopathology (Goldstein, 1989). However, tions show that neuroimaging measures are
neuroimaging has clearly demonstrated that able to explain 30–82% of the variance,
borderline personality disorder (BPD) can which in some cases exceeds the percentages
also be characterized by underlying neuroan- explained by currently available alternative
atomical differences (see White et al., 2008) methods (Hoeft, Veno, et al., 2007; Rich-
and complex gene–environment interactions ardson et al., 2004).
(Kendler et al., 2008). Several investigations Gene–brain–behavior relationships can
have now shown disrupted brain connectiv- also guide the development of treatments for
ity (particularly between frontal and limbic cognitive-behavioral symptoms in genetic
areas) in BPD, using a variety of neuroimag- disorders. For example, researchers noted
ing techniques (Grant et al., 2007; Koenigs- abnormalities in the basal ganglia and hip-
berg et al., 2009; Rusch et al., 2007; Volpe pocampi of individuals with FXS (Greicius
et al., 2008). Needless to say, there appear et al., 2004; Reiss & Dant, 2003). These
to be structural and functional abnormali- regions contain cholinergic pathways that
ties in the brain in individuals with all forms are associated with executive function and
of DSM-IV-identified personality disorders memory—areas of significant dysfunction
(Harenski, Kim, & Hamann, 2009). in FXS (Reiss & Dant, 2003; Sarter, Bruno,
It is likely that the combination of neuroim- & Givens, 2003; Sarter & Parikh, 2005). In
aging studies, genetic research, and a better addition, choline appears to be significantly
understanding of how environmental influ- reduced in the executive prefrontal cortex of
ences alter brain development will become individuals with FXS (Kesler et al., 2009).
most informative about particular vulnera- Based on the combination of neuroimaging
bilities, as well as what brings about wellness data and research regarding the influence
in developing children. Such improvements of the FMR1 gene on cholinergic neurons,
will undoubtedly improve our understand- clinical investigators initiated a drug trial
ing of all the multifactorial syndromes. of donepezil to augment acetylcholine func-
tion in individuals with FXS. The results
of this trial included significantly improved
The Central Theme : executive function and decreased problem
Gene –Brain –Behavior Relationships behaviors (Kesler et al., 2009). Though this
study involved a very small sample and an
The central theme of the discussion above is open-label design, it illustrates the potential
that genetic aberrations are often associated of neuroimaging research for contributing to
with altered neurodevelopment, affecting syndrome-specific interventions.
brain structure, function, and/or biochem-
istry. Furthermore, brain abnormalities tend
to result in cognitive-behavioral deficits, as Conclusions
many of the studies cited above have demon-
strated. For example, decreased left frontal Many genetic disorders are associated with
white matter NAA was higher in children abnormal neurodevelopment. These altera-
with Rett syndrome who had seizures than tions in neurobiological status are often
in those without, as well as in patients with related to cognitive-behavioral deficits. Ad-
higher clinical severity scores (Carter et al., vancing neuroimaging technologies allow for
2008). Lower inferior parietal lobe FA may increasing specificity and sensitivity in the
correspond to impaired arithmetic ability in identification of neural systems subserving
VCFS (Barnea-Goraly, Eliez, Menon, Bam- the cognitive deficits associated with these
mer, & Reiss, 2005). Increased cortical atro- genetic syndromes. Such data significantly
phy was associated with increased clinical se- improve clinical outcome prognosis accu-
verity ratings in children with Sturge–Weber racy and can provide biological targets for
syndrome (Kelley, Hatfield, Lin, & Comi, syndrome-specific treatment development.
74 BACKGROUND
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40(7), 2408–2412. phology and morphometry of the corpus callo-
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Chapter 5
Integrative Developmental
Neuropsychology
A General Systems and Social-Ecological
Approach to the Neuropsychology of Children
with Neurogenetic Disorders
Timothy B. Whelan
Melissa J. Mathews
The development of children with neurode- greater absenteeism, and increased behav-
velopmental and genetic disorders occurs, as ioral difficulties such as nervousness and ag-
it does for all children, in a dynamic web of gression (Butler & Haser, 2006; Hinton, De
exchange. As neuropsychologists, our focus Vivo, Fee, Goldstein, & Stern, 2004; Howe,
has traditionally been on the pathophysi- Feinstein, Reiss, Molock, & Berger, 1993;
ology of the nervous system and its conse- Moleski, 2000; Palmer, Reddick, & Gaj-
quences expressed cognitively, academically, jar, 2007; Pless & Roghmann, 1971; Rutter,
motorically, affectively, and so forth. Our Tizard, & Whitmore, 1970).
expertise is thus unique in attempting to Furthermore, when the affected organ—
grasp the meaning of relationships between the brain—is itself the organ most intimately
the brain and behavior, and yet we are at risk related to the capacity to adjust, the progno-
of painting clinical portraits of children that sis for successful coping drops still further.
are too narrow or monochromatic unless we Rutter, Graham, and Yule (1970) reported
constantly consider influences at other lev- from the classic Isle of Wight study that the
els of functioning. In this chapter, selected occurrence of psychiatric disorders among
aspects of the literature on children, illness, children with non-neurological chronic dis-
and psychosocial functioning are discussed ease was 11.6%; among those with epilepsy
and illustrated with case material. and no other pathology, it was 37.5%; and
To set the stage, it is important to empha- among children and adolescents with epi-
size that the prevalence of adjustment diffi- lepsy associated with organic brain disease,
culties among children with disabling medi- it was 58.3%. Breslau (1985) also noted a
cal conditions is high. It was known as early higher prevalence of psychological adjust-
as the 1980s that these children are at 1½ ment difficulties among children with brain-
to 3 times greater risk for behavioral, social, based disease than among either healthy
and psychological maladjustment than their children or those with other systemic diseas-
healthy peers (Perrin, 1986; Pless, 1984). es. More specifically, it has been shown that
Results of epidemiological and other stud- children with brain-related disorders exhibit
ies indicate that children with chronic illness higher rates of internalizing disorders than
experience lower academic achievement, do their nondisabled peers, accompanied by
84
Integrative Developmental Neuropsychology 85
increasing anxiety and social avoidance as clinical health psychology (Millon, Green,
they age into adolescence (Estes, Dawson, & Meagher, 1982).
Sterling, & Munson, 2007; Kuusikko et al., In addition to consideration of a general
2008). Children with brain-based develop- systems organization of the individual, it is
mental disorders and comorbid intellectual important to link our understanding to the
disorders may also be at increased risk for developmental psychology of families and
externalizing behavior problems, including children. Bronfenbrenner (1979) has writ-
aggression, hyperactivity, irritability, and ten about social ecology, defined as “the
self-injurious behaviors (Estes et al., 2007; study of the relation between the developing
McClintock, Hall, & Oliver, 2003; Sum- human being and the settings and contexts
mers, Houlding, & Reitzel, 2004). in which that person is actually involved”
A word of caution is nevertheless in order, (Kazak, 1989, p. 26). According to Kazak,
however: Some seemingly pathological be- who has applied these theories in families of
haviors may actually be adaptive in those chronically ill children—including children
with chronic illness (Drotar & Bush, 1985; with physical disabilities (Kazak, 1986),
Van Dongen-Melman & Sanders-Woudstra, phenylketonuria (Kazak, Reber, & Smitzer,
1986). Moreover, not all children are nega- 1988), and AIDS (Kazak, 1989)—the pre-
tively affected, and resiliency may be equally sumption in social ecology is that the child
impressive (Stabler, 1988). is at the center of concentric spheres of influ-
ence, with nearby rings representing family,
school, and neighborhood, and with more
Overarching Concepts distant impact coming from social values
and culture. Again, the impact of events is
It is not unusual in the fields of psychol- bidirectional: The child is influenced by the
ogy and medicine to organize a conceptual family, for instance, and the family is in-
framework for understanding disease and fluenced by the child. Thus, if the father of
health within general systems theory—a an adolescent boy with Duchenne muscular
general science of wholeness, examining dystrophy whose muscles have wasted to the
sets of elements standing in interrelationship point of personal immobility throws himself
(Bertalanffy, 1968). Within this theory, the into his office work, this may immediately
human organism exists as a hierarchy of sys- affect the son and his mother, who become
tems ranging from the molecular level of the occupied with more intimate personal care.
biological realm, to larger organ systems, to
cognitive and intrapsychic levels, and on to
family and social spheres. It is assumed that Models
these systems are interrelated, that events at
one level of the hierarchy have effects up and As the literature focusing on particular in-
down the system, and that the system main- fluences such as those described above ex-
tains a state of homeostasis during periods of panded, some researchers began to assemble
stress or stability. Therefore, because chang- models incorporating these various specific
es at one level have ramifications at many of thought. The disability–stress–coping
other levels, one may elect to treat the expe- model (Wallander & Varni, 1992; Walland-
rience of dysphoria by selectively inhibiting er, Varni, Babani, Banis, & Wilcox, 1989)
serotonin reuptake, or to utilize behavioral identifies both risk and resistance factors.
techniques with patients who have painful Among the former are qualities specific to
spinal degeneration. the disease, such as diagnosis, visibility, and
This conceptualization was the basis for brain involvement. Resistance factors are
seminal writings by George Engel (1977, both within the individual (e.g., competence
1980), which led health care practitioners and effectance motivation) and within the
to the reconceptualization of disease as a social ecology (e.g., family environment, so-
biopsychosocial phenomenon, and one can cial support).
see this influence in the earlier literature on In addition to perspectives from social
families with illness (Gochman, 1985; Kerns learning and attribution theories, concepts of
& Curley, 1985; Kerns & Turk, 1985; Leven- intrinsic motivation are important. It is gen-
thal, Leventhal, & Van Nguyen, 1985) and erally assumed that humans naturally strive
86 BACKGROUND
for effective interaction with their environ- in positive mood and number of friends. The
ment, and that successful mastery produces implication is that children with specific
feelings of efficacy and competence. These neurodevelopmental disorders and chronic
feelings in turn lead to further efforts to mas- illnesses may not follow patterns of intrinsic
ter additional tasks (Stipek & Weisz, 1981). motivation established in groups of healthy
However, the situation may not always be so children.
straightforward. In an examination of per- Perhaps the most encompassing of the ef-
ceptions of competence among children with forts to organize specific functional compo-
genetically based neuromuscular disease, nents of study is the transactional stress and
perceptions of physical competence were coping model of adjustment to childhood ill-
more closely related to general self-worth ness developed by Thompson, Gil, Burbach,
than to actual neuropsychological measures Keith, and Kinney (1993a, 1993b), Thomp-
of motor output, suggesting that children son, Gustafson, Hamlett, and Spock (1992a,
may make distorted appraisals of compo- 1992b), and Thompson and Gustafson
nents of their functioning in the service of (1996), which is derived from Bronfen-
maintaining positive global self-perceptions brenner’s (1977) ecological–systems theory.
(Whelan, 1986). In addition, a child’s overall As shown in Figure 5.1 and as explained in
perception of psychosocial competence may detail by Thompson, Gustafson, George,
be largely motivated by striving to maintain and Spock (1994), typical demographic vari-
global positive self-perceptions. In a study ables are noted, as are unique disease factors.
of pediatric patients with cancer in Taiwan Cognitive processes and coping methods are
(Chao, Chen, Wang, Wu, & Yeh, 2003), par- emphasized, as is family functioning.
ents’ views of the children differed from the Any model of child clinical neuropsychol-
children’s views of themselves. The children ogy requires additional complexity because
perceived no change in terms of academics, processes of development must be taken into
friends, temper, and mood; however, parents account (Whelan & Walker, 1997). The child
perceived their children as having a decrease is conceptualized on multiple levels standing
FIGURE 5.1. Transactional stress and coping model of adjustment to chronic illness. From Thomp-
son, Gustafson, George, and Spock (1994). Copyright 1994 by Plenum Publishing Corporation. Re-
printed by permission.
in interrelationship, with the hierarchy of contribute to the concept of handicapism,

systems set in temporal motion. Bernstein a social experience involving prejudice, ste-
and Waber (1990) have also written in this reotype, and discrimination. In essence, says
vein on their goal in developmental neurop- Resnick, there is a social construction of the
sychological assessment “not to diagnose reality of the disabled individual, in which
deficits in a child, but rather to construct a people and events are “instantaneously as-
Child–World System that characterizes the sessed in their compatibility or discordance
reciprocal relationship of the developing with the mainstream values” (1984a, p. 33).
children and the world in which that child Moreover, parents and professionals may
functions” (p. 312). Their approach was de- inadvertently occupy an important place in
rived from the systemic traditions of Luria this social construction, as well-intentioned
and Vygotsky, as well as the Wernerian ap- professional assistance sometimes places an
proach most thoroughly elaborated in neu- identified patient in a position of continual
ropsychology by Edith Kaplan. Bernstein dependence and gratitude within a larger
and Waber’s model considers manifestations culture that values self-reliance and inde-
of neurological and cognitive structures; pendence (Sanders, 2006; Smith, English, &
neurological and psychological timetables of Vasek, 2002).
development; alternative mechanisms (path- Furthermore, a dilemma exists in regard
ways and strategies); and context (including to the societal doctrine of normality, where
the role of experience and environmental certain behaviors and physical characteris-
interactions). Any attributions of difficulty tics are acceptable and where occurrences
are thus shifted from the child to the system, outside these bounds are regarded as devi-
and temporal/developmental processes are ant (Whelan & Walker, 1997). This point
considered central. of view may not be necessary or helpful for
This shift in thinking—from an individ- children who are born with genetic or neu-
ual child with a neurological or genetic dis- rodevelopmental disorders, since such chil-
order to the dysfunction of systems within dren may have always viewed their so-called
and surrounding the child—is difficult to “deficits” as part of their identity. “Handi-
maintain. After all, professional training cap” is thus defined from an “outsider’s
and individual academic interests tend to perspective” (Shontz, 1982), and “insid-
draw us as clinicians toward specific do- ers” may not perceive that there is anything
mains of expertise in our practices. More- about their condition to overcome (Massie,
over, there are powerful societal influences 1985). The critical question within such an
on professional thinking and on the think- individual’s system shifts to this: How does
ing of others in the child’s social ecology. As the individual achieve a complete sense of
described by Resnick (1984a) decades ago, fulfillment, given his or her uniqueness? The
to understand the sociological destiny of following section considers a child’s develop-
those with disability, it is necessary to un- ment, adjustment, and coping in the context
derstand the genesis of attitudes and expec- of the previously mentioned biopsychosocial
tations surrounding them. Resnick reviewed models.
an extensive literature indicating a number
of significant, though unfortunate, trends
with implications for psychological health, Critical Variables
school success, and vocational life. First,
children in general may prefer interactions Throughout the 1970s and 1980s, research-
with able-bodied peers rather than with dis- ers were accumulating data indicating that a
abled children, and this bias may increase conceptual grasp of the nature of coping and
as they get older (Ryan, 1981; Voeltz, 1980; adjustment of children with chronic illness
Weinberg, 1976; Weinberg & Santana, encompasses a broad array of factors (see
1978). Second, teachers may hold negative Thompson & Gustafson, 1996, for a detailed
attitudes toward disabled students (Good & review of this research). In the mid-1970s,
Brophy, 1978; Martinek & Karper, 1981). Monat and Lazarus (1977, p. 3) developed
Third, there are persistent biases against the notion that stress is a situation “in which
employment of persons with disabilities environmental demands, internal demands,
(Bender, 1981; Conley, 1973). Such findings or both tax or exceed the adaptive resources
88 BACKGROUND
of an individual, social system, or tissue sys- involvement seemed at risk for poorer self-
tem.” Researchers began to consider the ways concept and lower self-esteem (Lindemann
in which children may adjust to these stresses & Stranger, 1981). Below, we discuss those
when they involve illness. For example, Pless critical variables in the child’s biopsycho-
and Pinkerton (1975) described the concepts social environment—coping, self-concept,
of coping style and self-concept as central school, friends, and family.
to psychological adjustment to illness. They
placed these concepts against a backdrop in-
Self-Concept, Adjustment,
cluding family characteristics, the social en-
and Coping in the Disabled Child
vironment, the type of illness, and so forth.
Thus not only were they considering bio- Not all research suggests that children with
logical factors in illness; they were implying chronic illness are at risk for poor self-
that other sections of the child’s hierarchy of concept and lowered self-esteem. In a sample
systems and the social environment in which of disabled adults, adolescents, and children
they exist are important in adaptation. These in India, Ittyerah and Kumar (2007) found
domains in turn are available as potential that children’s self-concept was more posi-
targets of intervention. tive than that of adolescents and adults. In
Adjustment to stress also came under addition, the correlation between partici-
scrutiny, and what clinical psychologists had pant ratings of real self and ideal self was
typically considered defense mechanisms high for all age groups. Interestingly, posi-
began to be seen in a different, more positive tive self-concepts were related more to in-
light. Even earlier (Kroeber, 1964), parallels ternal factors (e.g., healthy coping mecha-
were drawn between more pathological ego nisms, ways of thinking about their disease),
defense mechanisms (isolation, projection, whereas negative self-concepts were related
repression) and coping mechanisms (objec- to uncontrollable external factors (e.g., pov-
tivity, empathy, suppression), the latter im- erty, negative treatment by others).
plying more active and effective attempts to Furthermore, risk for poor self-concept
deal with conflict. Lazarus (1983) struggled and self-esteem may depend on a variety of
especially with the conditions under which factors particular to the individual, such as
people may deceive themselves; he tried to gender (Shields, Murdoch, Loy, Dodd, &
distinguish classical denial (the negation of Taylor, 2006) and level of pain experienced
impulse, feeling, thought, or external real- as a result of the disease process (Russo,
ity) from partial denial (a temporary sus- Miller, Haan, Cameron, & Crotty, 2008).
pension of belief during periods of health In a meta-analysis regarding the self-concept
crisis). Moreover, he considered it possible of children with cerebral palsy (Shields et
that denial may reduce distress when there is al., 2006), female children appeared to be at
no direct action one can take to improve the somewhat greater risk than their male coun-
situation at one point in a disease process, terparts. Poor self-perceptions may spill over
whereas at another point it may be critical to into many areas of life, including physical
perceive dysfunction accurately in order to appearance, social acceptance, and athletic
take available steps to remedy or rehabilitate and academic competence. Therefore, it may
the situation. be especially important to be vigilant for
Apart from traditional models of psycho- these symptoms in young girls with develop-
logical adjustment, cognitive and developmental disorders such as cerebral palsy. Fur-
mental psychologists were contributing to thermore, the experience of pain contributes
the field. For instance, as ideas of self-worth to lower feelings of academic and behavioral
and self-concept were explored, some studies competence than in those children who do
reported that children with chronic illness not suffer from pain (Russo et al., 2008).
were negatively affected (e.g., Lineberger, It is difficult to understand those coping
Hernandez, & Brantley, 1984). In contrast, and adjustment factors that may be particu-
others (e.g., Kellerman, Zeltzer, Ellenberg, lar to a child without considering them in
Dash, & Rigler, 1980; Simmons et al., 1985) terms of their environmental contexts. In
reported no significant group differences subsequent sections, we attempt to outline
between ill and healthy children. In gen- those factors important to a child’s develop-
eral, though, ill children with neurological ment and coping. Individual characteristics
and family variables working together may to exhibit poor social competence that per-
be predictive of outcomes (Majnemer & sists over time (Cunningham, Thomas, &
Mazer, 2004; Schuengel et al., 2006), influ- Warschausky, 2007; Guralnick, Hammond,
encing coping and adjustment beyond the Connor, & Neville, 2006). This results in
medical facets of the disability. loneliness, being selected for fewer peer in-
Venning, Eliot, Wilson, and Kettler (2008) teractions, having fewer friends, and feeling
examined qualitative data regarding chil- less validated and cared for in the friend-
dren’s subjective experience of their chronic ships they do have (Bauminger, Shulman, &
illness, and outlined some basic principles Agam, 2004; Cunningham et al., 2007; Hall
related to well-being and coping for chroni- & MacGregor, 2000).
cally ill children. First, they found that the With increasing cognitive impairment and
experience of a chronic illness contributed to comorbid medical issues, social interaction
children’s sense of both personal and social and communication difficulties may increase
discomfort, including feeling different from (Voorman et al., 2006) because the ability to
those around them, feeling misunderstood, interpret social situations and solve problems
and wanting to avoid others. Second, these may be disrupted (Warschausky, Argento,
children reported feeling unable to live nor- Berg, & Hurvitz, 2003). Thus comorbid
mally, due to feelings of uncertainty about cognitive and medical issues may constitute
life and difficulty participating in activities. a predictor of peer relationships in children
However, some positive aspects were found, with neurodevelopmental conditions, where-
in that the children reported feeling that they as this may not be so for children without
had grown personally from the experience disabilities (Thomas, Warschausky, Golin,
(e.g., greater understanding and concern for & Meiners, 2008). Higher levels of func-
others), and that in some cases there were re- tioning may provide some protective ben-
wards such as strengthening the family unit efit in social relationships. High-functioning
and learning to manage the disease. Regard- children with autism often report feeling as
ing facilitation of the children’s coping ability, close to their friends as typically developing
Venning and colleagues found that children children, and report levels of self-concept
might want help adjusting to the diagnosis. similar to those of normally developing
Specifically, these children reported needing children in many areas of their lives (e.g.,
information about their condition and need- academic ability, appearance, conduct, gen-
ing support from others. Cultivating effective eral self-worth; Bauminger & Kasari, 2000;
coping strategies, accepting, normalizing, Bauminger et al., 2004). Greater feelings of
and finding meaning in their experience may self-worth and decreased feelings of loneli-
therefore be helpful in promoting children’s ness were reported if children also reported
adjustment to a chronic disease process. higher perceptions of companionship, in-
timacy, and closeness. Given that children
with disabilities often experience loneli-
Social Adjustment
ness, developing friendships could be key to
and Peer Relationships
self-esteem development and maintenance
Peer support is important because it pro- (Bauminger & Kasari, 2000; Bauminger et
motes psychological health and adjustment al., 2004).
(Varni, Katz, Colegrove, & Dolgin, 1994; When a disease is visibly disfiguring, the
Varni, Rubenfeld, Talbot, & Setoguchi, consequences may become more dire, with
1989). In their extensive review of the lit- these children being at greater risk of being
erature, Thompson and Gustafson (1996, treated poorly by their peers (Hearst, 2007;
p. 130) concluded that “children with Hunt, Burden, Hepper, Stevenson, & John-
chronic physical illness are at risk for dif- ston, 2006; Shaw, 1981). The dynamic inter-
ficulties in social adjustment and peer rela- play between the child and the environment
tionships as well as school adjustment and is evident in a series of case studies by Hearst
performance. These difficulties may vary as (2007). In early childhood, the formation of
a function of illness type, with children with reciprocal peer relationships is a critical task
illnesses that affect the CNS being at partic- of development; however, this may be quite
ular risk.” Furthermore, children with neu- difficult for children with a visible disability.
rodevelopmental disorders are more likely The challenge of forming relationships con-
90 BACKGROUND
tinues into middle childhood with the devel- Coping within the Family Unit
opment of increased cognitive capabilities
Coping within families involves multifacet-
and awareness. At this stage, children be-
ed, multidirectional interactions among all
come much more evaluative and self-critical.
family members, each influencing the oth-
Bidirectionally, children with a visible disfig-
ers. Parents of disabled children often report
urement may become much more critical of
themselves at the same time that teasing and more distress than parents without disabled
bullying begin to increase in frequency. children do (Yau & Li-Tsang, 1999); how-
ever, many families are resilient and report
adaptive, pleasant family functioning (Li-
Targets for Intervention Tsang, Yau, & Yuen, 2001; Wilgosh, Scor-
Children’s own attitudes, as well as the at- gie, & Fleming, 2000). In a study utilizing
titudes of parents, teachers, and principals, the biopsychosocial approach, parents of
were predictive of whether typically de- children with cystinosis (Spilkin & Ballant-
veloping fourth- and fifth-grade children yne, 2007) reported both positive and nega-
would include children with physical dis- tive aspects in family life. For example, they
abilities in interactions (Roberts & Lindsell, found that parents saw their children as hav-
1997). These findings not only reflect the ing an active role in the family, and that the
bidirectional nature of the biopsychosocial average family unit as a whole was relatively
environment, but suggest a potential avenue happy. However, many stresses were also re-
for intervention. When paraprofessionals ported, such as worry, feeling too much re-
are trained to facilitate social interaction be- sponsibility, and feeling that family life was
tween students with severe disabilities and dictated by the demands of the children with
their nondisabled peers, immediate increas- cystinosis.
es in interactions between students occur The picture with regard to sibling relation-
(Causton-Theoharis & Malmgren, 2005). ships and sibling adjustment suggests that
Encouraging social interaction may have family factors are also important. Overarch-
positive benefits for both disabled children ing parent and family factors (e.g., stress,
and those who are developing normally, communication, and family cohesiveness)
which may result in improved social behav- may be predictive of sibling relationships
iors (Roeyers, 1996). Furthermore, training and sibling adjustment (Giallo & Gavidia-
peers to recognize when a classmate is at- Payne, 2006), over and above peer influ-
tempting to communicate with them, teach- ences (Bellin & Rice, 2007). Furthermore,
ing them strategies to facilitate the commu- the degree of conflict experienced within a
nication and interaction, and instructing sibling relationship may influence psycho-
them to distribute those efforts over the day logical state (e.g., depression, anxiety), po-
resulted in greater positive social interaction tentially placing the healthy sibling at risk
for children with moderate developmental for adverse psychological outcomes (Stocker,
disabilities (Goldstein, English, Shafer, & Burwell, & Briggs, 2002; Verte, Hebbrecht,
Kaczmarek, 1997). Typically developing & Royers, 2006). However, siblings who
children who had more frequent interactions characterized their relationship as warm
with disabled children displayed higher ac- and caring typically experienced more posi-
ceptance and understanding of the children tive outcomes (Kim, McHale, Crouter, &
with disabilities (Diamond, 2001). Given Osgood, 2007; Seltzer, Greenberg, Krauss,
that children with developmental disorders Gordon, & Judge, 1997).
are at risk for poor social interactions, it The interface between child and maternal
may be useful to focus recommendations adjustment may be especially significant in
on those factors that help increase the prob- determining the outcome of the entire fam-
ability of success in their environment. Early ily system. Mothers of children with chronic
intervention may be critical, given that a illness may experience higher levels of nega-
child’s interactional patterns tend to remain tive affect, maladjustment, and depression
stable; if they are positive from the begin- than mothers of healthy children do (Berge,
ning, they are likely to remain so over time Patterson, & Rueter, 2006; Cadman, Rosen-
(Guralnick et al., 2006). baum, Boyle, & Offord, 1991; Wallander,
1993). Spilkin and Ballantyne (2007) found ance and interpersonal relationships); and
that mothers were more likely to endorse the various aspects of coping skills involving de-
feeling that the children’s illness was nega- fenses and problem solving. They considered
tively affecting their families. Mothers were all levels of a systems hierarchy, including
also more likely than fathers to report feel- physical and illness-related factors, personal
ings of worry and the view that the disease background, and social and environmental
was having specific negative consequences factors. These elements contribute to a set
for family time and finances. Furthermore, of adaptive tasks, such as dealing with stress
mothers and fathers may have difficulty associated with the condition itself and its
with different aspects of the illness, which treatment, maintaining relationships with
may contribute to reductions in marital sat- caregivers, managing distressing emotions,
isfaction. Fathers reported more stress re- preserving family and social relationships,
garding father–child interactions, maladap- and anticipating the future.
tive behavior, and perceived lack of support, Moos and Tsu (1977) described coping
whereas mothers reported feeling more stress skills as involving multiple factors, includ-
about specific aspects of the children’s dis- ing minimizing the seriousness of the situ-
ease (Macias, Saylor, Haire, & Bell, 2007). ation, seeking information and support,
However, the picture regarding marital sat- emphasizing problem-solving skills, and
isfaction is mixed, with some studies finding finding meaning in the illness. More re-
greater marital satisfaction (Kazak, 1987; cent research discusses these concepts in
Taanila, Kokkonen, & Jaervelin, 1996) and terms of family coherence, which may also
some studies finding no differences (Seltzer have consequences for a child’s health out-
& Greenberg, 2001). In a meta-analysis, comes. Optimal family functioning depends
Risdal and Singer (2004) found a small but on comprehending the dynamic, shifting
significant effect for the impact of having a responsibilities that will be a part of man-
child with a disability on marital adjustment aging chronic illness in the family. In addi-
and satisfaction, as it placed slightly more tion to understanding the difficulties inher-
strain on the marital relationship. ent in this position, family members must
In other words, these findings suggest be able to shift and adapt their own coping
that a child’s adjustment is affected by the strategies to meet these changing dynamics
experiences of maternal stress, relationships (Spilkin & Ballantyne, 2007). Families high
with other family members, and the family’s in coherence have the ability to reframe life
environmental support system—a notion di- situations in positive terms (Kelso, French,
rectly derived from social-ecological theory. & Fernandez, 2005; Lee, Lee, Park, Song, &
Thompson and colleagues have utilized this Park, 2004; Walsh, 2003) and believe that
model to understand the functioning of chil- they can anticipate and adapt to life events.
dren with cystic fibrosis, sickle cell disease, Of course, this may be commensurate with
and spina bifida. In the end, after consider- the severity of a child’s disease process and
ing the host of models that have now been the resources truly available to a family.
proposed, Thompson and Gustafson (1996, With regard to coherence, some patterns
p. 156) suggested that “stress processes, so- were evident in those families ranked as
cial support, and parenting are currently the high, medium, and low in coherence (Ret-
most prominent intervention targets.” zlaff, 2007). All families described an initial
crisis phase and feelings that were commen-
surate with crisis. However, those low in
Elements of Adaptive and Maladaptive
coherence experienced the crisis longer and
Coping in the Family
showed no definitive shift into more adap-
In 1977, Moos and Tsu developed a life cri- tive ways of functioning. Families high in
sis model of adjustment to childhood illness, coherence eventually began to rely on them-
in which the outcome of crisis precipitated selves to manage their situation; however,
by illness involves cognitive appraisals of the self-reliance was facilitated by positive social
meaning of the illness; adaptive tasks (i.e., experiences and strong family relationships,
dealing with symptoms of the illness and allowing them to shift their worldviews and
its treatments, maintaining emotional bal- focus on more positive aspects of their lives.
92 BACKGROUND
Those lower in coherence tended to focus Diagnosis in Systems and Sequences

mostly on the negative stressors.
Similar to a life crisis approach is one that Adam, the only child of an intact marriage,
sets a family systems model within a post- was born following a full-term pregnancy
traumatic stress framework (Gudmundsdot- complicated by maternal dehydration in the
tir, Gudmundsdottir, & Elklit, 2006), given first 4 months, which required several hos-
that chronic illnesses may threaten the life pitalizations. There was no maternal medi-
and physical ability of the child with the dis- cation or substance abuse. He was delivered
ability. Specifically, Gudmundsdottir and following a 37-hour labor, and although
colleagues (2006) looked at those risk (e.g., there was some meconium staining, there
illness characteristics, dependence for self- was no need for intensive care. However,
care, and psychosocial factors) and resis- at 1 week of age he developed a fever of
tance (e.g., individual characteristics, social 105°F with gastrointestinal distress, and the
environment, and coping abilities) factors distress persisted. At age 6 months, he was
proposed in Wallander and Varni’s (1998) diagnosed with transient hypogammaglobu-
disability–stress–coping model of adapta- linemia and Clostridium difficile, but treat-
tion to chronic illness. The experience of ment did not relieve his chronic diarrhea,
memories as traumatic strongly predicted pain, and sleep disturbance. He was fed by
overall psychological distress and was the nasogastric tube and was intermittently hos-
only predictor of a measure of overall im- pitalized for 4 years. Additional problems
pact on the family. However, coping abil- developed, including apnea, very occasional
ity (i.e., how the process was evaluated and partial and generalized seizures, stroke-like
managed) influenced which memories were episodes, irregular heart rate, stomach and
experienced as traumatic. leg pain, labile emotions, and unpredict-
In light of the relationship among cop- able and sometimes markedly dysregulated
ing, trauma, distress, and family impact, behaviors. Apart from primary nighttime
it is important to consider those factors enuresis, developmental motor and language
that contribute to successful coping within milestones were met in a timely way. Adam
families. Retzlaff (2007) studied those fac- was diagnosed at an early age with an in-
tors facilitating adaptive coping and ad- testinal pseudo-obstruction, and he had a
justment in families of children with Rett bowel resection. Only shortly before neu-
syndrome. He found that many elements ropsychological assessment at age 13, mus-
described by these families belonged to one cle biopsies were found to be consistent with
of two categories—stressors and resources. mitochondrial myopathy in both mother and
Stressors were frequently of the following child. A gastrostomy tube had recently been
types: emotional, disease-related, uncer- placed, and a psychotherapist was consulted
tainty, social rejection, lack of access to ex- in regard to Adam’s behavior problems and
perts, and social comparison with families in order to assist him with relaxation in the
of healthy children. Resources facilitating face of pain.
adjustment included material resources, ac- It might seem that a child with such a
cess to information about the disease, and lengthy history of intense medical difficul-
support in the couple, family, social, and ties, even though an encompassing diagno-
professional environments. In addition, sis was exceptionally elusive, would receive
changes in families’ worldviews were seen supportive services without debate or hesi-
as beneficial, and similar results have been tation; however, this was not initially the
found in several other studies (Kelso et al., case. Prior to the diagnosis of mitochondrial
2005; King et al., 2005; Poehlman, Clem- myopathy, the combination of vague somat-
ents, Abbeduto, & Farsad, 2005). The take- ic complaints such as belly or diffuse limb
home message appears to be that successful pain, disruptive behavior, and efforts to re-
coping is facilitated by support within the treat from the demands of the classroom be-
immediate family, the extended family, soci- cause of fatigue were suspected to represent
ety, and the medical community. Increased a psychiatric condition. More malignant was
ability to change one’s world view and re- the suggestion by some health care profes-
frame the situation may be aided by these sionals that this was a case of Munchausen
psychosocial factors. syndrome by proxy. That accusation polar-
ized the situation dramatically: The school as initial anxiety over the meaning of the di-
system became suspicious and withholding, agnosis evolves during the course of actual
and the parents became horrified that they treatment. Also, familiarity with a diagnosis
were accused of causing their son’s symp- may result in a more advanced conceptual
toms. Suits and charges were considered; the understanding; for example, a preschooler
family system reached a point at which in- may apply more sophisticated causal reason-
structional efforts (many of which were ening to a cold than to a newly diagnosed neu-
tirely appropriate) were rejected as unhelp- rological disorder (Siegel, 1988). Similarly,
ful; and Adam was increasingly drawn away there are developmental considerations in
from school. children’s understanding of the nature of a
With the formal diagnosis of mitochon- genetic or neurodevelopmental disorder, and
drial myopathy in both Adam and his moth- an extensive literature within pediatric psy-
er, the parents were no longer accused. They chology advises health care professionals to
embraced the disorder publicly, with Adam take the nature of cognitive functioning in a
becoming a regional poster child, and with Piagetian sense into account when they are
his mother becoming the subject of local conveying medical diagnostic and treatment
newspaper articles on the disorder. The information to children of different ages
mother continued to believe that her own (Brodie, 1974; Campbell, 1975; Mechanic,
life was precarious, though this was medi- 1964; Neuhauser, Amsterdam, Hines, &
cally unlikely. Neuropsychological evalua- Steward, 1978; Palmer & Lewis, 1976).
tion was able to define the direction of aca- Specific information concerning stages
demic modifications acceptable to both the of child cognitive functioning in a pediatric
school system and the family, and Adam’s context may be found in Perrin and Gerrity
functioning in school improved. Interest- (1981), Whitt, Dykstra, and Taylor (1979),
ingly, the family soon withdrew from psy- and Bibace and Walsh (1979). In some ways,
chotherapy, which could have helped them one can trace children’s movement toward
negotiate ongoing threats to the adjustment more systemic thinking when it comes to
of each individual. their own health. Thus a child functioning
In this case, when all the many influences at a preoperational level (between ages 2 and
on Adam within family and social systems 7) may consider illness prevention and recov-
recognized his illness, he got better. The im- ery to be associated with a rigid set of rules
provements did not result from more closely surrounding immediate and concrete per-
targeted medical treatments at a biological ceptions of experience—avoiding the touch
level; rather, the framework of expectations of friends, for instance, or staying in bed.
changed, promoting alterations in system Later, with the emergence of formal opera-
relationships and a shift in affect. In a cu- tions, illness may be conceptualized not only
rious way, impotence, guilt, and rage were in terms of internal organs whose malfunc-
diminished when the etiology of Adam’s tions are manifested in external symptoms,
compromises changed from a psychologi- but also in terms of psychological events as
cal to a genetic realm, and the psychological disease symptoms and causes of internal
health of the family system improved when dysfunction; the etiology of headache, for
the family members organized around this example, may include too much worry. The
rare illness. In the sense of social ecology, concepts of neurodevelopmental and genetic
the family had reached a new state of ho- disorders may be especially difficult to com-
meostasis—one seeming more functional to municate when they affect academic adjust-
the outsider, though still constrained within ment, and many parents and professionals
what Resnick (1984a, p. 41) has described have found the books by Mel Levine (1990,
as the “public relations representative” role, 1993) especially helpful.
in which the individual or family members
have placed upon them(selves) a constant
burden of explaining and interpreting. Patterns of Family Interaction
It should be pointed out that diagnosis is
not a one-time event. Kupst and colleagues Susan was a 10-year-old girl with a rare vari-
(1984) have studied different temporal reac- ant of a rare disorder, leukodystrophy, which
tions to the diagnosis of a child with cancer, had resulted in a broad set of impairments.
94 BACKGROUND
She became progressively ataxic, often using as well as a measure of almost omnipotent
a wheelchair, but still able to walk slowly control over parental behaviors. There were
and to participate in swimming. Purposeful minimal efforts to target these symptoms
movements could precipitate striking tituba- with psychotropic medication because of the
tion. There were concerns about early optic potential for negative side effects in a child
atrophy and the development of horizontal with great medical complexity. Efforts thus
nystagmus. Her seizures were under control, became psychotherapeutic, assisting Susan
but she was struggling to manage abrupt in decreasing her fears and apprehensions—
moments of bowel urgency, especially given some of which were primitive, vague, and
her motoric difficulties with self-toileting. nameless, but probably connected with fears
Her cognitive functioning dropped to the of death. For the mother, there were efforts
range of mild intellectual disability, and she to reframe “caring” as taking on the fright-
was placed in a substantially separate special ening task of letting her daughter “suffer”
educational setting. The prognosis for this limit setting, in the service of ultimately ac-
leukodystrophy was grave—gradually pro- quiring greater autonomy in some things as
gressive and devastating neurological com- she became more dependent in others. Nev-
promises, and a greatly restricted lifespan. ertheless, it was not the parents’ goal to es-
Such disturbances in the growth and de- tablish a typical set of boundaries and roles
velopment of a child are terrible in and of in parent–child or marital relationships,
themselves, as the expressions of a still- simply because they felt they had precious
forming nervous system in increasing disar- little remaining time with Susan and did not
ray because of progressive white matter dis- wish to spend it in active conflict. Thus in
ease. At issue in the context of this chapter many ways the family had reached a point of
are the various other influences in the ecol- homeostasis. As Kazak (1989, p. 26) points
ogy of Susan’s life. Susan developed symp- out, the construct of homeostasis may be
toms of anxiety and marked dependence used to appraise patterns of family interac-
on her mother, and she made increasing tion that serve to maintain a sense of sta-
demands on her. The mother was the only bility. In other words, “reactions that tend
one she permitted to assist her in toileting, to be viewed as maladaptive (i.e., overpro-
and if she was unavailable (at school, for tectiveness, enmeshed family relationships,
instance), Susan would not eat beforehand. denial) may actually function to maintain a
Separation became difficult. Indeed, she was protective homeostasis for the family.”
demanding ever more complex nighttime rit- On the other hand, as Kazak (1989) adds, a
uals: She wouldn’t go to sleep unless certain family system may become too harmful to its
lights were on; her mother not only had to members; abuse must be dealt with as an in-
be holding Susan’s hand, but also had to be dicator of a family system gone astray, rather
facing her daughter with her eyes open until than simply as a homeostatic variant. Inter-
Susan fell asleep; and she was expected to be ventions leading to a new steady state must be
in the same position when Susan woke. The implemented, as in the following case.
mother and father had discontinued attend- Gail was a child adopted in infancy by
ing a support group for parents of children enormously caring parents with gentle tem-
with academic special needs because their peraments; the adoptive father was a minis-
situation was so profoundly different from ter and academic at an exclusive liberal arts
that of the other parents. college. It wasn’t long, however, before it
In considering this system from a tradi- was clear that the child’s tempo and style of
tional neuropsychological point of view, interpersonal interaction were markedly dif-
one might focus on Susan herself and on the ferent from the parents.’ Gail ultimately de-
nature of her cognitive and motor impair- veloped severe attention-deficit/hyperactivity
ments. And, in fact, she did participate with disorder with highly impulsive features, as
motoric benefit in experimental drug trials well as comorbid symptoms of oppositional
coordinated at a national level for the treat- defiant disorder. The contrast between par-
ment of leukodystrophy. At another level ents and child was sharp, and before these
in the system hierarchy, however, she had diagnoses were made and interventions were
developed symptoms of an anxiety disor- implemented, the situation had deteriorated
der with an obsessive–compulsive quality, into regular and routine outbursts of harsh,
abusive physical punishment of Gail by the sophical history: Hope was among the evils
father. His image of himself as a progressive- in Pandora’s box in Greek tradition, and it
minded humanitarian was shattered as he is a virtue and central theme of the Judeo-
was pressed beyond the heretofore unsus- Christian message (Menninger, 1963). In
pected limits of his capacity to manage the more contemporary times, researchers have
situation. The presumption was that this attempted to operationalize the meaning of
child with a genetically based disorder was hope (Petiet, 1983). It can be classified as a
being raised by parents who did not share coping mechanism incorporating a realistic
her biology and whose style was so different appraisal of current circumstances, a future
as to be nearly irreconcilable. Even though orientation, expectant cognition, optimistic
a combination of medications, behavioral affect, and resultant motivation. As such,
and psychotherapeutic interventions, and re- hope is seen as a desirable state during medi-
spite greatly diminished the misfit between cal procedures and rehabilitation (Brackney
parents and child, the father still needed to & Westman, 1992; Brody, 1981; Lillis &
take daily refuge in books and music within Prophit, 1991; Rabkin, Williams, Neuge-
his library, which was specially constructed bauer, Reimien, & Goetz, 1990; Ruvelson,
for soundproofing and inaccessibility. In this 1990).
way, a new homeostasis was created.
Every disease has a natural history, and
the capacity of a child’s family system to ad- Social Culture
just may be a function of the interplay be-
tween normal developmental challenges and Information concerning contemporary cul-
the nature of the disease’s impact. One of the tural issues influencing the functioning of
most poignant accounts of this interaction children with neurodevelopmental or genet-
may be found in Resnick (1984b, p. 302): ic disorders is available elsewhere; a focus on
specific cultures is too broad for the scope
While his age cohorts were arguing with par- of this chapter. We briefly consider cultural
ents over the length of their hair, he needed factors here in terms of broad-system issues,
help washing his; while they were resisting with the understanding that conceptualizing
doing assigned chores, he was unable to per- a child in terms of his or her culture nec-
form any; while they were battling curfews, essarily requires understanding each indi-
he needed not only permission, but physical
assistance in order to be out. Instead of shar-
vidual child and family in their own context
ing his peers’ increased independence from within their culture. For example, genetic
parents and others, symbolized by mild acting disorders may express themselves according
out behaviors, this patient could merely fanta- to the culture in which they arise. As a par-
size his acting out, with his illness providing ticular instance, in many U.S. cities, a fam-
a constant reminder of his chronic dependent ily with Duchenne muscular dystrophy—a
status. relentlessly progressive and ultimately fatal
neuromuscular disorder that has an X-linked
As stated earlier, some research has pro- pattern of inheritance—may be looked upon
posed stages of parental adjustment, which as pathologically irresponsible if the mother
at some points and in some families may in- continues to have children, despite genetic
clude the experiences of fear, shock, numb- counseling concerning the probability of hav-
ness or detachment, relief, helplessness, ing another affected son. Most families with
denial, sadness or depression, anxiety, and this disorder in mainstream U.S. culture are
guilt (Drotar, Baskiewicz, Irvin, Kennell, & therefore relatively small, with few affected
Klaus, 1975; Hobbs, Perrin, & Ireys, 1985; individuals. By contrast, in San Antonio,
McCollum, 1981). Readers are referred to Texas, which has a high density of families
Whelan and Walker (1997) for further dis- with ties to the traditions of the Catholic
cussion of these issues within families. Church and of Mexico, large families with
Whereas the field of clinical psychology many affected individuals across the genera-
has often focused on such painful human tions may be more common and more likely
conditions, it is also possible to consider al- to be viewed with a charitable eye.
ternatives, and hope is one. This is a con- One of the best examples of writing con-
struct with a complex religious and philo- cerning cultural/sociological issues and
96 BACKGROUND
their political/economic correlates in the ests. The field appears robust, not only given
care of children with chronic illness is the its state at the moment, but also in historical
edited volume by Hobbs and Perrin (1985). context; clearly, the empirical research being
In it they organize representative chapters derived from existing descriptive models of
on specific conditions, including some with the ways in which children adjust to illness
clear neurodevelopmental consequences is much more integrated and detailed than
(e.g., neuromuscular disease, sickle cell dis- it was when the first edition of this book
ease, and spina bifida). The direction of that appeared. Clinically, too, there has been a
text, as well as of another by Hobbs and movement toward improved integration of
colleagues (1985) and of work by Nelson information from traditional clinical psy-
(1984), Resnick (1984a), Silber (1984), and chology and neuropsychology with practices
Strax and Wolfson (1984), extends to public derived from developmental pediatric psy-
policy. These writings probe such topics as chology and (because of the typical ecology
health care expenditure, integrating federal of children) from school psychology. This
programs at the state level, defining parental type of cross-fertilization suggests a produc-
opportunity costs and other economic costs tive future and holds promise for continued
of disabling conditions, the role of ethics and efforts at excellence in professional practice.
values in shaping public policy, and prepar-
ing professionals for new roles.
The last issue—preparing professionals for Acknowledgment
new roles—deserves a personal comment.
We wish to acknowledge the creative and intellectu-
Decades ago, one of us (Whelan) began to ally challenging input of Muireann McNulty in the
lament to colleagues who were supervising development of this chapter.
doctoral psychology trainees in the same
teaching hospital that there was a creep-
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P a r t II
Disorders Primarily Affecting

Learning and Behavior
Chapter 6
Learning Disabilities
Sam Goldstein
Adam Schwebach
Sean Cunningham
Learning disabilities (LD), including read- Within the framework of this chapter,
ing disabilities, are the most prevalent it is not possible to describe adequately or
group of neurobehavioral disorders served attempt to integrate the many competing
in the public schools (U.S. Department of viewpoints and claims surrounding the con-
Education, 1994). Researchers find that it is struct of LD. This task has admirably been
difficult to estimate the prevalence of LD in undertaken by other writers in the field, who
adults, however (Corley & Taymans, 2002). have approached LD from a broad historical
A genetic component to these disabilities perspective as well as from the viewpoint of
has been found (Astrom, Wadsworth, & best current practices (Lerner, 1993; Mercer,
De Fries, 2007; Kovas, Haworth, Dale, & 1991; Swanson, Harris, & Graham, 2003;
Plomin, 2007; Kovas, Haworth, Petrill, Torgesen, 1991). This chapter approaches
& Plomin, 2007; Kovas & Plomin, 2007); LD from biomedical, neuropsychological,
therefore, a chapter addressing the neurobe- and information-processing perspectives.
havioral and genetic aspects of LD is an ap-
propriate topic for inclusion in this text. Un-
like most other genetic disorders, LD do not The Concept
constitute a single, relatively well-defined
entity or syndrome. Rather, they encompass LD as a category of human exceptionality
an extremely heterogeneous group of prob- evolved from observations of physicians and
lems with diverse characteristics that can re- educators as they studied and attempted to
sult from a variety of biological influences, assist children with brain injuries. Alfred
including genetic factors, environmental Strauss and Laura Lehtinen published their
insults to the brain, and possibly (as recent classic work Psychopathology and Educa-
research on brain development suggests) tion of the Brain-Injured Child in 1947.
extreme lack of early environmental stimu- In 1966, Clements, as head of a task force
lation. As a result, the multifaceted field of sponsored by the U.S. Department of Health,
LD is complex and often contentious, with Education and Welfare, strongly supported
many competing theories, definitions, diag- use of the term minimal brain dysfunction,
nostic procedures, and suggested avenues of which became popularized as MBD (Mer-
intervention. cer, 1991).
105
106 DISORDERS PRIMARILY AFFECTING LEARNING AND BEHAVIOR
The terms minimal brain injury or MBD ing on the psycholinguistic-process model of
were used to describe children of normal in- Charles Osgood, Kirk described LD accord-
telligence who appeared similar to some ining to learning channels (auditory–verbal or
dividuals with known brain injury, in that visual–motor), learning levels (rote or con-
they exhibited a combination of hard or soft ceptual), and specific processes (perception,
signs of neurological deficiency concomi- reception, memory, integration, expression,
tantly with educational and sometimes be- etc.) (Kirk & Kirk, 1971). More recently,
havioral disorders. MBD was believed to be Naglieri and Das (2002), drawing on Lu-
responsible for observed deficits in processes ria’s model of intellectual processes, have
such as auditory and visual perception, sym- described four critical processes essential
bol learning, short- and long-term memo- for effective learning. Luria’s PASS model
ry, concept formation and reasoning, fine involves planning, attention, simultaneous
and gross motor functions, and integrative processing, and successive processing. Weak-
functions—deficits resulting in disorders of nesses in various combinations of these pro-
receptive and expressive language, reading, cesses have been associated with specific LD
writing, mathematics, physical skill devel- (Naglieri & Das, 2002).
opment, and interpersonal adjustment. In Although the view of LD as neurologically
addition, behavioral traits such as distract- based process deficits remained widespread,
ibility, impulsivity, perseveration, and disin- during the 1970s a behavioral approach to
hibition were often found in children with the topic was promulgated. Process deficits
MBD (Cruickshank, Bentzen, Ratzeburg, were roundly criticized as hypothetical con-
& Tannhauser, 1961; Fletcher, Shaywitz, structs that could not validly or reliably be
& Shaywitz, 1999; Gardner, 1973; Johnson diagnosed and that had little or no demon-
& Myklebust, 1967). Thus, from the first, strable relationship to effective interventions
the field of LD centered around a medical (Hammill & Larsen, 1974, 1996; Larsen,
model, with the term MBD being applied to Parker, & Hammill, 1982). Proponents of
an extremely heterogeneous group of indi- this view advocated criterion-referenced or
viduals. curriculum-based assessment of a multitude
Johnson and Myklebust (1967) discussed of specific skills, and interventions based on
the limitations of extant terminologies. They a detailed analysis of the component parts
suggested that minimal was inappropriate of each skill to be taught/learned, along
to describe individuals whose resulting dis- with ecological analysis and modification
abilities had a much greater than minimal of the learning environment. Well-designed
impact on their learning functions, and that and group-validated approaches to curricu-
the words brain injury or brain dysfunction lum instruction were held to be appropriate
were viewed as too stigmatizing by many af- and effective for all students, including slow
fected individuals and their parents. learners, without reference to supposed in-
In 1963, at a national organizing confer- ternal processing deficits or disabilities. This
ence of concerned parents and professionals approach, now referred to as response to
held in Chicago, Samuel Kirk proposed use intervention, has become increasingly popu-
of the term learning disabilities (LD) (Lern- lar and frequently advocated within special
er, 1993). This term was quickly accepted education programs in public schools.
by parents and continued to gain ascen- While debate raged, a third approach to
dance when federal and state governments understanding and assisting those with LD
adopted it at the time special education ser- added a new dimension. Based on research
vices were expanded to include students of centered at the University of Virginia (Hal-
average or better intelligence with otherwise lahan, 1980) and the University of Kansas
unexplained academic learning problems (Schumaker, Deshler, Alley, & Warner,
(Mercer, 1991; U.S. Office of Education, 1983), cognitive learning models were ap-
1977). Kirk viewed LD from a psycholin- plied to the understanding and treatment of
guistic perspective: He proposed that under- LD. Within a cognitive framework, learners
lying specific deficiencies in central nervous are viewed as directing their own learning
system (CNS) functioning result in deficits by focusing on topics and skills that are per-
in psychoneurological learning processes, sonally meaningful and by developing active
which in turn explain observed LD. Draw- strategies for information acquisition. One
Learning Disabilities 107
outgrowth of cognitive theory has been the lence and detection rates may, and indeed
holistic or constructivist approach to teach- probably do, differ. Depending on the strin-
ing and learning, including whole-language gency of identification criteria, prevalence
methods of reading instruction. Although estimates for LD have varied from as low
the tenets of cognitive theory have been ap- as 1% to as high as 30% of the school-age
plied to the population with LD in a num- population (Lerner, 1993). Mercer (1991)
ber of ways, a major emphasis has been on suggested that approximately 1.5% of stu-
helping students to develop more reflective, dents might have severe specific LD, while
accurate, and efficient approaches to learn- the inclusion of students with mild LD could
ing tasks (i.e., learning how to learn). Stu- raise that figure to about 4% or 5%. Other
dents are taught to consciously employ self- studies focusing on a specific classification
monitoring strategies and effective learning/ of LD have identified 5–8% of school-age
study strategies. This model, which empha- children as exhibiting arithmetic disabilities
sizes a focus on how students learn versus (Geary, 2003) and 5–17.5% as having dys-
what students learn, may have influenced lexia (Shaywitz, 1998). The number of chil-
the scientific discipline away from more def- dren thought to have some type of LD ex-
icit-based conceptualizations of LD (Wong, tends to 4.6 million, only half of whom are
1987). receiving special education services (Pastor
& Reuben, 2008). The most recent national
estimates indicate that 6–9.7% of children
Prevalence suffer from LD (Pastor & Reuben, 2008).
Many factors are associated with what
Determining prevalence rates, or the fre- some view as the burgeoning or even epi-
quency of occurrence, of LD in the popu- demic identification rate for LD. These fac-
lation might at first glance appear to be a tors can be divided into four groups: those
relatively straightforward process. How- related to definition/classification, available
ever, since prevalence rates for any disease diagnostic instrumentation, systems opera-
or disability are dependent on having a tion, and sociopolitical realities. The four
clear-cut definition of the disorder under factors are discussed in detail here because
consideration, and since there is no consen- they are central to some of the most impor-
sually accepted or experimentally validated tant and persistently ineluctable issues in the
definition of LD, the process of determin- field of LD.
ing the prevalence of LD is a quagmire. At As mentioned above, the primary factors
the present time, prevalence figures for this underlying the widely varying prevalence es-
nondefinitive disorder or group of disorders timates for LD are lack of a clear-cut defi-
cannot be determined precisely and are es- nition and lack of classification procedures
sentially broad estimates. However, “the derived from coherent theory. Lyon (1996)
DSM-IV-Text Revision does acknowledge stated: “Valid prevalence estimates depend
that the prevalence of different LD types is on a set of criteria for identification that are
difficult to establish because many studies clear, observable, measurable, and agreed
focus on the prevalence of Learning Disor- upon” (p. 58). Although research-based the-
ders in general without careful separation ory building in terms of definition and clas-
into specific Disorders of Reading, Math- sification is proceeding apace in the areas
ematics, or Written Expression” (Corley & of phonologically based reading disorders
Taymans, 2002, p. 55; see American Psy- and nonverbal learning disabilities (NLD)
chological Association, 2000). (Torgesen, 1993), for the broad field of LD
Important considerations regarding the de- this remains a distant goal. As noted ear-
termination of LD prevalence were present- lier, the concept of LD is multifaceted. Di-
ed by MacMillan (1993) and Lyon (1996). verse views are engendered by a wide array
In a discussion of operationalizing disability of associated medical and pedagogical dis-
definitions MacMillan described prevalence ciplines, including neurology, psychology,
rate as referring to the total percentage of neuropsychology, speech and language pa-
the population that is affected by a disorder, thology, optometry, occupational and physi-
while detection rate refers to the number of cal therapy, and education, as manifested
known or identified cases. For LD, preva- through university research, regular educa-
tion, special education, and private clinical there are measures available to assess these
assessment/tutoring. Each profession has its constructs, their specificity, adequacy, qual-
own set of theoretical considerations, meth- ity of standardization, and breadth of dis-
odologies, and predilections. In addition, semination are highly variable. The develop-
there is much variability within professional ment of psychometrically sound diagnostic
orientations. For example, among public instruments remains a primary goal; it will
school special education programs, the cri- reduce misidentification and eventually have
teria for designating students as having LD a positive impact on our understanding of
vary widely. Mercer, Forgnone, and Wolking the prevalence of LD, as well as specific sub-
(1976) and Mercer, King-Sears, and Mercer types of LD.
(1990) documented the range of definitions A third important (though somewhat
of LD and the lack of agreement in the di- overlooked) factor affecting LD prevalence
agnostic criteria adopted by state boards of rates consists of what MacMillan (1993)
education across the United States. The con- has termed system identification variables.
cept of IQ–achievement discrepancy, which This factor overlaps to some degree with
is presently the central feature of LD diag- the fourth factor, the effects of sociopoliti-
nosis in public schools, is operationalized cal realities. Broadly, system identification
differently by different states, with arbitrary encompasses the ecological processes within
cutoff points for both intellectual level and families, schools, and clinics that increase or
achievement level. One result of this highly decrease the likelihood of a given individu-
flexible decision making is that the percent- al’s being referred for evaluation and classi-
age of children designated as having LD dif- fied as having LD. Family system variables
fers from state to state, varying from 2.85% affecting whether parents seek LD assess-
to 9.43%—a threefold difference (Reschly ment for a child, or whether an individual
& John, 2004). seeks assessment for him- or herself, may
Another factor affecting the detection include socioeconomic status (SES), family
rate for LD is the availability of an appro- values regarding educational attainment for
priate range of reliable and valid assessment males versus females, the presence or ab-
measures. Although there is much criticism sence of comorbid conditions that create ad-
of IQ–achievement discrepancy as the basis ditional functional difficulties, the presence
for determining presence or absence of LD or absence of medical insurance coverage,
(Lyon, 1996; MacMillan, 1993; Mather & and so forth. Variables within educational
Roberts, 1994; Stanovich, 1993; Toth & Sie- systems that influence the prevalence of LD
gel, 1994; Zigmond, 1993), intelligence and include the educational philosophy of the
achievement will probably always be essen- school system, financial incentives for iden-
tial constructs for understanding individuals tification, the nature and quality of basic ed-
with LD, and therefore must be measured as ucation provided for all students, class size,
accurately as possible. In addition, to the ex- training of regular class teachers to accept
tent that types of LD are viewed as reflect- and deal with diversity, availability of other
ing specific process deficits or information- types of supportive services for students and
processing deficiencies, there must be a teachers, training/competence of special
variety of well-standardized instruments education diagnosticians, and the like. LD
for quantifying processing strengths and prevalence rates are also affected by socio-
weaknesses. For a given individual, it may political factors, such as increased attention
be important to assess any of the follow- to learning disabilities as a result of public
ing: phonemic awareness, phonological awareness and political advocacy; ambigu-
segmentation, grammatical and semantic ity in the definitions and overlap of disability
comprehension, rapid automatic naming categories; and the social desirability of an
(quick label retrieval), digit/sentence repeti- LD classification rather than a classification
tion, oral expression, tactile perception, di- of intellectual disability or mental retarda-
rectional perception, spatial organization, tion (Keogh, 1993; MacMillan, 1993). In
social perception, verbal and nonverbal con- addition, MacMillan (1993, citing Zigler &
cept formation, concrete and abstract prob- Hodapp, 1986) has suggested that for LD
lem solving, processing speed, and motor “the ratio of detected to undetected cases
coordination in its many forms. Although may (and probably does) vary by age, IQ
level, racial group, gender, and socioeco- (Huston, 1992). Various explanations have
nomic status” (p. 143). been suggested to account for the preponder-
Within school populations, data have ance of males with reading disability—for
been gathered on the prevalence of LD by example, genetic factors, factors associated
age, race, and gender. A report from the U.S. with differences in prenatal brain develop-
Department of Education (2007) presented ment, sex-linked differences in hemispheric
data showing that 1.22% of the students in specialization, postnatal maturational dif-
kindergarten were receiving special educa- ferences, and system identification variables
tion services for LD, whereas 6.49% of fifth (Kelley, 1993; Pennington, 2009; Thomson,
graders were receiving such services. Lerner 1990). Research on genetic factors as expla-
(1993, citing U.S. Department of Education, nations for these sex differences has been
1991) reported that the number of children equivocal, with some studies finding no dif-
with LD served in special education at each ferential genetic etiology between males and
age level increases rapidly from 6 years to females in the development of reading dif-
9 years, peaks and levels off for children ficulties (Hawke, Wadsworth, & De Fries,
ages 10–12, and then gradually declines to 2006). Although some of the variation in
age 18. Thus it appears that the majority of male–female prevalence or severity of read-
children with LD are first identified during ing disability can probably be attributed to
their primary and intermediate years of el- biological differences, findings from three of
ementary school, and that far fewer students the universities in the LD Research Network
are first identified during secondary school. indicate that nearly equal numbers of males
Lerner (1993) has also suggested that the and females manifest dyslexia (Lyon, 1996;
decrease in the number of students with LD Kolata, 1990; Shaywitz, Shaywitz, Fletcher,
served during their teen years may partially & Escobar, 1990). Moreover, recent stud-
be accounted for by the number of teenagers ies have found that there are confounds in
with LD who drop out of school. the research examining sex differences in
The U.S. Office of Civil Rights has been the prevalence of dyslexia, making it appear
concerned about the number of students from as if more males suffer from the disorder
racial and ethnic minority groups who are (Berninger, Nielsen, Abbott, Wijsman, &
identified as having disabilities and enrolled Raskind, 2008).
in special education. A 1994 survey by that When prevalence estimates are deter-
office (cited by Reschly, 1996) reported that mined through research-based epidemiolog-
a total of 8% of African American students, ical studies in which every child in a given
6.5% of European American students, and cohort of children is assessed for reading
5.6% of Hispanic students were enrolled disability, the ratio of males to females is
in special education under the categories of close to 1:1; when estimates are determined
mild mental retardation, severe emotional through prevalence figures for school-
disability, and LD. Although African Amer- identified or clinic-identified populations
ican students may be overrepresented and based on teacher or parent referral, the ratio
Hispanic students underrepresented over- of males to females is much higher. System
all, according to this survey the percentage identification variables resulting in gender-
of students from each group categorized as based ascertainment bias appear to account
having LD was relatively constant at 5.0% for the majority of this difference. As is true
of African Americans, 5.0% of European for boys in general, boys with reading diffi-
Americans, and 4.7% of Hispanics. culty display more behavioral problems, in-
The prevalence of LD by gender has long cluding regulation of activity level, than do
been a topic of discussion and concern. girls. Since their functional difficulties are
Lerner (1993, citing U.S. General Account- more readily perceived as problematic, more
ing Office, 1981) reported that of the spe- boys than girls are referred for assessment,
cial education students classified as having and consequently more are classified to re-
LD at that time, approximately 72% were ceive special education services (Shaywitz et
boys and 28% were girls. Research studies al., 1990).
of individuals with reading disability have Studies of adopted children have shown
typically estimated that the gender ratio that diagnoses of LD are four to five times
of males to females ranges from 2:1 to 5:1 more frequent in this group than in an
equivalent group of nonadoptees (Kenny, 1997), and semantics (Pugh et al., 1996).
Baldwin, & Mackie, 1967; Silver, 1970, However, a great deal of variability has been
1989). Because information about the bio- found within and between studies, such
logical parents of adoptees is often limited that multiple sites within similar regions
or confidential, it is difficult to determine of the brain have been implicated in these
the reasons for the high rate of LD among processes (Poeppel, 1996). Moreover, very
adopted children. few functional neuroimaging studies have
been conducted specifically with children, in
part due to the fact that PET requires the
Etiology application of radioactive material. At least
one study using fMRI has mapped language
Background:
dominance in children with partial epilepsy,
Neurobiological Findings
finding results similar to those observed in
From the time of the earliest medical re- adults (Hertz-Pannier et al., 1997). Read-
ports describing cases of dyslexia, researchers interested in an extended discussion of
ers have viewed LD as stemming from CNS learning and brain imaging are referred to
dysfunction, more precisely, from dysfunc- Berninger (2004).
tion of specific portions of the cerebral cor-
tex (Doris, 1986; Huston, 1992). This long-
Environmental Factors
standing presumption is being reinforced and
validated by modern cognitive neuroscience. The various types of LD have traditionally
Language-specific processing in areas of the been viewed as neurological deficits intrinsic
brain surrounded by the sylvian fissure has to genetic and other biological factors within
been associated with a variety of language individuals, and not as problems of environ-
functions. The temporoparietal cortex re- mental origin. However, research has docu-
ceives projections containing but not limited mented the intimate connection between
to visual and auditory information. The pos- environment and neuroanatomical devel-
terior superior temporal gyrus or Wernicke’s opment (Dawson & Fischer, 1994; Huten-
area is associated with a variety of language locher, 1991). The pervasive effects of early
functions, particularly involving comprehen- environmental programming on the forma-
sion. However, it is probably oversimplistic tion and pruning of neural networks, and
to describe temporoparietal areas as those the theoretical relationship of this process to
responsible for the reception of language the occurrence of neurologically based spe-
and frontal regions as those responsible for cific LD, are areas that are only beginning to
expressive language. It is more likely that a be considered.
distributed network is responsible for full The prenatal, perinatal, and postnatal en-
coherence of the language system (Joseph, vironmental factors associated with brain de-
Nobel, & Eden, 2001). velopment and brain injury are best viewed
Positron emission tomography (PET) at present as potential causes of LD, due to
and functional magnetic resonance imag- uncertainties and inconsistences in the rela-
ing (fMRI) have been used extensively to tionships among age at onset, the severity of
extend our understanding of how specific the circumstance or condition, the degree of
components of learning map onto the brain transient or permanent brain dysfunction,
(Ghilardi et al., 2000; Grahn, Parkinson, & and the broad range of possible effects on
Owen, 2009; Hubert at al., 2007; Rumsey learning. For example, clinical studies have
et al., 1997; Thiel, 2003). As these tech- documented cases in which major structural
niques have become more refined and tech- deficits (even loss of an entire brain hemi-
nologically advanced, our understanding of sphere) result in few observable signs of LD,
structural differences implicated in LD has whereas many individuals with severe LD
progressed. Despite their limitations, these have no obvious structural deficits (Bigler,
techniques have revealed much about struc- 1992; Satz, 1990). In addition, confounding
tures of the brain associated with visual variables such as SES, parenting style, and
word form (Fritch, Friston, Liddle, & Frack- early interventions mediate the degree to
owiak, 1991), orthography (Flowers, Wood, which a neurological abnormality will result
& Nailer, 1991), phonology (Rumsey et al., in impaired learning. In many cases of LD,
environmental etiology is presumably not a total number of subjects in this study was
factor. However, in some cases an environ- 1,044, making it an extensive family study.
mental cause is directly known or fairly cer- The results clearly demonstrated that read-
tain; in other cases the environmental con- ing disorders are familial in nature. Scores
tribution to etiology is cloudy, involving a for siblings of proband subjects were sig-
subtle interplay of potential factors that may nificantly lower than scores for siblings of
be undocumented or unknown. control subjects on measures of both reading
and symbol-processing speed. A similar pat-
tern of significant results was observed for
Genetic Factors
the parents of probands and controls. An in-
In the last 40 years, experimental research teresting finding was that, on average, broth-
has provided strong support for genetic fac- ers of probands exhibited significantly more
tors in some forms of LD. The familial oc- reading impairment than sisters of probands
currence of reading, spelling, and writing did. Similarly, fathers of probands were, on
disabilities has been investigated with a vari- average, less skilled readers than mothers of
ety of methodologies, such as study of family probands; however, the score difference be-
history and pedigree analysis, determination tween fathers and mothers was less than the
of concordance rates among identical and score difference between male and female
fraternal twins, comparison of linear regres- siblings (De Fries, 1991). Although read-
sion in reading scores between identical and ing disabilities have now conclusively been
fraternal twins, and chromosomal analysis shown to be familial in nature, familial oc-
of family members. currence suggests but does not demonstrate
The earliest widely cited family pedi- genetic heritability. Empirical investigations
gree study of reading disorder, conducted to ascertain the genetic inheritance of LD,
by Hallgren in 1950 (cited in Pennington, specifically reading disability, have includ-
2009), consisted of a statistical analysis of ed concordance studies of twins, multiple-
dyslexia in 112 families. Among first-degree regression studies of twins, segregation
relatives (parents and siblings of an identified analysis studies, and chromosomal linkage
child), the risk for co-occurrence of this dis- studies.
order was 41%, which is much higher than Comparisons of pairs of identical and fra-
the usual prevalence estimates for the gen- ternal twins have been used to investigate
eral population of 5–10%. Huston (1992), the genetic component of reading disability
reporting on Hallgren’s study, indicated that in the same way that other twin studies have
of the 112 families, in 90 families one par- researched the heritability of intelligence and
ent had dyslexia; in 3 families both parents a variety of other personal characteristics.
had dyslexia; and in 19 families neither par- Many twin studies have employed a com-
ent had dyslexia. Although Hallgren’s study parison of concordance rates to test for ge-
has been criticized for methodological flaws, netic etiology. A pair of twins is concordant
later studies carried out with greater techni- for reading disability if both twins have the
cal precision, such as that of Finucci, Guth- disability; if just one twin has a reading dis-
rie, Childs, Abbey, and Childs (1976), have ability, the pair is discordant. Identical twins
found similar familial rates in the range of have an identical genetic makeup, while fra-
35–45%. Finucci (1978) also published a ternal twins share about 50% of heritable
critical review of the early investigations of variation (LaBuda & De Fries, 1990). To
dyslexia and genetics. More recent studies the extent that reading disability is geneti-
continue to provide considerable evidence cally determined, the concordance rate for
that dyslexia and even dysgraphia have a pairs of identical twins should be consider-
developmental, genetic influence (Raskind, ably higher than for pairs of fraternal twins
2001). when at least one member of each identical
The Colorado Family Reading Study, and fraternal pair has been identified as hav-
begun in 1973, compared the reading abili- ing a reading disability.
ties of 125 children with reading disability Two of the earlier reports of concordance
(probands) and their family members to 125 rates for reading disability in twins were
matched control children without reading those of Hermann (1959) and Zerbin-Rudin
disability and their family members. The (1967). Both of these researchers pooled the
findings of smaller previous studies, possibly However, with IQ controlled for, Stevenson
with some overlap in their reporting of cases. and colleagues found a strong genetic influ-
The concordance rates reported by both au- ence on spelling ability.
thors were nearly identical. Their combined The most technologically sound large-scale
data, as reported by Huston (1992), showed twin study, the Colorado Twin Study, was
an average of 100% concordance for 29 begun in 1982 as part of the Colorado Read-
identical twin pairs and about 34% concor- ing Project. With IQ controlled for (Verbal
dance for 67 fraternal twin pairs. or Performance IQ = 90 or above) and other
Due to technical differences in the method types of selection criteria in place, the Colo-
for determining concordance rates, different rado Study examined reading disability in
authors sometimes report different concor- 101 pairs of identical twins and 114 pairs of
dance figures for the same study; that is, fraternal twins. The pairwise concordance
some authors report pairwise concordance rate of 52% for identical twins was lower
rates, and others report probandwise con- than for most earlier studies, while the rate
cordance rates. The first method counts each for fraternal twins was fairly typical at 33%
concordant twin pair one time. The latter (LaBuda & De Fries, 1990). Although there
method considers each member of a concor- is some variation in the concordance figures
dant pair as a separate research subject, and generated by different studies, on the whole
therefore counts each concordant pair twice. they do provide strong evidence for a genetic
Using probandwise concordance increases factor in the etiology of reading disability.
the percentage of concordance for both iden- In the search for the genetic mechanisms
tical and fraternal twin pairs (LaBuda & De underlying reading disability, two primary
Fries, 1990). For example, in the Zerbin- strategies have been employed: chromosom-
Rudin (1967) study, a pairwise concordance al linkage studies and segregation analysis.
rate for fraternal twin pairs was 34% (12 Working from phenotype (clinical manifes-
of 34 cases) as reported by Huston (1992); tation of disability) to genotype (underlying
however, the probandwise concordance rate genetic substrate of disability), segregation
for those same twin pairs was 52% (24 [12 analysis involves testing all members of af-
+ 12] of 46 [34 + 12]) cases, as reported by fected families for the presence of a reading
De Fries (1991). disorder and then fitting the data to poten-
Bakwin (1973) studied 31 pairs of identi- tial models of genetic transmission (e.g.,
cal and 31 pairs of fraternal twins, finding autosomal dominant, autosomal recessive,
84% pairwise concordance for identical twin codominant, or polygenetic models). Pen-
males and 83% for identical twin females. ningtonand colleagues (1991) after perform-
Interestingly, the pairwise concordance rate ing segregation analysis on four subject
for male fraternal twins was 42%, while the samples, found support for a major-gene
rate for female fraternal twins was just 8%. model, in which dyslexia in some families
Bakwin also investigated the environmen- is transmitted by one or more dominant or
tal factors of birthweight and birth order as partially dominant genes. They also found
predictors of reading disability, but found support for genetic heterogeneity (i.e., mul-
no significant differences between twins tiple genetic mechanisms in the transmission
with typical reading ability and twins with of dyslexia). Further research with more
reading disability on these variables. sophisticated segregation analysis has also
Stevenson, Graham, Fredman, and pointed toward a major-dominant-gene ef-
McLoughlin (1987) conducted a large-scale fect, which occurs frequently (57% of the
study of the reading and spelling abilities of population) and which, when present, in-
285 pairs of 13-year-old twins, who were creases an individual’s liability for reading
divided into several subgroups according problems (Gilger, Vorecki, De Fries, & Pen-
to type and severity of skill deficiencies. In nington, 1994). However, this putative gene
contrast to other concordance studies of is of low penetrance, such that only 3% of
twins, these authors reported relatively simi- individuals having one or two copies of the
lar pairwise concordance rates for identical defective allele demonstrated reading defi-
and fraternal twin pairs (32% and 21%, cits greater than 1.96 standard deviations
respectively). Their findings suggest a fairly below the population mean. Nonaffected in-
low level of heritability for reading disorder. dividuals (43% of the population) with two
normal alleles and no copies of the defective 6, between markers D6S109 and D6S1260
allele had an extremely low probability (p = (Turic et al., 2003). Other evidence points
.0027) of being classified as having a reading to the KIAA0319 gene on chromosome 6
disability. Genetic links to reading disabili- as influencing reading ability and suscepti-
ties have been complicated by studies finding bility to dyslexia (Paracchini et al., 2008).
that although alleles in specific genes have In addition, chromosome 15 and the region
been linked to reading disabilities, the genes including D15S146 and D15S994 on chro-
themselves do not contribute (Smith et al., mosome 15 have been linked to reading dis-
2001). abilities (Morris et al., 2000; Schumacher et
Working from genotype to phenotype, al., 2008).
linkage studies have been conducted to A high prevalence of reading disability
identify the specific chromosomes and the is found in individuals with abnormalities
genetic loci on those chromosomes that are in sex chromosome karyotypes—the most
associated with dyslexia. Through cytogenic common of which is the 47,XXY karyotype
studies of families in which several persons in males (Klinefelter syndrome), occurring
are identified as having dyslexia, the search in approximately 1 of 700 to 1 of 1,000
for a gene or genes that may cause dyslexia births (Berkow & Fletcher, 1992; Penning-
can be narrowed. Smith, Pennington, Kim- ton, Bender, Puck, Salbenblatt, & Robinson,
berling, and Ing (1990) and De Fries and 1982). Although such abnormalities are not
Gillis (1993) have summarized the complex frequent occurrences in the population with
principles of linkage analysis, which involve LD, the strong association between some
investigating both the link between marker sex chromosome anomalies and reading dis-
genes and the disability gene on a chromo- orders provides additional evidence for the
some, and the link between that chromo- genetic heterogeneity of reading disability.
some and the phenotypic occurrence of There is evidence that reading disability
reading disability. per se is not inherited, but that genetic varia-
The pioneering linkage study of Smith, tions influence specific subskills connected to
Kimberling, Pennington, and Lubs (1983) the reading process. Olson, Wise, Conners,
found evidence in some families for a link Rack, and Fulker (1989) found significant
between reading disability and a marker on heritability for a phonological coding task,
chromosome 15p. A later study with a larger but not for an orthographic coding task.
number of subjects provided additional sup- Pauls (1996) reported genetic linkage studies
port for this finding (Smith et al., 1990) and of individuals with dyslexia and their fam-
further suggested that the apparent linkage ily members, in which the individuals were
was present in approximately 15–20% of assigned to one of four research groups ac-
families with multiple cases of reading dis- cording to the primary deficient process evi-
ability. dent in their reading difficulty: phonological
A second possible genetic locus for reading segmentation, nonword reading, rapid nam-
disability in families not linked to chromo- ing, and single-word identification. Similar
some 15 was suggested by the observation of to previous findings, phonological segmen-
the co-occurrence of dyslexia and disorders tation showed linkage to the HLA region of
of the immune system that are coded to the chromosome 6. There was no evidence for a
human leukocyte antigen (HLA) region of connection between word identification and
chromosome 6 (Geschwind & Behan, 1982; chromosome 6; however, there was some evi-
Pennington, Smith, Kimberling, Greene, & dence that the word identification phenotype
Haith, 1987; Smith, Kimberling, & Pen- was tied to a variation in the same portion of
nington, 1991). Subsequent research to test chromosome 15 that was first implicated by
this hypothesis (Cardon et al., 1994) stud- Smith and colleagues (1983).
ied linkage in two independent samples, 126 In summary, family studies, concordance
sibling pairs and 50 fraternal twin pairs, in studies of twins, and multiple-regression
which at least one member of each pair had studies of twins have shown that reading
a reading disability. Analyses of the reading disabilities run in families, that they are her-
performance of pairs genotyped for DNA itable, and that the heritable component is
markers localized the reading disability approximately 50%. Presently, segregation
trait to a small region within chromosome analyses point to genetic transmission via
the effect of a partially dominant or domi- Among the interesting and promising
nant major gene. Genetic linkage studies attempts to define LD are studies involv-
have provided strong evidence that in some ing multivariate analysis. These studies
families and participant populations studied, have found that differences between good
reading disability is linked to chromosome and poor readers may reflect impairment
6p or chromosome 15p. Both segregation in minor skills such as oral word rhyming,
analyses and linkage analyses have led to the vocabulary, discrimination of reversed fig-
conclusion that phenotypic reading disabil- ures, speed of perception for visual forms,
ity is genotypically heterogeneous; that is, and sequential processing (Doehring, 1968).
increased susceptibility to reading disability In 1979, Petrauskas and Rourke utilized a
can be produced by multiple genetic profiles. factor-analytic method to describe the dif-
Furthermore, preliminary evidence suggests ficulties of a group of children with defi-
that within a single individual, the compo- cient reading. They found that these readers’
nent processes of reading may be influenced problems fell statistically into four subtypes:
by separate genes at different loci. (1) primarily verbal problems, (2) primarily
visual problems, (3) difficulty with concep-
tual flexibility and linguistic skills, and (4)
Subtyping no identified specific weakness. The first two
groups correspond with the dysphonetic and
Although public agencies have primarily dyseidetic groups in Boder’s analysis. The
chosen to define LD in terms of a discrep- third may reflect weaker intellectual skills,
ancy between achievement and IQ-based while the fourth may in fact reflect the long-
estimates of potential achievement, this sta- standing clinical perception that certain
tistical definition does little to facilitate an children experience achievement problems
understanding of the underlying processes that may be secondary to non-neurological
that contribute to successful—and, in this factors (e.g., emotional disorder).
case, unsuccessful—achievement. Although Mattis, French, and Rapin (1975) identi-
it has been suggested that LD is a broad, fied three distinct subgroups of children with
nonspecific symptom for which cause must LD, based on a factor analysis. These includ-
be identified, it has yet to be demonstrated ed (1) children struggling to read as the re-
that different causes lead to different types sult of language problems; (2) children with
of LD or, for that matter, require different articulation and graphomotor problems af-
treatments. fecting academic achievement; and (3) chil-
The work of Boder (1973) and Bakker dren with visual–spatial or perceptual disor-
(1979), though over 30 years old, exem- der. The third group displayed better verbal
plifies efforts to classify and identify LD than nonverbal intellectual abilities. Almost
on the basis of educational criteria. Boder 80% of the impaired children fell in the first
described three subtypes of children with two groups. Denckla (1972, 1977) reported
reading disabilities: (1) a dysphonetic group, similar statistics, noting that approximately
lacking word analysis skills and having 16% of children with LD experienced some
difficulty with phonetics; (2) a dyseidetic type of visual–spatial or perceptual–motor
group, experiencing impairment in visual problem.
memory and discrimination; and (3) a mixed Thus there is a strong tendency among
dysphonetic–dyseidetic group. The dyspho- factor-analytic studies to find a large group
netic group included two-thirds of those of children with problems related to verbal
identified as having reading disabilities, with weaknesses and a smaller but significant
the dyseidetic group constituting approxi- group related to perceptual weaknesses. Jo-
mately 10%. Bakker described L-type and schko and Rourke (1985), based on an anal-
P-type dyslexias. Children with L-type dys- ysis of the Wechsler Intelligence Scale for
lexia read quickly but made errors of omis- Children, found a clear distinction between
sion, additions, and word mutilation. Those children with learning problems stemming
with P-type dyslexia tended to work slowly from verbal weaknesses and those whose
and to make time-consuming errors involv- problems stemmed from nonverbal weak-
ing fragmentations and repetitions. nesses.
Satz and Morris (1981) found five distinct age between a younger group (5–8 years old)
groups of children with reading disabilities, and an older group (9–15 years old). On the
again falling along this verbal–nonverbal basis of an extensive neuropsychological bat-
continuum. These included (1) children with tery, these authors found a distinct pattern
language impairment; (2) those with specific of differences resulting in four subtypes. Jo-
language problems related to naming; (3) schko and Rourke noted that “although the
those with mixed global language and per- ACID subtypes generated in this research do
ceptual problems; (4) those with perceptual– not differ significantly in terms of level of ac-
motor impairment only; and (5) an expected ademic performance, the plots of the factor
group similar to that reported by Petrauskas score profiles for each of the reliable subtests
and Rourke (1979), in which no significant indicate that they have qualitatively differ-
impairments were identified. Some research- ent ability profiles which may have practical
ers have hypothesized that this last group of applications” (p. 77). However, even these
children simply has not experienced adequate authors noted that effective remediation has
education to develop essential achievement not been clearly tied to this manner of ability
skills, while others, as noted earlier, suggest profiling.
an emotional basis for this group of children’s The inclusion of LD among the disor-
problems. Using cluster analysis of a neurop- ders evaluated and diagnosed by the medi-
sychological battery, Phillips (1983) identical and mental health community has been
fied a fairly similar profile of five subtypes of considered an adjunct to formal psychiatric,
children with LD, including individuals with psychological, or neuropsychological evalu-
normal test scores, auditory processing prob- ation. However, as it has been recognized
lems, difficulty with receptive and expressive that children with LD appear more likely
language, spatial weaknesses, and a global than others to develop psychiatric prob-
pattern of low test scores. lems, efforts have been made to refine the
Rourke (1989) concluded that cluster- clinical diagnosis of learning impairments.
analytic studies have identified some asso- The Diagnostic and Statistical Manual of
ciation between learning delay and a wide Mental Disorders, fourth edition, text revi-
variety of perceptual, linguistic, sequential, sion (DSM-IV-TR) lists four academic skill
and cognitive skills. This finding has been disorders (American Psychiatric Associa-
reinforced by the work of others over a 50- tion, 2000): reading disorder, mathematics
year period (see Benton, 1975). According disorder, disorder of written expression, and
to Swartz (1974), a pattern consisting of de- learning disorder not otherwise specified. All
pressed scores on four Wechsler subtests, the four diagnoses require the collection of stan-
so-called “ACID” pattern (an acronym for dardized test data indicating performance
Arithmetic, Coding, Information, and Digit substantially below what would be expected
Span subtest), characterizes the weaknesses from the individual’s age, intelligence, and
of most children with LD. Although this educational experience. According to these
view is held by many others (see, e.g., Kauf- loosely definitive criteria, the problem must
man, 1997), not all children with LD display also interfere with the child’s academic per-
this pattern. Children who do, however, are formance or activities of daily living. The
thought to have a particularly poor prognosis “not otherwise specified” category reflects
for academic performance in reading, spell- LD as an isolated weakness—for example,
ing, and arithmetic (Ackerman, Dykman, & difficulty with spelling independent of other
Peters, 1977). Some researchers have sug- written language problems. DSM-IV-TR
gested that in a population of children with also contains a diagnosis of developmental
LD demonstrating this pattern, one subgroup coordination disorder, reflecting weak gross
experiences particularly poor auditory– or fine motor skills that may interfere with
verbal memory and sequencing, while a sec- academic achievement or daily living but
ond group experiences poor visual–spatial are not due to a specific medical condition.
abilities. This distinction is similar to that Readers interested in an extensive discussion
described by Joschko and Rourke (1985). of subtypes of LD in childhood are referred
However, Joschko and Rourke reported a to Silver and Hagin (1990) or Swanson and
further distinction in the ACID pattern by colleagues (2003).
A Neuropsychological Model related to phonological processes (Bishop &

for Assessment Adams, 1990; Pennington, 2009; Scarbor-
ough, 1990, 1998). A solid body of emerg-
The consensus in current factor-analytic re- ing research suggests that impairments in
search is that there are two broad groups of the capacity to process information sequen-
skills necessary for efficient learning: tially may form the basis of impairments in
phonological processing (Naglieri & Das,
1. Auditory–verbal processes. Weaknesses 2002). Furthermore, for many children,
in these areas result in reading disorders poor comprehension results from poor rote
and other language-based learning prob- language skills such as inability to distin-
lems. guish similar sounds, which then leads to
2. Visual–motor and perceptual processes. poor auditory discrimination and weak
Weaknesses in these areas may result in phonetics. Problems with verbal short-term
reading problems but more likely affect memory are also common among individu-
handwriting, mathematics, and certain als with reading impairments. Memory re-
social skills. quires phonological skill. Poor readers may
experience problems recalling letters, digits,
Tables 6.1 and 6.2 present models for con- words, or phrases in exact sequence. The
ceptualizing these skills and examples of majority of children with language-based
these skills, respectively, in 2 × 2 grids. The LD struggle to master basic foundational
model conceptualizes learning skills on rote/ academic skills; others are capable of learn-
automatic and conceptual levels, linguisti- ing to read, but when the curriculum be-
cally and visually. gins to accelerate in third or fourth grade
As it has also been demonstrated that and they must read to learn, they struggle
there is a significant but small group of chil- as the result of weak conceptual linguistic
dren experiencing achievement problems in skills. It is also not surprising that related
the absence of weaknesses in either of these language-based skills such as spelling and
skill sets, professionals are also urged to writing are impaired in children with read-
consider the impact of other factors related ing disabilities. For many, spelling is even
to achievement: an environment conducive more impaired than reading (Snowling &
to learning; problems with attention and im- Hulme, 1991).
pulse control; self-concept as a learner; and Weaknesses in visual–motor skills tend to
other emotional (e.g., depression/anxiety) cause problems with arithmetic and hand-
and behavioral (oppositional defiant disor- writing, often independent of associated
der, conduct disorder) problems (Goldstein reading disability. Included in problems for
& Mather, 1998). this group of children are difficulties involv-
As Tables 6.1 and 6.2 suggest, language- ing social awareness and judgment. These
based types of LD are directly related to problems do not appear to be primarily lan-
impaired language skills, especially those guage-based and have been referred to col-
TABLE 6.1. A Model for Conceptualizing Categories of Academic Skills

Auditory–verbal Visual–motor
Conceptual
Verbal conceptual skills Visual, nonverbal conceptual skills
Rote/automatic
Auditory motor skills Letter perception
Auditory perception Spatial organization and nonverbal integration
Rote auditory sequential memory Rote visual sequential memory and retrieval
Rote and association memory and retrieval Motor sequencing and fine motor control
Note. Adapted from table prepared by Sally Ingalls. Copyright 1991 by the Neurology, Learning, and
Behavior Center, Salt Lake City, Utah. Adapted by permission.
TABLE 6.2. A Model of Conceptualizing Specific Academic and Daily Living Skills
Auditory–verbal Visual–motor
Conceptual
•• Language semantics: Word meanings, definitions, •• Social insight and reasoning: Understanding
vocabulary strategies of games, jokes, motives of others,
•• Listening comprehension: Understanding and social conventions, tact
memory of overall ideas •• Mathematical concepts: Use of 0 in +, –, ×; place
•• Specificity and variety of verbal concepts for oral value; money equivalencies; missing elements;
or written expression etc.
•• Verbal reasoning and logic •• Inferential reading comprehension: Getting the
main idea, drawing conclusions
•• Understanding relationship of historical events
across time; understanding scientific concepts
•• Structuring ideas hierarchically; outlining skills
•• Generalization abilities
•• Integrating material into a well-organized report
Rote/automatic
•• Early speech; naming objects •• Assembling puzzles and building with
•• Auditory processing; clear enunciation of speech; construction toys
pronouncing sounds or syllables in correct order •• Social perception and awareness of environment
•• Naming colors •• Time sense: Doesn’t ask, “Is this the last recess?”
•• Recalling birthdate, phone number, address, etc. •• Remembering and executing correct sequence for
•• Saying alphabet and other lists (days, months) in tying shoes
order •• Easily negotiating stairs; climbing on play
•• Easily selecting and sequencing words with equipment; learning athletic skills; riding bike
proper grammatical structure for oral or written •• Executing daily living skills such as pouring
expression without spilling, spreading a sandwich, dressing
•• Discriminating sounds, especially vowels, self correctly
auditorily; blending sounds to form words; •• Using the correct sequence of strokes to form
distinguishing words that sound alike (e.g., mine/ manuscript or cursive letters
mind) •• Eye–hand coordination for drawing, assembling
•• Labeling and retrieval of letters, sounds, common art projects, and handwriting
syllables, sight words (b/d, her/here) •• Directional stability for top–bottom and
•• Phonic spelling left–right tracking
•• Listening and reading comprehension involving •• Copying from board accurately
short-term memory, especially for rote facts •• Viewing visual symbols accurately, visual
•• Mathematical labeling and retrieval: Counting discrimination, directionality, recognizing shapes
sequentially; labeling numbers (e.g., 16/60); or forms of words
memory for facts about numbers and sequences •• Spelling: Visual memory for the nonphonetic
of steps for computation (e.g., long division) elements of words
•• Recalling names, dates, and historical facts
•• Learning and retaining new scientific terminology
Note. Adapted from table prepared by Sally Ingalls. Copyright 1991 by the Neurology, Learning, and Behavior Center,
Salt Lake City, Utah. Adapted by permission.
lectively in the neuropsychology literature liably conclude that children with NLD ex-
as nonverbal learning disabilities (NLD) perience greatest deficits in visual-perceptual
(Pennington, 2009; Rourke, 1989). Children and organizational skills, psychomotor
with this pattern have been reported to ex- coordination, and complex-tactile percep-
perience problems with spatial organization, tual abilities (Harnadek & Rourke, 1994).
attention to visual detail, procedural skills, Finally, it is also suspected that individuals
and mathematics; problems in shifting psy- with NLD experience greater internalizing
chological set from one operation to anoth- problems related to depression and anxiety
er; graphomotor weaknesses; poor factual than those with language-based LD do. It is
memory; and poor judgment and reasoning unclear whether this pattern contributes to
(Rourke, 1985). Neuropsychologists can re- or is a consequence of NLD.
In their PASS model, Naglieri and Das ommended that neuropsychologists address
(2002) note characteristic weaknesses in collection of basic achievement data as fol-
planning and attention processes for youth lows:
diagnosed with attention-deficit/hyperactiv-
ity disorder (ADHD) receiving diagnoses of 1. Reading. A measure should be used to
ADHD, isolated weaknesses in planning for obtain single-word reading, reflecting pho-
youth with mathematics LD, and isolated netic skills and sight word achievement. An
weaknesses in successive processes for youth estimate of the ability to read within con-
with phonics-based reading disability. Read- text and comprehend what is read should
ers interested in the PASS model are referred also be obtained. Instruments such as the
to Naglieri (1999). Woodcock–Johnson III Tests of Achieve-
ment (Woodcock et al., 2001), the Gilmore
(Gilmore & Gilmore, 1968), the Gray Oral
Evaluating LD in the Context Reading Test—Fourth Edition (Wiederholt
of a Comprehensive & Bryant, 2001) or the Test of Reading
Neuropsychological Evaluation Comprehension—Fourth Edition (Brown,
Wiederholt, & Hammill, 2008) can provide
A number of volumes provide thorough, clinicians with these data.
in-depth models for assessment of LD with 2. Spelling. Estimates of sight word mem-
myriad tests and batteries. Interested readers ory for spelling and phonetic ability can be
are referred to Reynolds and Fletcher-Janzen analyzed qualitatively with the Wide Range
(2008), Goldstein (1997), and Mather and Achievement Test–4 (Wilkinson & Robert-
Goldstein (2008). Because of space limita- son, 2006).
tions, we only briefly review assessment mea- 3. Mathematics. The Wide Range
sures in this section. The basic task facing Achievement Test–4 (Wilkinson & Robert-
the professional is to answer questions con- son, 2006) or the Key Math–3 Diagnostic
cerning underlying neuropsychological skills Assessment (Connolly, 2007) can be utilized
essential to learning; both assets and liabili- to generate observations of conceptual ver-
ties must be identified. Screening of basic sus rote sequential mathematics skills.
academic skills must also be completed. In 4. Written language. Written language
many situations, the neuropsychologist can skills of thematic maturity, vocabulary, ca-
rely upon data collected at school to provide pacity to organize ideas, grammar, punctua-
these basic achievement measures. The most tion, and general execution can be assessed
widely used battery of such measures, the with the Story Composition subtest from the
Woodcock–Johnson III Tests of Achievement Test of Written Language—Third Edition
(Woodcock, McGrew, & Mather, 2001), is (Hammill & Larsen, 2009).
the most comprehensive. It offers by far the
most thorough, well-developed assessment
of academic skills, and its factor-analytic Comorbid Disorders
model fits well with this chapter’s discus-
sion of the underlying neuropsychological Caron and Rutter (1991) have reviewed
deficits contributing to LD. Subtest analysis the concept of psychiatric comorbidity and
often reveals patterns consistent with ver- summarized different scenarios for the ex-
bal, visual, rote, or conceptual weaknesses. istence of either true or artificial comorbid-
Although achievement–intelligence discrep- ity. As discussed by Lyytinen (1995), the
ancies are most widely used to identify LD, term comorbidity, broadly applied, may
the issue of high-IQ individuals with average refer to (1) the co-occurrence of two or
achievement identified as having LD contin- more presumably separate neurocognitive
ues to be controversial. An age–achievement disorders; (2) the co-occurrence of two or
discrepancy nonetheless is a good target for more independent conditions that are medi-
the neuropsychologist; a standard deviation ated by a common genetic or environmen-
and a half below the age mean can be used tal etiology; (3) conditions, possibly related,
as a cutoff. that share the same or overlapping risk fac-
In the absence of a comprehensive battery tors; (4) conditions that co-occur because
such as the Woodcock–Johnson III, it is rec- of the secondary effects of one disorder on
the other; (5) comorbid characteristics that a substantial portion of the covariance be-
combine to define a meaningful syndrome; tween dyslexia and ADHD.
and (6) conditions that result from interac- It is widely believed that both LD and
tive combinations of the other five states. ADHD are comorbid to a greater than aver-
The frequently observed comorbid condi- age degree with other categories of psychi-
tions associated with LD illustrate all six atric disorders, such as conduct disorder,
types of comorbidity, although in a given anxiety disorders, and depression. To date,
instance the specific forms of comorbidity few methodologically sound studies of popu-
may be questionable or undetermined be- lations with well-defined LD have evaluated
cause of present empirical limitations. In this premise. Porter and Rourke (1985), using
addition, an apparent comorbidity may be the parent interview Personality Inventory
a function of the current definitions of LD for Children (Wirt, Lachar, Klinedinst, &
and the other disorder(s) under consider- Seat, 1977) identified four distinct person-
ation or of the diagnostic procedures used ality patterns or subtypes as characterizing
for classification, rather than representing the majority of the children with LD in their
a true comorbidity. In addition, it may be study. Of those classified, 44% displayed bal-
unclear whether a given characteristic (e.g., anced, well-adjusted social-emotional func-
psychosocial deficit) is an integral part of tioning; 26% exhibited marked internalizing
an LD pattern or whether that characteris- psychological disturbances (depression, anx-
tic constitutes an associated comorbid con- iety, low social skills); 13% displayed rough-
dition (Lyytinen, 1995). ly normal personality functioning, but with
ADHD is probably the DSM-IV-TR di- a high degree of somatic concerns; and 17%
agnostic category that has the highest rate exhibited behavioral disturbance reflected
of comorbidity with LD. Among children in hyperkinetic, aggressive, and antisocial
diagnosed as having LD, the reported rate behaviors. Three studies that used the Min-
of ADHD has generally ranged from 15% nesota Multiphasic Personality Inventory to
(Shaywitz, Fletcher, & Shaywitz, 1992, assess emotional functioning in adults with
cited in Lyon, 1996) to as high as 85% (Safer LD (Balow & Blomquist, 1965; Gregg, Hoy,
& Allen, 1976); most studies, such as that King, Moreland, & Jagota, 1992; Spreen,
of Shaywitz and Shaywitz (1987), report a 1998, cited by Hooper & Olley, 1996) were
comorbidity figure between 30% and 40%. consistent in reporting more maladjustment
There have been conflicting views about and serious psychopathology (depression,
whether LD and ADHD are independent anxiety, social withdrawal, phobias, acting-
disorders or whether they are manifestations out tendencies, disorganized thoughts, etc.)
of the same underlying brain dysfunction. in the adults with LD than in their normal
James and Selz (1997) have suggested that counterparts. In contrast, Lamm and Epstein
due to methodological flaws in accumulated (1992) found few differences in degree of
research, this question has not been fully re- psychopathology between individuals with
solved; however, many experts have conclud- LD and control subjects who were assessed
ed that although they freuqently co-occur, via a structured rating scale. As reviewed by
there is strong evidence for the separateness James and Selz (1997), the emotional con-
of LD and ADHD (Barkley, 2006; Goldstein, sequences of LD may vary by subtype, but
1997; Pennington, Grossier, & Welsh, 1993; conflicting results have been reported. The
Shaywitz, Fletcher, & Shaywitz, 1995; Sil- most widely referenced psychopathology by
ver, 1990). After reviewing several possible subtype is the association of significant inter-
mechanisms for the comorbidity of ADHD nalizing problems (including social isolation,
with dyslexia, Pennington (2009) has sug- anxiety, depression, and suicide) with NLD,
gested that in most cases dyslexia leads to or, as it is often termed, right-hemisphere-
ADHD as a secondary symptom, but that based LD (Bigler, 1989; Hooper & Olley,
in a small percentage of cases there may be 1996; James & Selz, 1997; Rourke, 1989;
genetic correlation between the two disor- Voeller, 1986).
ders. In examining LD-ADHD comorbidity “Psychosocial adjustment difficulties fre-
in twin data, Light, Pennington, Gilger, and quently are assumed to be the major social-
De Fries (cited in Lyytinen, 1995) concluded emotional manifestation of learning disabil-
that shared genetic influences account for ities” (Hooper & Olley, 1996, p. 170). Two
of the earlier and persistent voices underscor- judgment; and young offenders with LD lack
ing the need for a sociological perspective on the strategic planning skills to avoid being
LD were those of Kronick (1974, 1976) and caught or to conceal their behavior when
Bryan (1974, 1978, 1991). Kronick explored being questioned by legal authorities. A
ways in which difficulties with attention, study by Waldie and Spreen (1993) provided
concentration, perception, inference, label- some support for the susceptibility hypoth-
ing of emotions, and communication of feel- esis that for those with LD, comorbid juve-
ings interfer with identity formation, disrupt nile delinquency is linked to impulsivity and
family relationships, and produce interac- poor judgment. For reviews of the literature
tional dysfunction. Bryan (1991) provided a on LD, juvenile delinquency, and substance
comprehensive review of research on the at- abuse, see Chitsabesan and Bailey (2006),
titudes of children and adolescents with LD Grigorenko (2006), and Katsiyannis, Ryan,
toward themselves, their social competence, Zhang, and Spann (2008).
their communicative competence, and teach- After reviewing relevant literature, Pol-
ers’ judgments of their school behavior. In loway, Smith, and Patton (1984) concluded
all areas, with the exception of knowledge that the social skill deficits observed in chil-
of social norms, the students with LD were dren with LD persists into adulthood. In a
found to be less socially competent than group of 93 adults diagnosed with LD at
their normally achieving classmates. Voeller the Learning Disabilities Clinic at North-
(1986) described children with NLD who western University, 25% expressed concerns
often failed to perceive social cues and thus about social difficulties (Blalock & Johnson,
had difficulty correctly interpreting their so- 1987). Their social problems included dif-
cial environment. These children tended to ficulties in making and keeping friends, as
push and crowd their peers, get into argu- well as problems related to their specific dis-
ments or fights with peers, and have diffi- abilities (e.g., following and participating in
culty maintaining friendships. They were conversational exchanges, locating address-
frequently considered “strange” or “weird” es, dancing, playing cards or word games,
by their classmates. writing personal notes and letters, etc.). In
Adolsecents with LD are statistically at general, the adults with NLD experienced
increased risk for juvenile delinquency and the greatest social problems and social isola-
substance abuse, but no causal link has been tion, but they were not always aware of their
established between LD and either of these social handicaps.
conditions (Morrison & Cosden, 1997). The frequently cited comorbidity of psy-
The reported prevalence of LD among juve- chopathology and psychosocial difficulties
nile offenders generally ranges from 35% to with LD may result from several different
65%, but these figures cannot be accepted at direct or indirect mechanisms or from a dy-
face value, due to the methodological limi- namic combination of mechanisms. As de-
tations of the research. No specific preva- scribed by Hooper and Olley (1996), these
lence figures for substance abuse among mechanisms may include the following:
adolescents with LD were located. The risk
for both juvenile delinquency and substance (1) Behavioral disruption that arises directly
abuse is increased when LD is accompanied from abnormal brain activity; (2) heightened
by hyperactivity and/or conduct disorder exposure to failure, frustration, and social
(Morrison & Cosden, 1997). stigma due associated disablities; (3) the possi-
A number of hypotheses have been pro- ble effects of brain damage or anomalous neu-
posed to account for the link between LD rodevelopment on subsequent temperament
and juvenile delinquency or substance abuse. and personality development; (4) adverse fam-
ily reactions ranging from overprotection to
The most frequently offered explanations
scapegoating; (5) the individual’s own reaction
suggest the following: Low self-esteem and to being handicapped and its effect on his or
stresses associated with school failure lead her actual capacity to cope and compete; and
to delinquency or substance abuse; youth (6) possible adverse effects from treatments
with LD are more susceptible to delinquent themselves (e.g., lack of or poor treatment for
acts as a result of impulsivity, limited under- specific learning problems) that may restrict
standing of cause and effect, or poor social normal activities and socialization. (p. 164)
Although individuals with LD are in- and math deficits in identical and fraternal
creased risk for psychopathology and psy- twin pairs. Their data indicated that ap-
chosocial deficits, there is wide variation in proximately 26% of observed reading deficit
their patterns of social-emotional adjust- was due to genetic factors that also influ-
ment, and group findings do not dictate in- enced math performance.
dividual outcomes. The majority of children A final category of comorbidity involves
and adults with LD do not exhibit significant LD patterns that are observed in associa-
emotional disorders and function well in so- tion with specific disorders or genetic syn-
ciety. Morrison and Cosden (1997) view LD dromes (e.g., Klinefelter syndrome, Turner
as a risk factor that in and of itself does not syndrome, fragile X syndrome, Tourette
predict positive or negative outcomes. They syndrome, neurofibromatosis, etc.). LD is a
propose that other internal and environmen- frequent concomitant of syndromes associ-
tal risk–protective factors interact with the ated with sex chromosome aberrations. In
presence of LD to mediate nonacademic out- Klinefelter syndrome (47,XXY in males), af-
comes such as emotional adjustment, adoles- fected individuals are of normal intelligence
cent problems (e.g., dropping out of school, but frequently demonstrate specific deficits
juvenile delinquency, substance abuse), and in Verbal IQ, auditory processing, efficient
adult adaptation. Although the present dis- use of language, and reading (Berkow &
cussion of social-emotional development Fletcher, 1992). Turner syndrome (complete
and adjustment in persons with LD has been or partial absence of one X chromosome,
limited in scope, Mercer (1991) and Bender usually observed in females) affects cognitive
(1994) provide more extensive reviews of and learning processes to a variable degree.
these issues. A typical phenotypic presentation involves
Two additional types of comorbidity with characteristics associated with NLD, such as
LD are mentioned here. First, one diagnostic visual–spatial deficits, weakness in numeri-
category or subtype of LD may be viewed cal and mathematical understanding, and
as comorbid with another. Since reading is social learning deficits (Mazzacco, 1996).
an essential educational tool, and since 80% Additional information about the patterns
of children identified as having LD have of learning abilities and LD that accompa-
difficulty acquiring reading skills (Lerner, ny specific genetic disorders is presented in
1993), reading disability or dyslexia is often other chapters of this text.
considered a child’s primary deficit, with co- Comorbidity in neurocognitive disorders
occurring deficits in other skill areas (e.g., and LD is a complex topic that has received
mathematics or graphomotor production) considerable emphasis in the research litera-
considered secondary or comorbid deficits. ture (e.g., Lyytinen, 1995). Future investiga-
It is possible for two distinct patterns or tions of comorbidity will assist practitioners
subtypes of LD to co-occur; for example, to view individuals with LD from a more ho-
deficits in phonemic awareness and process- listic perspective. This should result in great-
ing can co-occur with deficits in visual– er intervention efforts aimed at modifying
spatial perception and spatial organization, the nonacademic risk factors that impede
affecting one or more academic skill areas. successful long-term outcomes, and at en-
However, two co-occurring academic defi- hancing the protective factors that enhance
cits (e.g., reading disability and math dis- such outcomes. Furthermore, explorations
ability) may actually be manifestations of a of comorbidity among LD categories or sub-
single pattern of neurocognitive deficit with types will contribute to the all-important
a shared information-processing bottleneck process of defining more distinct and em-
that impedes acquisition of skills in both pirically defensible LD subtypes. Subtypes
academic areas (Lyytinen, 1995). Lyytinen of LD comorbid with other conditions have
cites two companion articles (Ackerman & been identified in the contemporary empiri-
Dykman, 1995; Räsänen & Ahonen, 1995) cal literature (Hendriksen et al., 2007). For
that examine the co-occurrence of reading instance, recent studies have examined co-
and mathematics disorders. Light and De morbidity of LD with ADHD and autism
Fries (1995) assessed the genetic and envi- (Barnard, Muldoon, Hasan, O’Brien, &
ronmental etiologies of comorbid reading Stewart, 2008; Karande et al., 2007).
Interventions 1996; Stanovich, 1993; Stanovich & Siegel,

1994; Torgesen, Wagner, & Rashotte, 1994;
Since views differ regarding the nature and Wagner & Torgesen, 1987). A number of
etiology of LD, views also differ about what well-designed longitudinal studies have doc-
constitutes appropriate and effective inter- umented the efficacy of instruction in pho-
ventions for individuals with LD. Lyon and nological awareness and/or phonemic analy-
Moats (1988) have discussed critical issues in sis and synthesis for the initial development
the instruction of students with LD. Numer- of reading skills and for improving reading
ous authors, representing different theoreti- in children with reading disabilities (Ball
cal orientations and instructional paradigms, & Blachman, 1988; Blachman, Ball, Black,
have presented intervention methodologies & Tangel, 1994; Hatcher, Hulme, & Ellis,
developed or adapted for pupils with LD. 1994; Lundberg, Frost, & Petersen, 1988;
These include the psycholinguistic-process Storch & Whitehurst, 2002).
or specific-abilities approach (Johnson & At the conclusion of their research report,
Myklebust, 1967; Kirk & Kirk, 1971); be- Hatcher and colleagues (1994) suggest that
havioral approaches, including direct in- children differ in their ability to acquire pho-
struction and data-based instruction (Linds- nological competence, and pose the ques-
ley, 1971; Lovitt, 1984; Marston & Tindal, tion of how best to facilitate acquisition of
1995; Wendling & Mather, 2008; White, underlying phonological skills. In this criti-
1986); cognitive approaches, including cal area of instruction, research-based prac-
constructivism and instruction in learning tices have emerged. Torgesen, Wagner, and
strategies (Deshler & Lenz, 1989; Mercer, Rashotte (1997) have discussed approaches
Jordan, & Miller, 1994; Swanson, 1993; to the prevention and remediation of phono-
Wong et al., 1991; Wong, Graham, Hoskyn, logically-based reading disabilities. Hatcher,
& Berman, 2008); and neuropsychological Hulme, and Snowling (2004) compared
approaches (D’Amato, Fletcher-Janzen, & three theoretically based approaches to read-
Reynolds, 2005; Hooper, Willis, & Stone, ing instruction and found that for children
1996; Rourke, Fisk, & Strang, 1986). Mer- at risk of reading failure, direct instruc-
cer (1991) and Lerner (1993) have provided tion in phonemic awareness and phoneme–
lucid discussions of these instructional ap- grapheme correspondence had a beneficial
proaches and their application to individuals effect on the development of reading skills,
with LD. Mercer and Mercer (1993), Mather whereas typically developing children did
(1991), Mather and Jaffe (2002), Lerner not require the same explicit instruction to
(1993), and Mather and Goldstein (2008) make gains in reading. Research with the
outline a broad array of specific teaching Auditory Discrimination in Depth program
strategies and techniques that have been (Lindemood & Lindemood, 1969) showed
utilized successfully with atypical learners, that intensive instruction led to significant
including those with LD. gains in reading and spelling skills for 281
Research has led to better development of subjects ages 5–55 years (Truch, 1994). Em-
causal theories of LD and to promising av- ploying a different approach, Merzenich
enues of intervention for the LD subtypes or and colleagues (1996) acoustically modified
specific information-processing weaknesses speech to train sound discrimination abili-
explicated by those theories. According to ties in children with language-based learn-
Torgesen (1993), “The two most completely ing impairments. Subjects engaged in highly
developed current causal theories of learn- motivating discrimination tasks with speech
ing disabilities are the nonverbal learning stimuli altered by a computer algorithm,
disabilities syndrome . . . and the theory of which stretched the duration or increased
reading disabilities involving limitations in the volume of sound elements critical to the
phonological processing” (p. 158). discrimination process. After a few weeks’
A great deal of attention and research instruction, children in the study markedly
has been directed toward understanding improved their ability to discriminate pho-
phonological processing skills and their re- nemes and recognize both brief and fast se-
lation to the development of reading skills quences of speech stimuli. They also showed
(Lyon, 1996; Pennington, 1991; Shaywitz, significant improvement in language com-
prehension abilities. Although acoustically References

modified speech is a logically conceived and
an exciting intervention concept, experts Ackerman, P. T., Dykman, R. A., & Peters, J. E.
(1977). Teenage status of hyperactive and non-
in the field of dyslexia and LD, as reported hyperactive learning disabled boys. American
by Travis (1996), have suggested caution in Journal of Orthopsychiatry, 47, 577–596.
regard to its potential benefits. More recent American Psychiatric Association. (2000). Diag-
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Chapter 7
Attention-Deficit/Hyperactivity Disorder
Sam Goldstein
The childhood cognitive and behavioral community-based settings, the ratio is 3:1
problems categorized as disorders of atten- (for a review, see Barkley, 2006). The inci-
tion, impulsivity, and hyperactivity have dence of diagnosis continues to increase,
presented a clinical challenge for neuropsy- with a 70% increase in the diagnosis of
chologists over the past 60 years. The symp- children and nearly a 100% increase in the
tom constellation referred to as attention diagnosis of adults between 2000 and 2003
deficit disorder (ADD) or attention-deficit/ (Centers for Disease Control and Prevention
hyperactivity disorder (ADHD) (American [CDC], 2005)—a pattern that has contin-
Psychiatric Association [APA], 2000) has ued (Castle et al., 2007). It is now estimated
become one of the most widely researched that between 4% and 8% of the population
areas in childhood and adolescence, with an has received a diagnosis of ADHD (CDC,
increasing emphasis on research throughout 2005; Cuffe, Moore, & McKeown, 2005).
the adult lifespan. Problems arising from this Female adults are the fastest-growing group
constellation of symptoms have constituted (Medco Health Solutions, 2005). Studies
the most chronic childhood behavior dis- using broad-based definitions of ADHD find
order over nearly 40 years (Wender, 1975) a prevalence of nearly 16% in adults, where-
and the largest single source of referrals to as studies using narrower definitions report
mental health centers (Barkley, 2006; Cas- a rate of 3–4% (Faraone & Biederman,
tle, Aubert, Verbrugge, Khalid, & Epstein, 2005). Prevalence has also been reported to
2007; Gadow, Sprafkin, & Nolan, 2001). be higher in populations of individuals with
ADHD is among the most common dis- other impairments (Altfas, 2002).
orders of childhood. It is estimated that it Even as professionals utilize the current
affects between 5% and 8% of the popula- diagnostic criteria involving symptoms of
tion throughout life. Estimates vary, with inattention, hyperactivity, and impulsivity,
the APA (2000) suggesting a prevalence of research data increasingly suggest that for
3–7%. Statistics vary depending on popula- the majority of affected children, impulsivity
tions studied, thresholds, and definitional and impaired executive functions represent
criteria (Sherman, Iacono, & McGue, 1997). core deficits (for reviews, see Barkley, 2006;
In clinic-referred settings, males outnumber Goldstein & Naglieri, 2006; Goldstein &
females 6:1. In epidemiological studies of Schwebach, 2005). Children with ADHD
131
typically experience difficulty in all aspects Toward a Working Definition

and situations of their lives. Their behavior of ADHD
is often uneven, unpredictable, and inconsis-
tent. Professionals evaluating ADHD today From a neuropsychological perspective, the
must be concerned not only with the core concept of attention as an executive function
symptoms of this disorder and their direct, has gained increasing popularity. Sustained
immediate impact on children, but with the mental effort, self-regulation, planning, exe-
significant secondary impact these problems cution, and maintenance are considered mea-
have upon children’s current and future lives, sures of executive functioning (Daigneault,
as well as the lives of their family members. Braun, & Whitaker, 1992). These executive
In particular, an increasing body of research functions are impaired in individuals with
is demonstrating the increased vulnerability ADHD (Biederman et al., 2008). Nearly
of adults with ADHD to psychiatric, emo- 20 years ago, Mirskey, Anthony, Duncan,
tional, cognitive, academic, vocational, sub- Ahearn, and Kellam (1991) developed a neu-
stance, and antisocial problems (Barkley, ropsychological model of attention involving
Fischer, Smallish, & Fletcher, 2004; Bar- four basic concepts: the ability to focus, ex-
kley & Gordon, 2002; Cuffe et al., 2009; ecute, sustain or code, and shift. Eight tra-
Murphy, Barkley, & Bush, 2002; Rabiner, ditional assessment measures of attention
Anastophoulos, Costello, Hoyle, & Swartz- were used in a factor-analytic study to arrive
welder, 2008; Robin, Tzelepis, & Bedway, at this model.
2008; Sprafkin, Gadow, Weiss, Schneider, Increasingly, there is a consensus that
& Nolan, 2007). ADHD represents a problem of faulty per-
The controversy and at times confusion formance rather than faulty input. It is not
concerning various aspects of ADHD may in so much that this population of individuals
part result from the tradition of viewing this does not know what to do, but that they do
disorder as a unitary phenomenon with a sin- not do what they know consistently. It is a
gle cause. Voeller (1991) suggests that rather problem of inconsistency rather than inabil-
than viewing ADHD as a single behavioral ity (Goldstein & Goldstein, 1998). Even in
abnormality with associated comorbidities, their adaptive skills, this pattern of differ-
it may be better to conceptualize ADHD as a ence between possessing a skill and using it
“cluster of different behavioral deficits, each efficiently has been well defined for individ-
with a specific neuro-substrate of varying uals with ADHD (Stein, 1997).
severity occurring in variable constellations It is quite likely that attention as a theoret-
and sharing a common response to psycho- ical or laboratory-measured concept is quite
stimulants” (p. S4). There is no doubt, how- different from the symptom of inattention as
ever, that the cluster of symptomatic prob- it is defined for ADHD. Nonetheless, prior
lems constituting the diagnosis of ADHD to a review of the currently accepted ADHD
represents a distinct disorder from others of diagnostic criteria and related issues, a brief
childhood and adulthood (Accardo, Blondis, discussion of attention as a theoretical con-
& Whitman, 1990; Biederman et al., 1996; struct is valuable.
Mrug et al., 2009). A significant percentage Attention is considered a generic term
of affected youth continue to demonstrate used to designate a group of hypothetical
the condition into adulthood, often under- mechanisms that collectively serve a func-
reporting their symptoms and impairment tion for the organism (Mesulam, 1985).
relative to observers’ reports (Barkley et al., In 1798, Alexander Crighton provided the
2004). The consensus among researchers earliest known reference to attention. In his
and clinicians is that the core symptoms of two-volume work summarizing the avail-
ADHD affect a significant minority of our able knowledge from throughout the world
population. For affected individuals, how- on the human mind and mental illness, the
ever, ADHD represents a poor fit between chapter titled “On Attention and Its Dis-
societal expectations and these individuals’ eases” was apparently the first formal effort
abilities to meet those expectations. This in the scientific literature to define attention,
phenomenon is distinct from other disorders and in particular to describe the adverse
of childhood and adulthood, and can be reli- processes that occur when human beings
ably evaluated and effectively treated. struggle with attention. Crighton defined
Attention-Deficit/Hyperactivity Disorder 133
attention as a process by which “an object of the variance and involved skills related to
of external sense or of thought occupies the visual–motor scanning and shifting abilities.
mind in such a degree that a person does not The capacity to divide attention appeared
receive a clear perception from any other to be key to this task. The second factor
one” (p. 254). This theme was also reflected accounted for 16% of the variance and re-
but not cited in George Still’s three pub- flected immediate attention and conceptual
lished lectures before the Royal Society of tracking consistent with the ability to re-
Medicine in the journal Lancet in 1902. Still peat digits both forward and backward. The
based his comments on observations of more third factor accounted for 13.5% of the vari-
than 26 patients who were studied relatively ance, reflecting sustained, effortful process-
intensely. ing consistent with distractibility tasks. This
Beginning with James (1890), research- breakdown is consistent with factor analyses
ers have identified attentional processes as by other investigators (Shum, MacFarland,
essential prerequisites for higher cognitive & Bain, 1990).
functions. Hypothetical models of the devel- As the fifth edition of the Diagnostic and
opment of attention have included a stage- Statistical Manual of Mental Disorders
wise model (Blondis, Snow, Stein, & Roizen, (DSM-5) is not expected to be published
1991), as well as a model of a maturational until 2013, it is important for profession-
process similar to the maturation of other ex- als to possess a working understanding of
ecutive or intellectual skills (Hagen & Hale, ADHD based on current knowledge. In
1973). Although Posner and Snyder (1975) other words, it is important to possess a
described attention as a complex field of working understanding of the DSM-IV-TR
study, others have suggested that attentional diagnostic criteria for ADHD, a practical
skills can be operationally and statistically understanding of the symptoms’ impact
defined with some confidence (Gordon & upon an individual’s functioning, and a di-
McClure, 1983). Skinner (1953) defined at- agnostic strategy. The traditional disease
tention as a functional relationship between model is not relevant to the definition of
stimuli and response. His belief was that at- ADHD (Ellis, 1985). ADHD is more like
tention is not a thing, entity, or mental func- obesity or intelligence: Individuals differ not
tion, but is a description of a set of relations in having or not having the traits, but in the
between stimuli or events and responses to degree of manifestation. ADHD symptoms
them. Gibson and Radner (1979) defined are multidimensional rather than unitary
attention as the ability to perceive the envi- (Guevremont, DuPaul, & Barkley, 1993).
ronment in relation to a specific goal. Posner However, there continues to be discussion
(1987) suggested that attention may consist as to which dimensions represent the most
of automatic versus conscious aspects. Fus- clearly distinguishing deficits of the disor-
ter (1989) provided a concept of inhibition der. The frequency and severity of symptoms
interference in his neuropsychological model fluctuate across settings, activities, and care-
of executive function related to attention. givers (Tarver-B ehring, Barkley, & Karls-
All of these theories, including Titchener’s son, 1985; Zentall, 1984). Neuropsycho-
(1924) description of attention as a pattern logical profiles have also been demonstrated
of consciousness, appear to be an extension to differ between subtypes (Chabildas, Pen-
of James’s (1890) characterization of atten- nington, & Willcutt, 2001). However, these
tion as bimodal. James hypothesized that at- differences have not lent themselves to a dif-
tention is either passive, reflective, nonvolun- ferential diagnosis. There is a general con-
tary, and effortless, or active and voluntary. sensus, however, that symptoms of ADHD
James defined sustained attention as the ac- fall into two broad factors: symptoms relat-
tive and voluntary type, which is dependent ed to the behavioral manifestation of faulty
on repeated redirection of focus toward the attention, and those related to hyperactivity
object of attention and on resistance to at- and impulsivity (Crystal, Ostrander, Chen,
tractions that coexist in the process. & August, 2001; Faraone, Biederman, &
Finally, Picano, Klusman, Hornbestel, Friedman, 2000). Symptoms of hyperactivity
and Moulton (1992) conducted a factor and impulsivity appear to co-occur at such a
analysis that suggested three factors for at- high frequency that it is difficult to separate
tention. The first factor accounted for 35% them on a factor-analytic basis. However,
research has demonstrated subtype differ- females more often demonstrate the inat-
ences in neuropsychological profiles and tentive type of ADHD (Biederman et al.,
patterns of comborbidity (Eiraldi, Power, & 2002). This overrepresentation has not been
Nezu, 1997). It is also important for neurop- well explained by any theoretical model (Sil-
sychologists to recognize that at times the verthorn, Frick, Kuper, & Ott, 1996), nor
lines blur between the symptoms and con- is it understood why preliminary research
sequences or impairments of ADHD. Thus suggests that females with ADHD may be
a diagnostic strategy for ADHD should in- less likely than males to demonstrate execu-
clude identifying not only the symptoms, but tive function deficits (Seidman et al., 1997).
thr skills and life areas hypothesized to be The hyperactive–impulsive population was
directly impaired by the symptoms (Gordon also younger than the other two groups in
et al., 2006). Having the symptoms without the field studies. Moreover, they had fewer
negative consequences would in fact pre- disruptive symptoms of oppositional defiant
clude the diagnosis of ADHD according to disorder or conduct disorder than those with
DSM-IV-TR criteria. the combined type of ADHD.
The DSM-IV diagnostic criteria published A number of researchers have demonstrat-
(APA, 1994) represented an effort to move ed the validity of the DSM-IV/DSM-IV-TR
forward and correct the mistaken notion diagnostic conceptualization for ADHD,
that ADHD represents a unipolar disorder. utilizing a variety of clinical and laboratory
The field studies for the ADHD diagnosis measures. Such research has included a full
were more comprehensive and better struc- battery of neuropsychological tests (Brand,
tured than previous efforts. The DSM-IV- Das-Smaal, & De Jonge, 1996; Halperin et
TR (APA, 2000) criteria are identical to al.,1993; Harrier & DeOrnellas, 2005), re-
the DSM-IV criteria; readers are referred versal and memory tasks (O’Neill & Doug-
to DSM-IV-TR for the complete list. Since las, 1996), executive function tasks (Clark,
DSM-III, each succeeding diagnostic proto- Prior, & Kinsella, 2000; Geurts, Verte,
col has focused increasingly on the issue of Oosterlaan, Royers, & Sergeant, 2005; Hart
impairment. Impairment has been and will & Harter, 2001), and neurological evalu-
continue to be a critical linchpin in making ation (Luk, Leung, & Yuen, 1991). The
the diagnosis of ADHD, but is not well ex- general consistency of symptoms, comor-
plained by symptom severity (Gordon et al., bidity, and related findings among large,
2006). The measurement of neuropsycho- well-controlled clinic and epidemiological
logical processes may also be considered as studies suggest that the conceptualization
part of the DSM-5 criteria for ADHD (Na- of ADHD in DSM-IV and DSM-IV-TR has
glieri & Das, 2006). been fairly well refined. Nonetheless, these
Of the 276 children diagnosed with ADHD criteria continue to focus excessively on in-
in the DSM-IV field studies, 55% had the attention as the primary problem for the
combined type, 27% the inattentive type, disorder, limiting the focus on the impact of
and 18% the hyperactive–impulsive type impulsivity as the core deficit. This perpetu-
(Lahey et al., 1994). Fewer than half (44%) ates a number of major misconceptions, in-
of those with the hyperactive–impulsive type cluding the notion that the inattentive type
of ADHD received a DSM-III diagnosis of of ADHD represents a subtype of the com-
ADD with hyperactivity; these two diag- bined disorder (Anastopoulos, Barkley, &
noses, therefore, only partially overlapped. Shelton, 1994). Increasing research suggests
The hyperactive–impulsive group had fewer that it does not. It is more likely that the in-
symptoms of inattention than the children attentive type represents a distinct disorder,
with the combined type did. They also had primarily reflecting difficulty in attending to
fewer symptoms of hyperactive–impulsive repetitive, effortful tasks and problems with
problems, suggesting that the hyperactive– organization. Carlson and Mann (2002) de-
impulsive type represents a less severe scribed children with the inattentive type of
variant of the disorder. The hyperactive– ADHD (as distinct from the combined type)
impulsive group contained 20% females, the as possessing hypoactivity, lethargy, and a
combined group 12%, and the inattentive lack of ability to stay focused. The problems
group 27%. This latter number corresponds this group experiences may very well be the
with neuropsychologists’ perceptions that result of faulty skills as opposed to incon-
sistent or inadequate use of skills. Emerg- mensional basis, these children represent the
ing data are also raising questions about the extreme of what is observed.
lack of stability of DSM-IV-TR ADHD sub- 3. Overarousal. Due to their lack of in-
types over time as children mature (Lahey, hibition, children with ADHD tend to be
Pelham, Loney, Lee, & Wilcutt, 2005). excessively restless, overactive, and easily
aroused emotionally. The speed and inten-
sity with which they move to the extreme of
A Practical Definition of ADHD their emotions are much greater than those
of their same-age peers.
In clinical settings, it is suggested that neu- 4. Difficulty with gratification. Children
ropsychologists apply a practical definition with ADHD, due to their lack of inhibition,
of ADHD as a means of translating his- require immediate, frequent, predictable,
tory and test data into functional behavior. and meaningful rewards. They experience
Such a process may also assist parents and difficulty in working toward a long-term
educators in understanding the children they goal, and thus often require brief, repeated
live with and educate; it provides a logical payoffs rather than a single long-term re-
framework within which to evaluate and ward. They also do not appear to respond
understand the seemingly illogical pattern to rewards in the same manner as other
of behavior this group of children exhibits. children do (Haenlein & Caul, 1987); that
The practical definition contains five com- is, rewards do not appear to be effective in
ponents, with the first, impulsivity, consid- changing their behavior on a long-term basis.
ered to be the major contributing force in Moreover, they appear to require more tri-
shaping the other four components. These als to consistently demonstrate mastery over
components are briefly presented below. The behaviors that are within their repertoires.
interested reader is referred to Goldstein and This may be the result of a faulty ability to
Goldstein (1998) for an extended review. develop a self-cueing process necessary to
know what to do and when to do it. Because
1. Impulsivity. Children with ADHD of their impulsivity, their behavior may re-
have difficulty thinking before they act. They main consequentially bound.
do not efficiently weigh consequences before It also appears that these children, because
acting and do not reasonably consider the of their behavior, frequently receive more
consequences of their past behavior. They negative reinforcement than others. Thus
struggle to follow rule-governed behav- they are victims both of their temperaments,
ior (Barkley, 2006), due to their problems which make it difficult for them to persist,
with separating experience from response, and of their reinforcement histories, which
thought from emotion, and action from re- reinforce them for starting but often not
action. In the heat of the moment, their lim- for finishing tasks. It is important to keep
ited capacity for self-control is quickly over- in mind that these children like rewards and
whelmed by their immediate need to act. do not like punishments; in this respect, they
2. Inattention. Children with ADHD are similar to everyone else. Nonetheless,
have difficulty remaining on task and fo- over time they learn to respond to demands
cusing their attention, in comparison to placed upon them by the environment when
children without ADHD of similar chron- an aversive stimulus is removed contingent
ological age. A more precise review of the upon performance, rather than when they
available literature, however, suggests that are promised a future reward.
their problems do no occur during highly 5. Emotions and locus of control. Due
motivating or interesting tasks, but rather to their impulsivity, children with ADHD
when tasks are repetitive, effortful, uninter- often appear to be on a roller-coaster ride of
esting, and not of the children’s choosing. In emotions throughout their childhood. When
these circumstances the children’s inability they are happy, they are so happy people tell
to inhibit their desire to move off this task is them to calm down. When they are unhap-
limited, and thus they find themselves doing py, they are so unhappy people tell them to
anything else that appears to be more inter- calm down. They may learn that their emo-
esting or less effortful. Although this pattern tions are not valued and often lead them into
is true to some extent for everyone on a di- trouble. They may also be more prone to de-
velop an external locus of control, to proj- chromosome 6 identified by Cardon and col-
ect blame onto others, and to be unwilling leagues (1994) may be a locus for ADHD as
to recognize and accept the role they play well (Warren et al., 1995). Faraone and col-
in their own behavior. They appear more leagues (2005), following an analysis of 20
vulnerable to certain personality problems, twin studies, computed a heritability of 76%
especially those related to antisocial diffi- for ADHD. Moreover, it would appear that
culty, in part because of these qualities com- some of these genes interact with the envi-
bined with their life experiences. They may ronment in such a way that the remaining
be more prone to depression as well, in part 24% contributed by the environment is still
due to the lack of balance between success- quite genetically significant.
ful and unsuccessful experiences on a day- A recent report of a genome-wide associa-
in-and-day-out basis. tion scan of ADHD notes that earlier stud-
ies have converged in agreement that genes
Increasingly, these core problems have contribute substantially to the development
been considered under the umbrella of of ADHD. However, despite numerous link-
concepts such as self-regulation (Goldstein age and candidate gene studies, a strongly
& Brooks, 2007), executive functioning consistent and replicable association has
(Barkley, 2008), or planning (Goldstein & not been identified (Neale et al., 2008).
Naglieri, 2006). Regardless of the overall To search for ADHD susceptibility genes,
concept or term used to describe these pro- Neale and colleagues (2008) genotyped ap-
cesses, it would appear that ADHD rep- proximately 600,000 gene segments in 958
resents a constellation of symptoms and ADHD-affected family trios. This led them
consequent impairments resulting from inef- to analyze nearly half a million gene splices
ficiency in goal-directed behavior. Children in nearly 3,000 individuals constituting over
with ADHD struggle to formulate goals and 900 complete trios, using the ADHD diag-
plans efficiently, to sequence them temporal- nosis as phenotype. None of the association
ly, and to execute them, as well as to evalu- tests achieved genome-wide significance, sug-
ate and reevaluate outcomes in light of the gesting that larger samples may be required
intended objectives. to identify the true risk loci for ADHD.
Eaves, Silberg, and Hewitt (1993) note
two complementary approaches to the ge-
Genetics and Other netic analysis of ADHD. The first, a di-
Etiological Considerations mensional approach, involves the study of a
normal trait or range of activity; it assumes
The genetic contribution to ADHD has been that ADHD is at one end of the continuum
postulated by a number of authors since or trait. The second, a categorical approach,
the early 1990s (Hechtman, 1993; Rut- is based on studying children of families
ter et al., 1990; Stevenson, 1992; Swanson who meet diagnostic criteria; it assumes
et al., 2000). There is no single gene that that ADHD is a discrete disorder (Faraone,
causes ADHD, but several genes are likely Biederman, Chen, & Krifcher, 1992). It is
to enhance susceptibility (Faraone & Khan, important for neuropsychologists to recog-
2006). The underlying genetic mechanism nize that dimensional approaches have been
has been suggested to be associated with a found to predict life outcome better than
single dopamine transporter gene (Cook et categorical approaches (Fergusson & Hor-
al., 1995); with variations in the DRD4 (La- wood, 1992).
Hoste et al., 1996) and DRD5 (Lowe et al., Among investigators taking the dimen-
2004) receptor genes; and with a variation sional approach, Willerman (1973) found the
in the DAT1 transporter gene (Winsberg & heritability of scores on an activity question-
Comings, 1999). There is also evidence that naire to be 0.77 for a sample of 54 monozy-
the gene synaptosomal protein of 25 kilo- gotic and 39 dizygotic twin pairs. However,
daltons (SNAP-25), a gene that controls syn- Goodman and Stevenson (1989) reported a
aptic vesicle transmission, may also in con- heritability estimate of greater than 1.00 in
tribute in part to ADHD (Faraone & Kahn, a sample of 285 twin pairs. This finding ap-
2006). Furthermore, it has been suggested peared to be due to an extremely low dizy-
that the trait locus for reading disability on gotic correlation. Corresponding dizygotic
correlations for father and teacher reports monozygotic twins were significantly higher
were much higher, resulting in heritability than for dizygotic twins. As Levy and col-
estimates from 0.48 to 0.68. A subsequent leagues note, ADHD has an exceptionally
twin study by Thapar, Hervas, and McGuf- high heritability compared with other be-
fin (1995), using the same three activity items havioral disorders. These authors reported
used by Goodman and Stevenson, confirmed that 82% of monozygotic twins and 38%
the low dizygotic correlation in maternal of dizygotic twins met an eight-symptom
ratings; Thapar and colleagues suggested ADHD cutoff for proband concordances.
that the role of reciprocal sibling interac- Studies linking polymorphisms in the
tions may be different in dizygotic versus dopaminergic system to ADHD (Comings,
monozygotic twins, or that mothers may ex- Wu, & Chiu, 1996) and the DRD4 recep-
aggerate differences between their dizygotic tor polymorphisms to dimensional aspects
twins. The low dizygotic correlation may, of impulsivity (Benjamin et al., 1996; Eb-
however, be unique to these specific ques- stein et al., 1996) suggest that the polymor-
tions about activity level. Edelbrock, Rende, phisms identified to date do not account for
Plomin, and Thompson (1995) reported cor- all of the relevant heritable variation. The
relations (predominantly from mothers’ rat- findings of Sherman and colleagues (1997)
ings) of .86 for monozygotic twins and .29 suggest that future molecular genetic stud-
for dizygotic twins, giving a heritability esti- ies of ADHD may yield more information
mate of 0.66. Zahn-Waxler, Schmitz, Fulker, defining ADHD as a disorder composed of
Robinson, and Emde (1996) obtained a very two quantitatively, continuously distributed
similar estimate (0.72). However, somewhat dimensions—inattention and hyperactivity–
lower heritability values were obtained from impulsivity—rather than a homogeneous
fathers’ and teachers’ ratings, and the cor- categorical disorder.
relations between raters was low. Recently Faraone and colleagues (2008)
Employing the categorical or diagnostic genotyped nearly 6,000 single-nucleotide
approach, Goodman and Stevenson (1989) polymorphisms across a genome of over
demonstrated a probandwise concordance 1,000 individuals from families with chil-
rate of 51% in 39 monozygotic twin pairs dren diagnosed with ADHD. They then per-
and 30% in 54 dizygotic twin pairs, yield- formed two nonparametric linkage analyses
ing a heritability estimate of 0.64. De Fries on these families: (1) an affected-sibling-pair
and Fulker (1985, 1988), utilizing a statis- linkage analysis on 217 families with 601
tical method developed by Gillis, Gilger, siblings diagnosed with ADHD; and (2) a
Pennington, and De Fries (1992), estimated variance-components linkage analysis, using
the heritability of ADHD as 0.91 ± 0.36 for the number of ADHD symptoms as the phe-
twins participating in a research project. notype, on 260 families with 1,100 phe-
The issue of phenotypic definition, as in- notypic siblings. From these analyses, the
dicated by the variation in estimates of sib- authors concluded that their findings of an
lings’ risk (53%, 25%, or 17%, depending absence of regions of significant or sugges-
on whether the behavior is defined as hy- tive linkage indicate that there are probably
peractivity, ADD, or ADHD), speaks to the no genes of large effect contributing to the
complexity of relating phenotype to geno- ADHD phenotype. It has further been dem-
type (Biederman, Faraone, Keenan, Knee, & onstrated that the gender differences found
Tsuang, 1990; Biederman et al., 1992; Safer, in ADHD could be sexually dimorphic. Bie-
1973; Faraone et al., 1992). Levy, Hay, Mc- derman, Kim, and colleagues (2008) found
Stephen, Wood, and Waldman (1997), study- some evidence suggesting this to be the case.
ing a cohort of 1,938 families with twins Genetic associations for ADHD appeared
and siblings ages 4–12 years recruited from stronger when stratified by gender and in
the Australian National Health and Medical the same direction as indicated by previous
Research Council Twin Registry, reported neurobiological studies. Associations were
that ADHD is best viewed as the extreme stronger in males for two candidate genes
of behavior that varies genetically through- (COMT and SLC6A4), and stronger in fe-
out the entire population, rather than as a males for two others (SLC6A2 and MAOA).
disorder with discrete determinants. In this Furthermore, these authors reported a statis-
study, as in others, heritability estimates for tically significant gender effect for COMT.
The etiology of ADHD must also be con- ADHD were found in another study to be
sidered in relation to other genetic disor- unable to active the caudate nucleus, sug-
ders and to teratogens. Fragile X syndrome, gesting core abnormality in this function for
Turner syndrome, Tourette syndrome, neu- ADHD (Vaiyda et al., 2005). These authors
rofibromatosis, sickle cell anemia, phenylke- concluded that children with ADHD experi-
tonuria, Noonan syndrome, and Williams ence reduced engagement of a frontostriatal–
syndrome are all chromosomal and genetic temporoparietal network when engaging in
abnormalities in which attentional problems inhibitory tasks.
and ADHD have been reported (Hagerman,
1991; Mautner, Kluwe, Thakker, & Laerk,
2002). Bastain and colleagues (2002) suggest Developmental Course
that expensive laboratory tests for genetic and Comorbidity
disorders are not indicated unless a genetic
disorder is suspected because of family his- Although the core problems children with
tory, clinical signs, or low IQ. Exposure to ADHD experience reflect similar difficulty
various toxins (e.g., alcohol and cocaine ex- with impulsivity, inattention, and hyperac-
posure in utero, lead and vapor abuse), peri- tivity, each child’s presentation is unique in
natal complications, medical problems (e.g., terms of the manifestation of these problems
hypothyroidism, encephalitis), and even ra- and associated comorbid factors (Goldstein
diation therapy secondary to leukemia have & Goldstein, 1998). As an increasing body
all been reported as responsible for creation of scientific data is generated concerning the
of inattention and impulsivity problems developmental course and adult outcome of
(for reviews, see Barkley, 2006; Goldstein children with ADHD, it appears that the co-
& Goldstein, 1998). ADHD and depressive morbid problems they develop predict their
symptoms are commonly identified after pe- life outcomes better than the diagnosis of
diatric traumatic brain injury, but may pre- ADHD itself does. ADHD in isolation ap-
date the trauma (Bloom et al., 2001). pears to best predict school struggles, diffi-
The neurobiology of ADHD implicates culty meeting expectations without the home
impairment in brain structure—particularly setting, and possible mild substance abuse as
differences in size of certain structures, inter- an adult. However, it does not predict the
acting with metabolic differences (Zametkin significant negative emotional, behavioral,
& Rapoport, 1987). In efficient brain me- and personality outcomes that have been re-
tabolism in prefrontal and cingulate regions, ported.
as well as in the right thalamus caudate, Infants who have been noted to demon-
hippocampus, and cerebellum, has been strate difficult temperament do not handle
reported in adults with ADHD (Zametkin, changes in routines well. They exhibit a low
Nordahl, & Gross, 1990). Regional ab- frustration threshold and a high intensity of
normalities of glucose metabolism demon- response (Carey, 1970; Chess & Thomas,
strated by positron emission tomography 1986; Thomas & Chess, 1977). In follow-
studies generally demonstrate a fundamen- up studies of such infants, as many as 70%
tal biological difference between individu- develop school problems (Terestman, 1980).
als with and without ADHD. Castellanos These infants appear at greater risk than
and colleagues (1996) suggest that connec- others of receiving a diagnosis of ADHD.
tions among the right prefrontal cortex, It is also important to note that these dif-
caudate, and cerebellum reflect the brain’s ficult infants exert a significant negative im-
so-called “braking system”—a system that pact on their developing relationships with
operates inefficiently in individuals with caregivers—relationships that are critical in
ADHD. Semrud-Clikeman and colleagues predicting children’s life outcomes (Houshy-
(2000) found reversed caudate asymmetry ar & Kaufman, 2005; Katz, 1997).
on magnetic resonance imaging scans of 10 Although early symptoms of ADHD may
males diagnosed with ADHD. They noted be viewed as transient problems of young
that findings in the right prefrontal cortex, children, research data suggest that ignor-
cerebellum, and basal ganglia appeared to ing these signs results in the loss of valuable
be associated with behavioral measures of treatment time. At least 60–70% of children
inattention and inhibition. Children with later diagnosed with ADHD could have
been identified by their symptoms during the pothesized that ADHD may prevent a child
preschool years (Cohen, Sullivan, Minde, from achieving his or her academic potential
Novack, & Helwig, 1981). Young children (Stott, 1981), the presence of a learning dis-
manifesting symptoms of ADHD are more ability may make a child appear more inat-
likely to present with speech and language tentive than others (Aaron, Joshi, Palmer,
problems (Baker & Cantwell, 1987), and to Smith, & Kirby, 2002; McGee & Share,
develop a wide range of behavioral problems 1988).
(Cantwell, Baker, & Mattison, 1981; Cohen, Sociometric and play studies suggest that
Davine, & Meloche-Kelly, 1989; DuPaul, children with ADHD are not chosen as often
McGoey, Eckert, & VanBrakle, 2001), than by their peers to be best friends or partners
are children not suffering from these symp- in activities (Bagwell, Molina, Pelham, &
toms. Research also cogently suggests that Hoza, 2001; Pelham & Milich, 1984). They
the comorbidity of speech and language disappear to be cognizant of their difficulties—
orders with ADHD merits routine screening an awareness that probably precipitates
of children suspected of having either type lower self-esteem for children with ADHD
of problem, especially during their younger (Glow & Glow, 1980). Moreover, they ap-
years. Children with concurrent ADHD and pear to experience either high-prevalence,
language disorders appear to have a much low-impact problems that result in poor
poorer prognosis than those with those with social acceptance or low incidence, high
ADHD alone (Baker & Cantwell, 1992). impact problems that result in social rejec-
Within school settings, children with tion (Pelham & Milich, 1984). In addition,
ADHD appear to be victims both of their these children have difficulty adapting their
temperaments and of their learning histo- behavior to different situational demands
ries, which often involve beginning but not (Whalen, Henker, Collins, McAuliffe, &
completing tasks. The negatively reinforc- Vaux, 1979). It has been suggested that the
ing model utilized by most educators in this impulsive behavioral patterns of children
circumstance tends to focus on misbehavior with ADHD are most responsible for their
rather than on termination of the behavior. social difficulty; this may place those with
This may further disrupt the classroom by comorbid hyperactive–impulsive problems
having a disinhibitory effect on other stu- of greater severity at even greater risk of de-
dents. Although many years ago it was sug- veloping social difficulties (Hodgens, Cole,
gested that children with ADHD were intel- & Boldizar, 2000; Pelham & Bender, 1982).
lectually less competent than their peers, ADHD has also been found to be a risk fac-
it now appears more likely that weak per- tor for a wide variety of ineffective social
formance on intellectual tasks results from coping strategies as youth make the transi-
the impact of impulsivity and inattention tion into adolescence (Young, Chadwick,
on test-taking behavior than from an innate Heptinstall, Taylor, & Sonuga-Barke, 2005).
lack of intelligence (Barkley, 1995). Kaplan, It should be noted as well that children who
Crawford, Dewey, and Fisher (2000) identi- demonstrate satisfactory symptom and im-
fied a normal IQ distribution in children di- pairment reduction with medication appear
agnosed with ADHD. Children with ADHD to exhibit fewer chronic social impairments
often underperform but may not under- (Gallagher et al., 2004).
achieve during the elementary years. How- Some primary symptoms of ADHD may
ever, it has been reported that by high school diminish in intensity by adolescence (Weiss
at least 80% of these children fall behind in & Hechtman, 1979). However, most ado-
a basic academic subject requiring repetition lescents with ADHD continue to experience
and attention for competence, such as basic significant problems (Milich & Loney, 1979;
math knowledge, spelling, or written lan- for reviews, see Barkley, 2006; Goldstein &
guage (for reviews, see Barkley, 2006; Gold- Ellison, 2002). At least 80% of adolescents
stein & Goldstein, 1998). Depending on with ADHD continue to manifest symp-
diagnostic criteria, approximately 20–30% toms consistent with ADHD. Sixty percent
of children with ADHD also suffer from a develop at least one additional disruptive
concomitant, often language-based, learn- disorder (Barkley, Fischer, Edelbrock, &
ing disability (for a review, see Willcutt & Smallish, 1990). Between 20% and 60%
Pennington, 2000). Although it has been hy- of adolescents with ADHD are involved in
antisocial behavior, whereas the usual oc- goal for researchers and clinicians. Thus,
currence is 3–4% (Satterfield, Hoppe, & when one reviews the extensive literature
Schell, 1982). At least 50–70% of these ado- attempting to hypothetically and objec-
lescents develop oppositional defiant disor- tively define specific neuropsychological
der, often during their younger years, with impairments occurring consistently in chil-
a significant number progressing to conduct dren with ADHD, it is not surprising that
disorder (Barkley et al., 1990). However, no tried and true battery or specific pattern
the high prevalence of antisocial problems of impairment has come to light. As Levine
in adolescents with ADHD is likely to re- (1992) has noted, ADHD symptoms appear
flect the comorbidity of ADHD with other to reflect “elusive entities and . . . mistaken
disruptive disorders, principally conduct identities.” The comorbidity issue, and many
disorder (Barkley, McMurray, Edelbrock, tests’ lack of specificity in discriminating
& Robbins, 1989). As Barkley (1997) suc- ADHD from other disorders, further com-
cinctly points out, the preponderance of the plicate this endeavor. Compromised scores
available data suggests that while ADHD is may be due to a variety of causes, leading
clearly a risk factor for the development of some researchers to suggest that a profile
adolescent antisocial problems, life experi- of test scores be utilized in defining and ex-
ences (principally factors within families) plaining neuropsychological impairments in
most powerfully contribute to the onset and children with ADHD (Aylward, Verhulst, &
maintenance of delinquency, conduct disor- Bell, 1993; Naglieri, 2000). Neuropsycholo-
der, and subsequent young adult antisocial gists should be aware that clinic or labora-
problems (see also Dalsgaard, Mortenson, tory tests alone or in combination have been
Frydenberg, & Thomsen, 2002). found to result in classification decisions
that frequently disagree with a diagnosis of
ADHD based on parent interview, history,
Neuropsychological Impairments and behavior rating scales (Doyle, Bieder-
man, & Seidman, 2000; DuPaul, Anasto-
The ecological validity of laboratory tests to poulos, Shelton, Guevremont, & Metevia,
identify the presence of ADHD symptoms and 1992). Furthermore, although Szatmari, Of-
to determine their severity has been increas- ford, Siegel, Finlayson, and Tuff (1990) re-
ingly questioned (Barkley, 1991b; Barkley & port that neuropsychological tests appear to
Grodzinsky, 1994). Because ADHD is a dis- distinguish children with ADHD from those
order defined by behavior in the real world, with pure anxiety or affective (mood) disor-
it is not surprising that laboratory measures ders, they may not as efficiently distinguish
frequently fall short in identifying and defin- ADHD from other disruptive disorders.
ing symptoms of the disorder, in comparison These authors concluded that neuropsycho-
to naturalistic observation, history, and or- logical test scores are more strongly associ-
ganized report in the form of questionnaires. ated with externalizing than with internaliz-
Nonetheless, it has been increasingly recog- ing diagnoses. They also appear to correlate
nized that neuropsychologists take comfort with psychiatric symptoms at school but not
in supplementing their clinical impressions at home. Moreover, scores on traditional
with laboratory-generated, objective scores neuropsychological instruments used to
(DuPaul, Guevremont, & Barkley, 1991). It infer attention and impulse problems often
is acknowledged that these scores cannot be do not correlate with each other (Naglieri,
used alone to make the diagnosis of ADHD, Goldstein, Delauder, & Schwebach, 2005).
but they may be helpful in the process of Thus it is not surprising that Barkley (1991a)
differential diagnosis (e.g., when is impul- suggests that when results of standardized
sivity a function of ADHD vs. other disor- behavior ratings, observations, and history
ders?), as well as in determining severity or conflict with laboratory measures, the latter
related prognosis in a group of individuals should be disregarded in favor of the former,
with ADHD (Gordon, 1995; Hall, Halperin, as these are considered more ecologically
Schwartz, & Newcorn, 1997). valid sources of data.
The development of a norm-referenced, Cherkes-Julkowski, Stolzenberg, and Sie-
psychometric assessment battery specifical- gal (1991) suggest that perhaps performance
ly designed for ADHD has been an elusive on neuropsychological tests by children with
ADHD is a function of an inability to con- lect data concerning the child’s behavior at
trol focus of attention. These authors suggest home, with friends, and at school; academic
that when prompts are provided during test- and intellectual functioning; medical status;
ing, children with ADHD perform signifi- and emotional development. It is suggested
cantly better. In a study evaluating children that professionals consider the following
with ADHD with and without medication, multistep process to accompany the evalua-
compared to children with learning disabili- tion of ADHD:
ties and a group of nondisabled controls, the
greatest gains for prompts were observed in 1. A complete history must be obtained.
the unmedicated group with ADHD. How- This is not a cursory process. Sufficient
ever, neuropsychologists should be cau- time (approximately 1½–2 hours) should be
tioned that prompts, especially on measures set aside to obtain a narrative of the child’s
designed to evaluate response inhibition may development, behavior, extended family
actually test a child’s ability to follow direc- history, family relations, and current func-
tions rather than to inhibit. Neuropsychol- tioning. Within the context of the interview,
ogists should also keep in mind that there efforts should be made to trace a develop-
are data suggesting that level of reinforce- mental course that appears to fit the picture
ment during test performance may have an of ADHD, as well as to identify core symp-
impact on scores as well. Devers, Bradley- toms and those related to other childhood
Johnson, and Johnson (1994) found that a disorders. Obtaining thorough knowledge
12-point improvement in Verbal IQ scores of the diagnostic criteria for common and
accrued when token reinforcers followed im- uncommon (e.g., high-functioning autism)
mediately for correct responses. The impact childhood internalizing and externalizing
of praise on test performance has not been disorders should be a paramount concern for
systematically evaluated. Finally, Draeger, the neuropsychologist, to facilitate the iden-
Prior, and Sanson (1986) reported a greater tification of high- as well as low-prevalence
deterioration in the performance of children disorders.
with ADHD on a continuous-performance 2. Data obtained from the history should
test than in control children’s performance be supplemented by the completion of sev-
when the examiner left the room. These au- eral standardized, factor-analyzed ques-
thors suggest that even an examiner’s pres- tionnaires concerning children’s problems.
ence acts to mitigate test performance. It At least two adults who interact with the
may well be that some children who perform child on a regular basis, ideally a parent and
poorly on test measures under these circum- a teacher, should be requested to complete
stances have an application deficit rather questionnaires. For general child assess-
than an ability deficit. ment, valuable questionnaires are the Child
Behavior Checklist (CBCL; Achenbach &
Rescorla, 2001) and the Behavior Assess-
Evaluation ment System for Children, Second Edition
(Reynolds & Kamphaus, 2004). The CBCL
Due to the pervasive, multisetting nature of is a well-developed questionnaire that orga-
problems related to ADHD, and ADHD’s nizes childhood behavior on a disruptive–
high comorbidity with other childhood nondisruptive continuum. Research indi-
disorders, assessment for ADHD involves cates that the Attention Problems scale in an
a thorough emotional, developmental, and earlier version of the CBCL correlates well
behavioral evaluation. It should be noted, with the two-factor DSM-IV ADHD diag-
however, that the diagnosis of ADHD nosis (Achenbach, 1996). The Conners 3rd
should be firmly based on the accepted stan- Edition (Conners, 2008), the Comprehen-
dard, which at present is the DSM-IV-TR sive Teacher’s Rating Scale (Ullman, Sleator,
diagnostic criteria set. Professionals should & Sprague, 1988), the Childhood Attention
be aware that efforts to include additional Problems Scale (Edelbrock, 1990), and the
data to prove or disprove the diagnosis run Academic Performance and ADHD Rat-
the risk of introducing increasing variance ing Scales (DuPaul, 1990) are also helpful.
(Naglieri, Goldstein, & Schwebach, 2004). However, these questionnaires alone do not
The comprehensive evaluation should col- provide sufficient information for diagnosis;
they simply provide an organized report of possess poor negative predictive power (i.e.,
behavior. They describe what the observer if a child passes a task, conclusions cannot
sees, but not why it is being seen. be drawn one way or the other concerning
3. From the history and questionnaires, the diagnosis) (McGee, Clark, & Symons,
the professional should be able to generate a 2000). Nonetheless, many neuropsycholo-
consistent set of data and a series of hypoth- gists rely on such instruments to provide ad-
eses to explain the child’s behavior across a ditional data as part of the diagnostic pro-
variety of settings. cess, rather than specifically to confirm or
4. Requests should be made to review disconfirm the diagnosis of ADHD (Riccio,
school records, including report cards and Reynolds, & Lowe, 2001). The interested
results of group achievement testing. If weak reader is referred to Homack and Reynolds
performance or learning disabilities are sus- (2005) for a thorough review of the litera-
pected, or if the child is already receiving ture concerning computerized assessment
special education services, the neuropsychol- of ADHD. Although several studies have
ogist should review all assessment data as suggested that measurement of specific in-
well as the child’s individualized education tellectual processes may differentiate youth
program. Then it is proper to decide which with various subtypes of ADHD (Naglieri,
tests and what amount of time should be 1999; Paolito, 1999), data generated by in-
used to arrive at the most accurate evalua- struments such as the Cognitive Assessment
tion of the child. Neuropsychologists should System (Naglieri & Das, 1997) are not nec-
be cautioned that, as just reviewed, no spe- essary in making the diagnosis of ADHD
cific laboratory tests to evaluate ADHD but can provide useful information concern-
have demonstrated sufficient positive and ing differences in cognitive processes among
negative predictive power to be relied on. diagnosed youth.
The primary purpose of face-to-face assess-
ment with a child should be to address is-
sues related to the child’s emotional status, Treatment
self-esteem, cognitive development, and pos-
sible learning disabilities. Observation of the Treatment of ADHD must be multidisci-
child’s behavior during assessment may also plinary, multimodal, and maintained over
yield clues regarding his or her interpersonal a long period (for reviews, see Goldstein
style and temperament. & Ellison, 2002; Goldstein & Goldstein,
5. Although a number of paper-and- 1998; Teeter, 1998). By far the most effec-
pencil tasks have been used over the years tive short-term interventions for ADHD are
in research settings to identify symptoms of combinations of medical, behavioral, and
ADHD, most have not lent themselves easily environmental techniques.
to clinical use. In research studies some of Medication has demonstrated the ability
these tests, such as the Matching Familiar to reduce the manipulative power of a child’s
Figures Test (Kagan, 1964), have appeared behavior in eliciting certain responses from
to show strong positive and negative predic- teachers, peers, and family members. An
tive power for identifying impulsive children. extensive literature attests to the benefits of
However, in clinical practice, such instru- medicine, specifically stimulants, in reducing
ments have not proven reliable for confirm- key symptoms of ADHD and thus improving
ing the diagnosis of ADHD. Computerized daily functioning (Klein, 1987; for reviews,
instruments designed to measure sustained see Barkley, 2006; Goldstein & Goldstein,
attention and the ability to inhibit impulsive 1998). Stimulants and other drugs principal-
responding (Conners, 2004; Gordon, 1993; ly affecting dopamine and norepinephrine
Greenberg, 1991) have become increasingly (Volkow et al., 2001) have consistently have
popular among neuropsychologists. Howev- been reported to improve academic achieve-
er, it is important to remember that although ment and productivity, as well as accuracy of
these instruments may demonstrate strong classwork (Douglas, Barr, O’Neill, & Brit-
positive predictive power (i.e., if a child fails ton, 1986); improved attention span, read-
such a task, it strongly confirms the pres- ing comprehension, complex problem solv-
ence of symptoms related to ADHD), they ing, and inhibitory processes have also been
noted (Balthazor, Wagner, & Pelham, 1991; retical construct that the core problem for
Pelham, 1987). Related problems, including ADHD reflects an inability to take sufficient
peer interactions, peer status, and even re- time to think or respond consistently to con-
lationships with family members, have been sequences.
reported to be improved with stimulants as
well (Whalen & Henker, 1991).
Behavior management increases the sa- Summary
lience of behaving in a way consistent with
environmental expectations. The manipula- Professionals must be prepared to rely exten-
tion of the environment (e.g., making tasks sively upon history, report, and observation,
more interesting and payoffs more valuable) and less so upon structured laboratory test-
reduces the risk of problems within the natu- ing, in attempting to understand the behav-
ral setting. Zentall (1995) suggests that stu- ior and problems of children with ADHD.
dents with ADHD possess an active learn- This chapter has provided an overview of
ing style, with a demonstrated need to move, the current literature concerning the defini-
talk, respond, question, choose, debate, and tion, genetic, neurobiology, evaluation, and
even provoke. Thus, in classroom settings, treatment of ADHD in children.
children with ADHD do not fare well in sed-
entary situations. Interventions for manag-
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Chapter 8
Oppositional, Conduct,
and Aggressive Disorders
Lisa L. Weyandt
Genevieve Verdi
Anthony Swentosky
Aggression, disruptive behaviors, and act- Although the theoretical and empirical em-
ing-out behaviors are common at various phasis of researchers historically centered on
stages of development. When these external- specific stimuli and events that elicited ag-
izing behaviors increase in frequency and gressive behaviors, contemporary research
duration, however, and cause impairment in emphasizes the assessment of aggressive
child and family functioning, they become individuals within bioecological systems. A
causes of concern for individuals, families, second change identified by Hartup (2005)
and society at large. The purposes of the is that research on aggression and antiso-
present chapter are to provide a brief his- cial behavior has converged into one field of
tory of oppositional defiant disorder (ODD) study, whereas early explorations tended to
and conduct disorder (CD), and to review approach the two categories of behavior as
the current literature concerning develop- distinct and unrelated. A final major trend in
mental course, genetic factors, and biologi- the aggression literature relates to the study
cal markers of the behaviors characterizing of aggression via a developmentally oriented
these disorders. Information is also provided paradigm. Early studies (Kuhn, Madsen, &
concerning assessment and treatment strate- Becker, 1967; Noble, 1973; Rosekrans &
gies for children and adolescents with ODD Hartup, 1967; Rule & Duker, 1973) on ag-
and CD. gression typically assessed individuals only
at one particular time point; very little at-
tention was given to age differences. Today,
History however, the most informative studies of ag-
gression are developmental in nature, often
The nosology of ODD, CD, and aggression employing longitudinal designs to better
has evolved over the last 40 years in terms identify the precursors and outcomes of ag-
of conceptualization, research approaches, gressive behaviors in children and adoles-
and treatment protocols. Hartup (2005) cents (Broidy et al., 2003; Tremblay et al.,
notes that three specific changes have oc- 2005).
curred in the understanding of the develop- Despite these methodological shifts and
ment of aggression in individuals, as well as numerous other methodological improve-
the way the subject is empirically assessed. ments in the study of how aggression, CD,
151
and ODD develop, many uncertainties and Three different subtypes were identified in
opportunities for improved research remain. DSM-III-R (APA, 1987):
For instance, it is difficult to determine
whether children and adolescents in previ- 1. Group type
ous studies of CD and ODD would meet 2. Solitary aggressive type
current diagnostic criteria for these disor- 3. Undifferentiated type
ders (Robins, 1999). As the theoretical and
methodological changes concerning CD and Also, in DSM-IV-TR it is explained that
ODD have occurred, the diagnostic crite- ODD is “often,” but not always, a devel-
ria of these disorders have also evolved. In opmental antecedent of CD (APA, 2000,
fact, CD and ODD were not recognized of- p. 101), supporting the nature of the DSM-
ficially by the American Psychiatric Associa- IV-TR diagnoses of ODD and CD as based
tion (APA) until 1980, when the Diagnostic on developmentally oriented examinations of
and Statistical Manual of Mental Disorders child and adolescent behavior. As illustrated
(DSM-III) was published. Since 1980, the in Table 8.1, the diagnostic criteria for CD
diagnostic criteria for these disorders have have also expanded from 13 possible symp-
become more developmentally focused and toms in DSM-III-R to 15 possible symptoms
more empirically based (APA, 2000). For in DSM-IV-TR. Fewer criteria are included
example, the DSM-IV-TR (APA, 2000) de- in the current symptomology for ODD;
scribe these three subtypes of CD: DSM-III-R lists nine possible symptoms,
whereas DSM-IV-TR has only eight possible
1. Childhood-onset type symptoms. As seen in Table 8.2, the use of
2. Adolescent-onset type swearing or obscene language is the omitted
3. Unspecified onset (in which the age of symptom. These changes in diagnostic em-
onset of CD is unknown) phasis and specific diagnostic criteria under-
TABLE 8.1. Comparing DSM-III-R and DSM-IV-TR Diagnostic Symptoms for CD

DSM-III-R DSM-IV-TR
1. Frequent initiation of physical fights 1. Frequent initiation of physical fights
2. Use of a weapon in more than one fight 2. Use of a weapon that can cause serious injury
3. Physical cruelty to people to others (e.g., a bat, brick, gun, knife)
4. Physical cruelty to animals 3. Physical cruelty to people
5. Stealing while confronting a victim (e.g., 4. Physical cruelty to animals
mugging, snatching a purse, etc.) 5. Stealing while confronting a victim
6. Forcing someone into sexual activity 6. Forcing someone into sexual activity
7. Deliberately setting fires 7. Deliberately setting fires with the intention to
8. Deliberately destroying others’ property (other cause serious damage
than by setting fires) 8. Deliberately destroying others’ property (other
9. Breaking into someone else’s home, building, or than by setting fires)
car 9. Breaking into someone else’s home, car, or
10. Frequent lying (other than to avoid sexual or building
physical abuse) 10. Frequent lying to obtain favors or goods, or to
11. Stealing without confronting a victim, more get out of obligations
than once (including forgery) 11. Stealing things of nontrivial value without
12. Running away from home overnight at least confronting a victim (e.g., shoplifting, but not
twice while residing in parents’ or parental breaking and entering; forgery)
surrogates’ home (or once without returning) 12. Running away from home overnight at least
13. Frequent truancy from school (for older person, twice while residing in parents’ or parental
frequent absence from work) surrogates’ home (or once without returning
for a long period)
13. Frequent truancy from school, beginning
before 13 years of age
14. Frequently staying out at night despite parents’
prohibitions, beginning before 13 years of age
15. Frequent bullying, threats, or intimidation of
others
Oppositional, Conduct, and Aggressive Disorders 153
TABLE 8.2. Comparing DSM-III-R and DSM-IV-TR Diagnostic Symptoms for ODD

DSM-III-R DSM-IV-TR
1. Frequent loss of temper 1. Frequent loss of temper
2. Frequent arguements with adults 2. Frequent arguements with adults
3. Frequent active defiance or refusal of adults’ 3. Frequent active defiance of or noncompliance
rules or requests (e.g., refusal to do home chores) with adults’ rules or requests
4. Frequent deliberate acts that annoy other people 4. Frequent deliberate annoyance of other people
(e.g., grabbing other children’s belongings) 5. Frequent blame of others for own mistakes or
5. Frequent blame of others for own mistakes misbehavior
6. Frequent touchiness or readiness to be annoyed 6. Frequent touchiness or readiness to be annoyed
by others by others
7. Frequent anger and resentment 7. Frequent anger and resentment
8. Frequent spitefulness and vindictiveness 8. Frequent spitefulness and vindictiveness
9. Frequent swearing or use of obscene language
score the fact that a complete understanding kinen, & Rose, 2005; Gelhorn, Sakai, Price,
of ODD and CD has not yet been achieved. & Crowley, 2007; Maughan, Rowe, Messer,
As reflected in the changes accompanying Goodman, & Meltzer, 2004) increases the
the DSM-IV-TR diagnostic criteria for ODD difficulty in identifying and treating these
and CD, an effective method for improving behaviors and disorders separately.
the understanding of these disorders is ex- The literature points to numerous rel-
amining these disorders in reference to their evant risk factors for aggressive behavior,
developmental courses (Broidy et al., 2003; ODD, and CD, providing the foundation
Tremblay et al., 2005). for an understanding of the multifaceted
developmental characteristics and processes
that may lead to these outcomes. Moreover,
Developmental Courses identifying youth at greater risk for diagno-
sis may help reduce prevalence rates through
The development of aggressive and antisocial prevention, intervention, and individualized
behaviors, and of the behavioral disorders treatments (Tremblay & Cote, 2005). Iden-
that they characterize, is a dynamic process tifying these youth is an arduous task, how-
in which multiple factors play a part (Burke, ever, because youth often follow multiple
Loeber, & Birmaher, 2002). Environmental blurred developmental pathways that lead to
factors (Burke et al., 2002; Burt, Krueger, outcomes of varying severity (Broidy et al.,
McGue, & Iacono, 2001), family and pa- 2003; Nagin & Tremblay, 1999).
rental factors (Frick et al., 1992; Joussemet Efficiently organizing and effectively
et al., 2008; Tremblay et al., 2005), genetic interpreting the relevant research in this
factors (Eley, Lichtenstein, & Moffitt, 2003; area constitute a unique challenge because
Rhee & Waldman, 2002), individual per- of the vast diversity in the methodological
sonal factors (Morrell & Murray, 2003), approaches and perspectives used to ac-
and biological factors (Beauchaine, Hong, complish these tasks. For purposes of clar-
& Marsh, 2008; Raine, 2002) have all been ity, the developmental course of aggression,
identified as influences in the development ODD, and CD are explained here from three
of these disorders. Any number of these fac- separate perspectives: (1) childhood charac-
tors may combine cumulatively or interac- teristics as predictors, (2) age differences in
tively to have particularly potent effects on prevalence rates, and (3) developmental tra-
infant and youth development (Odgers et al., jectories. The separation of these three dif-
2007). To add to the complexity, the simi- ferent approaches is not intended to imply
larity of various behavioral symptoms (e.g., that the approaches are mutually exclusive
loss of temper, display of anger, physical or completely distinct from each other. In-
fighting, violation of rules) that are represen- deed, throughout much of the existing litera-
tative of aggressive and antisocial behaviors, ture, overlap among these perspectives is the
ODD, and CD (Dick, Viken, Kaprio, Pulk- norm rather than the exception. This orga-
nizational method simply provides a struc- researchers have consistently illustrated the
ture for the organization and clarification of existence of neuropsychological deficits such
the current literature base (Lahey, 2008). as verbal difficulties, inattention, and prob-
lems with cognitive flexibility, concept for-
mation, and planning abilities in aggressive
Childhood Characteristics
adolescents and youth with CD.
It is a truism of developmental psychology In addition to neuropsychological defi-
that experiences and environmental circum- cits, children who demonstrate delinquent
stances during childhood and adolescence behaviors and conduct problems often have
can have lifelong effects on individuals (Afifi, academic difficulties, such as reading and
Brownridge, Cox, & Sareen, 2006; Bifulco, vocabulary problems (Arnold et al., 2005;
Brown, Moran, Ball, & Campbell, 1998; Willcutt & Pennington, 2000; Williams &
Kendler, Neale, Kessler, Heath, & Eaves, McGee, 1994). Dionne, Tremblay, Boivin,
1992; Moffitt, 1993a; Reid & Patterson, Laplante, and Pérusse (2003) explored the
1989; Surtees et al., 2003). Although the relationship between expressive vocabulary
particular mechanisms through which these and physical aggression in 19-month-olds,
effects occur are debatable, understanding finding a significant negative correlation (r
the childhood experiences and character- = –.20). Similarly, Bennett, Brown, Boyle,
istics that may lead to aggressive behavior, Racine, and Offord (2003) found after con-
ODD, and CD will result in a better under- trolling for income, gender, maternal de-
standing of these behaviors and disorders. pression, family functioning, and previous
Risk factors are identifiable beginning at CD symptoms that low reading achievement
the earliest stages of development; certain at school entry predicted conduct problems
personality and cognitive characteristics of at a 30-month follow-up. Numerous ad-
infants and toddlers have been hypothesized ditional studies have supported a relation-
to increase the risk of future oppositional ship between poor academic performance
and conduct problems. Moffitt (1993a) has and increased risk for aggressive behavior,
posited that neuropsychological deficits, dif- ODD, and CD (Henrich, Schwab-Stone,
ficult infant and child temperaments, and Fanti, Jones, & Ruchkin, 2004; Loveland,
negative parenting behaviors and attitudes Lounsbury, Welsh, & Buboltz, 2007; Swaim,
interact during infancy and early childhood Henry, & Kelly, 2006).
to foster the development of antisocial be- A “difficult” child temperament has like-
haviors representative of ODD and CD. Sup- wise been linked to subsequent conduct prob-
port for several components of this theory is lems. Lahey and colleagues (2008) found that
found in the work of Lynam, Moffitt, and maternal ratings of infant fussiness, positive
Stouthamer-Loeber (1993), who conducted affect, predictability, and activity level each
a longitudinal study involving boys from made independent contributions to mater-
infancy to age 13. Results indicated that nal ratings of conduct problems during ages
13-year-old boys who engaged in high lev- 4–13. Similarly, negative emotionality at 17
els of delinquency had significantly lower IQ months was found to be related to reactive
scores than boys who engaged in lower levels aggression at 72 months (Vitaro, Barker,
of delinquent behaviors. Similarly, Piquero Boivin, Brendgen, & Tremblay, 2006), in-
(2001) found that in a sample of 207 children dependently of harsh parenting practices. In
and adolescents, Verbal and Performance addition to childhood temperament, parent-
scores on the Wechsler Intelligence Scale for ing style has been correlated with child risk
Children had a significant effect on later en- for aggression behaviors. Maternal attribu-
gagement in violent and nonviolent offend- tions of internal, global, and stable causes of
ing. Furthermore, children and adolescents oppositional behavior have also been found
with higher scores on the Verbal scale of this to be predictive of oppositional behavior in
assessment were significantly less likely than children (Johnston, Hommersen, & Seipp,
those with lower scores on the Verbal scale 2009). Controlling or power-assertive par-
to participate in both violent and nonvio- enting has been found to be related to high
lent offending as juveniles (Piquero, 2001). rates of physical aggression in children and
In a review of the literature on this topic, adolescents (Cote, Vaillancourt, Barker,
Teichner and Golden (2000) concluded that Nagin, & Tremblay, 2007; Joussemet et
al., 2008; Olweus, 1980). Rowe, Maughan, that may present in later childhood or ado-
Pickles, Costello, and Angold (2002) found lescence render a previously diagnosed child
that rates of such adverse parenting practices ineligible for the ODD diagnosis. Research
as overintrusive parenting, inadequate su- suggests that oppositional behaviors in chil-
pervision, and harsh discipline were higher dren diagnosed with a behavioral disorder
in children and adolescents diagnosed with may not decrease in late childhood or early
CD and ODD than in children and adoles- adolescence, but instead typically increase in
cents without these disorders. number of symptoms and severity (Maughan
Current research suggests that the rela- et al., 2004). It is necessary to consider spe-
tionship between child and parent charac- cific diagnostic criteria in interpreting the
teristics may be bidirectional. Reid and Pat- relational trends between ODD and CD.
terson (1989) postulated that the effects of A consistent and robust finding regard-
difficult infant temperament, as well as other ing the prevalence rates of CD is that CD
childhood risk factors, on later antisocial be- is much more commonly diagnosed in males
havior are mediated by irritable, ineffective than in females (Loeber, Burke, Lahey, Win-
discipline and poor parental monitoring. ters, & Zera, 2000; Maughan et al., 2004).
Recent studies support this interpretation Findings regarding the gender difference
of the findings, further suggesting that dif- in prevalence rates of ODD are also fairly
ficult child temperament and poor parenting consistent, with most studies indicating an
practices reciprocally influence each other; equal gender prevalence or a slightly greater
that is, a difficult child temperament elic- rate of occurrence among males (Loeber et
its harsh parenting practices, which in turn al., 2000). Maughan and colleagues (2004)
exacerbate the difficult child temperament conducted a cross-sectional study using a
(Burke, Pardini, & Loeber, 2008; Lahey nationally representative sample of 10,438
et al., 2008). Burke and colleagues (2008) youth ages 5–15 years, finding that 0.8%
found that boys who demonstrated more of females and 2.1% of males met DSM-IV
adverse child behaviors at ages 1 and 2, criteria for CD. The prevalence rates in the
and whose parents could also be classified sample for ODD were 1.4% for females and
as unresponsive, were at increased risk for 3.2% for males. Rowe and colleagues (2002)
manifesting conduct problems at ages 3–3½. conducted a longitudinal study using a rural
These findings indicate that even during the community sample of 4,500 children ages 9,
first years of life, the interplay between child 11, and 13 years, and obtained similar re-
temperament and parenting behaviors can sults: 1.1% of females and 3.1% of males met
increase the risk of behavioral problems in DSM-IV criteria for CD, whereas 1.5% of
later childhood or adolescence. girls and 2% of boys met criteria for ODD.
Although the differences between males and
females in CD prevalence rates may appear
Age Differences in Prevalence Rates
minimal, they represent statistically signifi-
Despite the overlap in DSM-IV-TR (APA, cant differences that are consistently found
2000) diagnostic criteria for CD and ODD, across many studies (Gelhorn et al., 2007;
research suggests that prevalence rates for Lahey et al., 2000; Sakai, Risk, Tanaka, &
ODD tend to decline in late childhood and Price, 2008). Given these findings, it is not
early adolescence, whereas rates of CD in- surprising that boys also demonstrate higher
crease steadily through midadolescence rates of physical aggression (Joussemet et
(Maughan et al., 2004). Maughan and col- al., 2008) and aggressive behavior in school
leagues (2004) have suggested that this de- (Thomas, Bierman, Thompson, & Powers,
crease in overall prevalence of ODD is not 2008) than girls. These gender differences
due to a true decrease in oppositional behav- are also consistent across parent and youth
iors, but rather to a proportional increase reports (Lahey et al., 2000).
in CD symptoms and diagnoses. Because
of the diagnostic criterion specifying that a
Developmental Trajectories
child with ODD can no longer be diagnosed
with that disorder once he or she meets di- Arguably the most popular approach to
agnostic criteria for CD (APA, 2000), the studying the origins of aggression, ODD, and
increasingly intense aggressive behaviors CD involves examining the developmental
trajectories of these behaviors and disorders dividuals following the adolescence-limited

(Broidy et al., 2003; Tremblay et al., 2005; course of antisocial behaviors are considered
White, Bates, & Buyske, 2001). Researchers to be demonstrating normal adaptive behav-
developing trajectory models begin by exam- iors. By contrast, those following the life-
ining manifestations of physical aggression course-persistent trajectory are believed to
among very young children. Tremblay and have neuropsychological deficits that inter-
colleagues (2005) conducted a longitudinal act negatively with suboptimal childrearing
study of 572 families, administering assess- environments and lead to a continued and
ments of physical aggression at 17, 30, and increased likelihood of antisocial behaviors.
42 months after birth. Across this early age Partial support for Moffitt’s developmental
range, three trajectories of physical aggres- trajectories of antisocial behavior was dem-
sion were found: (1) children who displayed onstrated in a study by White and colleagues
little or no aggression (28% of the sample), (2001). In addition to the adolescence-
(2) children who followed a rising trajectory limited, life-course-persistent, and no-
of modest physical aggression (58% of the antisocial-behavior groups, an additional,
sample), and (3) children following a rising late-onset group was identified. This group
trajectory of high physical aggression (14% consisted of adolescents who displayed very
of the sample). This study also found that little delinquency in early adolescence, but
children whose mothers engaged in coercive displayed increasing delinquency from late
parenting had a history of antisocial behav- adolescence to adulthood.
ior during their school years, smoked dur- Subsequent studies examining possible de-
ing pregnancy, or started childrearing early velopmental trajectories of aggressive, oppo-
were at increased risk for following a rising sitional, and antisocial behaviors are char-
modest- or high-aggression trajectory, as acterized by considerable variability in the
were children whose parents had low in- number and types of trajectories identified.
comes, had problems living together, or were For example, Broidy and colleagues (2003)
separated. analyzed data from six different sites located
Numerous developmental trajectory stud- in three different countries, examining the
ies have been carried out that involve older developmental trajectories of aggressive and
children and adolescents, and that are gen- delinquent behavior in children and adoles-
erally more refined and complex in terms cents. For the male subsample, the number of
of methodology. Some studies examine the developmental trajectories identified ranged
developmental trajectories of aggressive be- from three to four, while the number of de-
haviors (Brame, Nagin, & Tremblay, 2001; velopmental trajectories identified for female
Murray-Close, Ostrov, & Crick, 2007; participants ranged from two to four. No-
Tremblay et al., 2005), while other studies tably, no evidence was found for late-onset
examine the trajectories of delinquent or an- physical aggression for boys or girls.
tisocial behaviors (Connell & Frye, 2006; A longitudinal study conducted by Nagin
Hoeve et al., 2008; Landsheer & van Dij- and Tremblay (1999) followed boys from 6
kum, 2005). Also, the number of external- to 17 years of age and identified four distinct
izing behavior trajectories that are identified developmental trajectories for both aggres-
often depends on the specific sample ana- sive behaviors and oppositional behaviors:
lyzed (Broidy et al., 2003). a chronic-problem trajectory, a high-level
Moffitt (1993a) proposes a dual- near-desister trajectory, a moderate-lev-
taxonomy model of antisocial behaviors in el desister trajectory, and a no-problem
which most delinquent individuals follow trajectory. Two subtypes of the chronic-
an adolescence-limited course, while a small problem trajectory were found. A chronic-
group of delinquent individuals follow a life- oppositional-behavior trajectory was associ-
course-persistent course of antisocial behav- ated with future covert delinquency, whereas
ior. Individuals in the adolescence-limited a chronic-physical-aggression trajectory was
group are hypothesized to display transient associated with future overt delinquency
antisocial behaviors due to a biological and and more serious delinquent acts. No evi-
social maturity gap that leads to the mimick- dence emerged for a subgroup displaying a
ing of temporarily desirable behaviors of an- late-onset or adolescent-onset trajectory of
tisocial models. According to this theory, in- either category of externalizing behavior. A
similar four-trajectory model was found for gregation studies have also endeavored to
conduct problems among 2- to 8-year-old measure the overall genetic contribution to
boys from low-income families. Shaw, Gil- the development of aggressive and opposi-
liom, Ingoldsby, and Nagin (2003) identified tional behaviors (Rhee & Waldman, 2002).
a persistent-problem trajectory, a high-level
desister trajectory, a moderate-level desister
Twin and Adoption Studies
trajectory, and a consistent low-level trajec-
tory. Twin and adoption studies have provided the
Although trajectory studies differ with preponderance of information to date about
regard to the specific behaviors of interest, genetic influences on aggressive and opposi-
the literature has consistently supported the tional behaviors. Eley and colleagues (2003)
notion that a particular group of children found strong genetic effects on childhood ag-
and adolescents demonstrates a chronic or gressive antisocial behavior. In adolescence,
life-course-persistent trajectory; that is, they however, the strength of genetic influences
display elevated levels of these problematic has been observed to be commensurate with
behaviors throughout their lives. The indi- that of environmental influences.
viduals who follow these chronic trajecto- Twin studies have indicated that the
ries are typically at very high risk for poor high comorbidity among ODD, CD, and
developmental outcomes (e.g., continued use attention-deficit/hyperactivity disorder
of physical violence, adolescent offending, (ADHD) can be largely explained by shared
health problems) (Bongers, Koot, van der genetic influences, although the presence of
Ende, & Verhulst, 2007; Broidy et al., 2003; each individual disorder is also attributed
Odgers et al., 2007). in part to unique genetic influences (Dick et
al., 2005). In a study (Burt et al., 2001) of
11-year-old twins (n = 1,506), CD was pri-
Genetics and Family Patterns marily influenced by genetic factors, while
ODD was strongly influenced by both ge-
The current paradigm for understanding netic and environmental factors. In a related
genetic contributions to aggressive and op- study of 584 adolescents from 293 same-sex
positional behaviors is based on the theory twin pairs, Young and colleagues (2009)
of polygenetic inheritance. It is now widely found that conduct problems in childhood
accepted that the development of these be- were more heritable than those presenting
haviors, and therefore the development of during late adolescence. The authors suggest
ODD and CD, does not result from one that in late adolescence, shared environmen-
specific problematic gene (Burt & Mikola- tal influences may make a larger contribu-
jewski, 2008; Caspi, McClay, Moffitt, Mill, tion to the emergence of conduct problems
& Martin, 2002; Haberstick, Smolen, & than they do during childhood.
Hewitt, 2006; Pérusse & Gendreau, 2005; A meta-analysis (Rhee &Waldman, 2002)
Plomin, Nitz, & Rowe, 1990; Schmidt, Fox, of 51 twin and adoption studies operation-
& Hamer, 2007; Schmidt, Fox, Rubin, Hu, alized aggressive and oppositional behav-
& Hamer, 2002). Initial studies of the genet- iors in four different ways: DSM diagnosis
ic contributions to externalizing disorders of antisocial personality disorder (APD) or
used antiquated methodologies like chromo- CD; delinquency and criminality; aggres-
somal analyses and single-gene approaches sive behavior; and antisocial behavior. The
to examine the co-occurrence of a particu- combined additive and nonadditive genetic
lar gene whose location was hypothesized effects on these operationalizations of ag-
to be correlated with a specific behavior or gressive behavior had a heritability rate of
disorder (Plomin et al., 1990). In more re- 41%. Heritability rates were also found to
cent years, molecular genetic studies use a differ significantly, depending on whether
candidate-gene approach, which attempts to aggressiveness was assessed through self-
identify and locate multiple genes that may reports or through reports by others, with
influence the physiological systems believed heritability rates being significantly lower
to be involved in aggressive and oppositional when self-reports were used. This finding
behavior (Pérusse & Gendreau, 2005). Twin suggests that heritability rates differ accord-
studies, adoption studies, and familial aging to measurement method.
Further evidence supporting the hypoth- ters, mothers, uncles, aunts, and grandpar-
esis that heritability rates of aggression vary ents all predicted boys’ delinquency, having
as a function of assessment method comes an arrested father was the strongest of these
from studies of genetic influences on ag- predictors. In a related study, Jafee, Moffitt,
gressive behaviors that have used laboratory Caspi, and Taylor (2003) found that fathers’
observational methods of measuring such antisocial behavior was a significant predic-
behaviors. In one of the very few studies tor of children’s antisocial behavior. Fur-
(Plomin, Foch, & Rowe, 1981) using an ob- thermore, living with fathers who frequently
servational measure of physical aggression, demonstrated antisocial behavior explained
no hereditary influences on observed aggres- a significant amount of additional variance
sive behaviors were found. In a study analyz- in children’s antisocial behavior. These re-
ing the genetic and environmental influences sults indicate that children whose fathers en-
on child conduct problems and parenting gage in high levels of antisocial behavior are
behaviors, Deater-Deckard (2000) found at an increased risk of engaging in their own
significant genetic influences when par- antisocial behaviors if their fathers live in
ent reports of child conduct problems were the home. Collectively, these studies provide
used, but no significant genetic influence further evidence for both genetic and envi-
when observational measures were used. ronmental influences on the development of
Although more studies using observational childhood antisocial behaviors.
measures are desperately needed, the range
of genetic influence in research to date var-
ies from 0% when behavioral measures are Biological and
used to at least 41% when self-reports and Neuropsychological Markers
reports by others are used (Deater-Deckard,
2000; Rhee & Waldman, 2002). The body of research concerning biological
and neuropsychological markers for ODD
and CD has contributed few definitive an-
Familial Aggregation
swers to date, but a significant number of
and Transmission
potentially informative hypotheses have
A substantial amount of research suggests emerged, many of which are likely to be
that delinquent behavior (Farrington, Jo- clarified in future studies. Many researchers
liffe, Loeber, Stouthamer-Loeber, & Kalb, in this field have suggested that biological
2001); APD and CD (Lahey et al., 1988); deficits in certain individuals may predis-
and childhood-persistent aggression and pose them to engage in aggressive or antiso-
childhood-persistent antisocial behavior all cial behaviors.
tend to aggregate in families (Zoccolillo et Various specific biological markers for
al., 2005). Specifically, Lahey and colleagues conduct problems have been presented in the
(1988) showed that youth with childhood- literature (Anastassiou-Hadjicharlambous
onset CD were more likely to have a fam- & Warden, 2008; Kruesi et al., 1992; Raine,
ily history of antisocial behavior than youth 2002; Steiner & Dunne, 1997). These in-
with adolescent-onset CD. clude responses to medication and irregu-
Loeber and Dishion (1983) found that pa- lar neurotransmitter functions, such as ob-
rental criminality was one of four primary served suppressed levels of central serotonin
predictors of young male delinquency. In a in aggressive children. Prenatal maternal be-
study of 1,517 European American and Af- haviors have also been identified as potential
rican American boys using parental reports contributors to an individual’s development
of family delinquency and criminality, 8% of of CD through influencing the noradrener-
the families in the study accounted for 43% gic functioning and cholinergic receptors of
of the total reported arrests (Farrington et the child (Raine, 2002). Depressed cortisol
al., 2001). Similarly, having one relative who levels have been presented as another pos-
was arrested increased the probability that sible biological marker for traits of CD in
another family member would be arrest- both males (Loney, Butler, Lima, Counts,
ed. Also, male relatives who were arrested & Eckel, 2006; McBurnett et al., 1991) and
tended to be married to females who were females (Pajer, Gardner, Rubin, Perel, &
arrested. Although arrests of brothers, sis- Neal, 2001). Yet another possible marker of
aggressive disorders in children may be lev- fined (Frick & Morris, 2004), linked with
els of the thyroid hormones triiodothyronine low fear response and heightened reactivity
(T3) and free thyroxine (FT4) (Ramklint, (Nigg, 2006).
Stalenheim, von Knorring, & von Knorring, Though a dearth of research on the topic
2000). Adults with a history of CD exhib- makes findings difficult to generalize, it has
ited elevated levels of both T3 and FT4. also been suggested that gender differences
One frequently presented biological cor- exist in various autonomic correlates with
relate of conduct disorders in children is a aggression. Reduced autonomic function-
depressed autonomic nervous system, with ing has been observed in aggressive boys
resulting insufficient physiological arous- with conduct problems, but not necessarily
al. For example, work by Anastassiou- in girls with conduct problems (Beauchaine
Hadjicharlambous and Warden (2008) et al., 2008). Striatal hyperdopaminergic
found that children with a CD diagnosis who functioning has also been associated with
scored highly on measures of callousness and externalizing behavior disorders in boys,
lack of emotionality were observed to display with research indicating that externalizing
a smaller change in physiological arousal (as pathologies such as ADHD and CD are
measured by heart rate) than peers. Ortiz and characterized by deficits in predicted reward
Raine (2004) conducted a meta-analysis of 40 processing (Beauchaine et al., 2008). These
studies (with an overall sample of 5,868 chil- findings are noteworthy, as they suggest
dren) and found that antisocial children had that associated antisocial behaviors may be
significantly lower resting heart rates than extremely difficult to change in young men
either psychiatric or normal controls. Raine once they have been acquired.
(2002) likewise identified low physiological More recently, researchers have begun to
arousal (as demonstrated by low resting heart focus on neuroimaging studies and anatomi-
rate) as a biological marker for children and cal correlates of conduct problems. Specifi-
adolescents exhibiting antisocial and aggres- cally, several studies have implicated abnor-
sive behavior, linking the sluggish autonomic malities in the prefrontal cortex as biological
response to reduced noradrenergic function- correlates of such problems. Berman and
ing. A related biological marker of aggres- Siegal (1976) were among the first to suggest
sive disorders related to temperament is low impaired frontal lobe functioning as a cor-
withdrawal response, often typified by low relate of aggressive and antisocial behaviors.
levels of fear response (Fowles, 1980, 2000; Both prefrontal structural and functional
Fung et al., 2005). Low physiological arousal deficits have since been correlated with anti-
puts individuals at risk for CD (McBurnett, social and aggressive behavior in both youth
Harris, Swanson, & Pfiffner, 1993), via a and adults. Baving, Laucht, and Schmidt
hypothetical pathway characterized by low (2000), for example, observed atypical pat-
arousal both at baseline and in the presence terns of frontal brain activity in school-age
of stimuli (Raine, 2002). boys and girls with ODD. It has also been
The hypothesized lack of fear response suggested that such brain differences may
in individuals with CD has been assessed in vary on the basis of gender. Nevertheless, an
several ways, with perhaps the most well- atypical activation pattern of cognitive activ-
received research demonstrating reduced ity has been observed in both boys and girls
electrodermal responses to possible pun- with ODD. Raine (2002) posits that the pre-
ishment (Fowles, 2000; Fung et al., 2005) frontal cortices of youth with conduct disor-
among aggressive individuals. This biologi- ders may develop more slowly than those of
cal deficit may have long-reaching implica- peers, resulting in the lack of inhibitory con-
tions, as children with abnormally low levels trol over maladaptive behaviors commonly
of fear may never form appropriate guilt re- associated with the diagnosis of CD. Func-
sponses to inappropriate behavior, may never tional abnormalities linked specifically to in-
develop a social conscience, and may not ex- hibition have been identified processes in the
perience appropriate concern about possible brains of boys with CD (Rubia et al., 2008).
punishment resulting from maladaptive be- Among adolescent boys diagnosed with CD,
haviors (Kochanska, Murray, & Coy, 1997). a pattern of brain atypicality has been ob-
Indeed, distinct temperamental pathways to served in the bilateral temporoparietal re-
conduct problems have therefore been de- gion, commonly thought to be associated
with self-monitoring of task performance al., 2008), other data suggest that few if any
(Rubia et al., 2008). A comparison group of significant gender differences exist (Herba,
boys with ADHD demonstrated a deficit in Tranah, Rubia, & Yule, 2006). It is impera-
activation of the left prefrontal cortex, com- tive to note, however, that executive func-
monly associated with inhibitory control. tioning deficits are not unique to CD; they
These findings support the possibility that have been found in children and adults with
although individuals with ADHD and CD a variety of disorders, such as hydrocepha-
may present with a similar behavioral phe- lus, meningitis, phenylketonuria, traumatic
notype, unique cognitive abnormalities are brain injury, autism, obsessive–compulsive
contributing to the behaviors in each group disorder, Gilles de la Tourette syndrome,
of individuals. It is important to note once and ADHD (Weyandt, 2005).
again that these neuroanatomical studies are Furthermore, evidence for executive dys-
correlational in nature, and do not reveal the function varies widely across studies. Chil-
underlying causes of the differences found. dren with comorbid attention and opposi-
Furthermore, results across studies are high- tional disorders have been observed to score
ly conflicting; some studies report anatomi- significantly lower on measures of executive
cal or functional differences between chil- functioning, language comprehension, and
dren with and without antisocial behaviors, short-term memory than their nondisordered
while others do not (Weyandt, 2005). peers (Youngwirth, Harvey, Gates, Hashim,
A number of researchers (Seguin, Nagin, & Friedman-Weieneth, 2007). In numerous
Assaad, & Tremblay, 2004; Teichner & studies, however, after ADHD is controlled
Golden, 2000) have also hypothesized that for, executive function deficits in youth with
individuals with CD and other aggressive conduct problems are dramatically reduced
disorders exhibit deficits in neuropsychologi- (Olvera et al., 2005; van Goozen et al., 2004;
cal executive functions. In both genders, CD Youngwirth et al., 2007). Other research has
has been linked to significant impairment suggested the possibility that children with
in cognitive ability, inhibition/set shifting, ODD do not experience impaired executive
planning ability, verbal memory, and visual– functioning in terms of controlling inhibi-
spatial tasks (Olvera, Semrud-Clikeman, tions, but rather in relation to self-regulating
Pliszka, & O’Donnell, 2005). Verbal skill their behavior under conditions of motiva-
deficits have been repeatedly observed in in- tional inhibition (van Goozen et al., 2004).
dividuals with CD (Olvera et al., 2005; Mof- Recently, Weyandt (2009) has emphasized
fitt, 1993b). Indeed, some have hypothesized that executive function deficits are not
that deficits in verbal/language ability may unique to particular disorders (such as CD/
contribute to many of the maladaptive be- ODD); nor are they necessary or sufficient
haviors manifested by youth with aggressive for diagnosis. Findings are mixed in terms
disorders; their noncompliance may in part of what comorbid disorders are related to
be attributable to poor comprehension and impaired executive functioning in children
undeveloped problem-solving skills. Other with externalizing disorders, and future re-
executive functioning deficits observed search should attempt to clarify the relation-
among individuals with CD have included ship among executive function deficits, ex-
problems with abstract reasoning and con- ternalizing behavior type, gender, age, and
cept formation, sustaining attention and severity of behavior disturbance. Additional
concentration, planning abilities, formulat- studies suggest that adolescents with aggres-
ing goals, initiating purposive sequences of sion and conduct issues experience impaired
behavior, inhibiting impulsive behaviors, functioning of motor inhibition (Herba et al.,
and self-monitoring (Moffitt, 1993b). Gaps 2006). Although many studies have found
exist in the research, however. For example, evidence of neuropsychological impairment
much remains to be explored regarding pos- in youth with CD, it is important to note
sible gender differences in the manifesta- that many such youth have quite normal
tion of aggressive disorders. Whereas some neuropsychological functioning (Teichner &
of the literature suggests that girls with CD Golden, 2000). Future research should strive
may exhibit specific deficits in neuropsycho- to discern whether specific executive func-
logical functioning (e.g., in overall cognitive tion deficits are characteristic of and unique
ability and visual–spatial abilities) (Pajer et to aggressive disorders.
Although the specific biological factors as research indicates that the offspring of
that contribute to CD and other forms of parents with substance use disorders were at
aggressive behavior remain under investiga- greater risk for a diagnosis of CD (Johnson,
tion, it appears highly likely that conduct Cohen, Kasen, & Brook, 2008). Further-
problems have a genetically heritable com- more, research has found that a child who
ponent, as noted earlier. For example, twin is exposed to or victimized by violence is
studies have found higher concordance rates likelier to become oppositional, as is a child
of elevated levels of aggressive disorders and whose family is unstable (in terms of geog-
antisocial behaviors in monozygotic twins raphy, financial well-being, or relationships);
than in dizygotic twins (Reid, Dorr, Walker, who is frequently unsupervised; who experi-
& Bonner, 1986; Scourfield, Van den Bree, ences precocious exposure to substance use;
Martin, & McGuffin, 2005). More recently or whose parents have a history of ODD,
(Dick et al., 2004), a genome screen of indi- CD, or ADHD (Mayo Clinic, n.d.). Certain-
viduals with CD identified regions on two ly, however, it is difficult to know whether
chromosomes (19 and 2) that may influence a child with CD has inherited a biological
whether or not an individual will develop basis for the behaviors or is merely model-
CD. Although much related research must ing the aggressive and antisocial behaviors
be done in the future to clarify the findings, of one or both parents (Holmes, Slaughter,
the results of the genome screen indicate a & Kashani, 2004).
probable genetic etiology for CD. Both dispositional and contextual risk fac-
tors for developing CD have likewise been
identified. In addition to the biological fac-
Risk Factors tors discussed previously, dispositional risk
for Phenotypic Expression factors include a preference for dangerous
activities, high level of impulsivity, academic
Although a genetic and biological predispo- underachievement, and deficits in processing
sition to conduct problems is well illustrated social information (Frick, 2004). Contex-
by the literature, it is also certain that exog- tual risk factors for CD include all those for
enous factors contribute to the development ODD, as well as parental psychopathology,
of maladaptive behaviors consistent with peer rejection, impoverished living condi-
ODD or CD. Several psychosocial and en- tions, and association with deviant peers.
vironmental factors are believed to increase Clearly, several categories of risk factors
individual risk for developing conduct prob- for phenotypic expression of aggressive be-
lems. For example, a child born with a bio- haviors have been identified: individual, ge-
logical predisposition to develop CD may be netic, environmental, and familial. Table 8.3
exposed prenatally to substances that add to summarizes the known risk factors for CD
his or her risk for developing this disorder, and ODD. Although a significant number
TABLE 8.3. Risk Factors for Developing CD or ODD

CD ODD
•• Impulse control dysfunction (as with ADHD) •• Having a parent with a mood or substance use
•• Difficult temperament in early childhood disorder
•• Aggression toward peers/rejection by peers •• Being abused or neglected
•• Social withdrawal/lack of social skills •• Harsh or inconsistent discipline
•• Depression/anxiety •• Lack of supervision
•• Academic underachievement •• Poor relationship with one or both parents
•• Poor parental relations: inconsistent supervision, •• Family instability (e.g., divorce, multiple moves,
harsh punishment, rejection, parental alcoholism or changing schools or child care providers
•• Large family size (4+ children) frequently)
•• Exposure to violence and neglect •• Parents with a history of ADHD, ODD, or
•• Prenatal malnutrition and exposure to toxins conduct problems
•• Financial problems in the family
•• Exposure to violence
•• Substance abuse in the child or adolescent
of risk factors exist for these disorders, an nificant negative impact on his or her social,
equally substantial number of interventions occupational, or academic functioning, the
and treatment options have been identified individual may be diagnosed with CD.
for implementation when such behaviors As also noted earlier, three subtypes of
occur. CD have been identified: childhood-onset
type, adolescent-onset type, and unspecified
onset. All of these may be described as mild,
Assessment moderate, or severe in nature (APA, 2000).
The first two subtypes differ somewhat in
Appropriate assessment of an individual terms of their manifestations in observable
who is displaying symptoms of ODD or behaviors. The childhood-onset type of CD
CD should follow a multimethod, multi- often presents in the form of physical aggres-
informant, multisetting strategy (Steiner & sion and poor peer relationships. The ado-
Dunne, 1997). Data should be obtained from lescent-onset type is characterized by fewer
both the individual and his or her parents, instances of aggressive behaviors, and poor
and from other family members as appropri- social relations typically involve interactions
ate. A thorough developmental and social with authority figures rather than peers. Re-
history of the individual must be obtained, gardless of subtype, the behavior problems
particularly in regard to relevant DSM-IV- associated with a CD diagnosis tend to pres-
TR criteria (APA, 2000). The evaluator ent across settings and to impair functioning
should investigate the presence and quality in school, home, and the community (APA,
of peer and sibling relationships, as well as 2000). In addition to the diagnostic crite-
school functioning. A multisetting approach ria already discussed, CD is often typified
is of particular importance here, as some by a lack of empathy or concern for others
individuals with ODD or CD encounter and an absence of (appropriate) emotions
problems in some settings long before oth- of guilt or remorse (APA, 2000). Individu-
ers; for instance, an individual who is mal- als with CD often exhibit precocious sexual
adaptive at home and school may be func- and substance-related behaviors and are
tional in some community settings. Other likelier than peers to engage in reckless or
types of assessment that may add important risk-taking acts. Common comorbid diagno-
information to the evaluation include a fam- ses for individuals with CD include ADHD,
ily assessment; a physical examination; and as well as learning, anxiety, mood, and
a thorough assessment of the individual’s substance-related disorders (APA, 2000).
cognitive, behavioral, and social function- According to APA (2000), an individual
ing (Hughes, Crothers, & Jimerson, 2007; who fails to meet the diagnostic criteria for
Steiner & Dunne, 1997). CD but demonstrates a similar pattern of
The essential diagnostic feature of CD, ac- maladaptive tendencies may be diagnosed
cording to DSM-IV-TR (APA, 2000) is “a with ODD. Typically, individuals with ODD
repetitive and persistent pattern of behavior do not display the same severity of behavior
in which the basic rights of others or major as those with CD; nor do their transgres-
age-appropriate societal norms or rules are sions typically include violence/aggression
violated” (p. 98). The individual being as- toward others, destruction of property, or
sessed must meet at least three of the criteria theft (APA, 2000). The essential feature of
listed in the right column of Table 8.1, which the ODD diagnosis is a pattern of “negativ-
fall into four categories of maladaptive be- istic, hostile, and defiant behavior” (APA,
haviors: aggression to people and animals 2000, p. 102) lasting 6 months or more;
(criteria 1–6 and 15 in the table), destruc- it must exist independently of a psychotic/
tion of property (criteria 7–8 in the table), mood disorder diagnosis, and must cause
deceitfulness or theft (criteria 9–11 in the significant impairment in an individual’s
table), and serious violations of rules (crite- functioning. Four of the eight criteria listed
ria 12–14 in the table). If it is determined in the right column of Table 8.2 must be
that an individual had met at least three of displayed over the course of the 6-month
these criteria in the last 12 months (and at period.
least one within the last 6 months), and that For individuals with ODD, related behav-
the behaviors in question are having a sig- iors can be manifested in a number of differ-
ent ways (APA, 2000). ODD-related behav- Treatment

iors emerge most often in the home, but can
be problematic in school or social settings as Treating children and adolescents with dis-
well. Conflicts with authority figures (such ruptive behavior disorders, as well as study-
as teachers and parents) can become coming the treatment of children with such
monplace for an individual with ODD, as disorders, is an arduous task due to the het-
can precocious substance use, mood lability, erogeneity of risk factors (Teichner & Gold-
and a low tolerance for frustration. Children en, 2000; Tremblay et al., 2005; Powell,
with ODD are likelier than their peers to be Lochman, & Boxmeyer, 2007) and develop-
codiagnosed with ADHD, learning disor- mental pathways (Broidy et al., 2003; Mof-
ders, and communication disorders (APA, fitt, 1993a; White et al., 2001) encompassed
2000). in these disorders. In addition, as children
Specific assessment tools have been iden- grow older, the number of experienced risk
tified as effective in determining whether factors inevitably increases, requiring a
or not an individual has CD or ODD. One wider range of factors that treatments need
instrument designed to assess the possible to address. Therefore, earlier interventions
presence of CD in a child or adolescent is the are preferable because they can target chil-
Antisocial Personality Disorder Question- dren’s problematic behaviors at a time when
naire (Myers, Stewart, & Brown, 1998), a they are less complex and stable (Jensen,
structured interview designed to assess both 2008). Many different treatment approach-
CD and APD. The reliability and validity es are used to treat aggression, ODD, and
of the questionnaire have been determined CD. Some treatment approaches have been
by associations with more well-established studied more extensively than others (Kaz-
assessment procedures (Brown, Gleghorn, din, 1997), and some have shown to be more
Schuckit, Myers, & Mott, 1996). Other, effective than others. Evidence supporting
more widely used comprehensive assessments some of the major treatment approaches is
of mental health have also been found to be discussed below. This discussion does not
appropriate tools for evaluating the presence provide an exhaustive explanation of all
of CD or ODD in children and adolescents. available treatments; it simply touches upon
The National Institute of Mental Health’s some of the most commonly used treatments
Diagnostic Interview Schedule for Children, for these disorders (Frick, 2001; Kazdin,
Version IV (DISC-IV), for example, has been 2007).
found to demonstrate reliability and validity
in evaluating individuals suspected of hav-
Cognitive Problem-Solving
ing CD. The DISC-IV does not solely assess
Skills Training
CD; rather, it is designed to assess a large
number of psychiatric disorders in children Among the most widely used cognitive-
and adolescents (Shaffer, Fisher, Luca, Dul- behavioral treatments for aggression, ODD,
can, & Schwab-Stone, 2000). A subcategory and CD is cognitive problem-solving skills
of questions from the assessment specifically training (CPST) or cognitive-behavioral
addresses behaviors relevant to the diag- skills training. This therapeutic approach
nostic criteria for CD. The Child Behavior attempts to train children and adolescents
Checklist (CBCL; Achenbach & Rescorla, to alter the deficient cognitive processes
2001) includes inventories to be completed that are believed to lead to their disruptive
by parents, teacher, and the individual ex- behaviors. The primary goals of CPST and
periencing disordered behavior; earlier ver- similar treatments are to help children and
sions of the CBCL have been identified as adolescents improve their inhibition of im-
reliable and valid for purposes of diagnosing pulsive and aggressive actions, recognize in-
both ODD (Abolt & Thyer, 2002) and CD dividual and social problems, consider alter-
(Lowe, 1998). As stated previously, however, native solutions to problems, and select and
it is important to note that both of these dis- pursue the most adaptive solutions (Frick,
orders are best evaluated via a multimodal 2001; Kazdin, 1997). Although there is an
approach; as such, the implications of any evidence base that supports the use of CPST
singular assessment should be interpreted (Dangel, Deschner, & Rasp, 1989; de Cas-
with caution. tro, Bosch, Veerman, & Koops, 2003; Frick,
2001; Kazdin, 1997), more research needs to however, their common side effects have led
be done to determine how CPST needs to be to an increased interest in atypical antip-
modified for different age groups and differ- sychotics (Findling, 2008). Of the atypical
ent cultures (Kazdin, 1997), as well as how antipsychotics used for aggression, ODD,
to improve generalization of newly learned and CD, risperidone has been the most ex-
behaviors (Frick, 2001). tensively studied. Risperidone was found to
be effective and well tolerated in reducing
conduct and behavioral problems in chil-
Parent Management Training
dren ages 5–12 (Aman, De Smedt, Derivan,
The most researched and most effective Lyons, & Findling, 2002). Also, Buitelaar,
treatment for ODD and CD to date is par- van der Gaag, Rutger, Cohen-Kettenis, and
ent management training (PMT; Brestan Melman (2001) found that risperidone was
& Eyberg, 1998; Taylor & Biglan, 1998). effective and well tolerated in treating ado-
PMT focuses on improving parent–child lescents with extreme aggression. Although
interactions through implementing more many possible psychopharmacological inter-
efficient and consistent disciplinary strate- ventions exist for treating symptoms of ODD
gies, changing the antecedents of behaviors and CD, these medicines must be adminis-
in order to increase the likelihood of chil- tered with caution because of the potential
dren’s prosocial behaviors, and improving side effects. It is also important to note that
parents’ abilities to monitor and supervise the U.S. Food and Drug Administration has
their children appropriately (Frick, 2001). not approved any medication specifically for
The American Psychological Association’s the treatment of CD or ODD.
Division 12 considers PMT an empirically
validated treatment for children with oppo-
Multisystemic Therapy
sitional behavior (American Psychological
Association Task Force, 1993). Costin and Because of the complexity in the risk factors,
Chambers (2007) showed that PMT was ef- causal factors, and developmental pathways
fective in treating primary-school-age chil- associated with aggression, ODD, and CD,
dren with ODD in a community-based set- it has been suggested that multiple treatment
ting, regardless of whether or not they had approaches originating from multiple theo-
another comorbid disorder. As one might retical traditions may be best for reducing the
expect, one of the key limitations of PMT symptoms of these disorders (Jensen, 2008).
is that it can often be difficult to maintain Multisystemic therapy (MST) often takes a
parental participation throughout the entire family-based approach to treatment while
course of treatment (Frick, 2001). also including PMT, CPST, and even psy-
chopharmacological strategies that may be
most appropriate for any given child or ado-
Psychopharmacological
lescent (Kazdin, 1997). In a meta-analysis
Interventions
of the effectiveness of MST for treating an-
Various types of medications have demon- tisocial behaviors in youth, Curtis, Ronan,
strated minimal to modest levels of effective- and Borduin (2004) found that youth and
ness for treating symptoms of aggression, families who received MST were offending
ODD, and CD. Connor, Barkley, and Davis less and functioning better afterward than
(2000) demonstrated that clonidine, an anti- 70% of the youth and families who received
hypertensive medication, was effective in re- alternative treatments. In a review of the
ducing ODD and CD symptoms in children literature on effective treatments for delin-
and adolescents with either ODD or CD and quent youth, Kurtz (2002) states that MST
comorbid ADHD. Studies have shown evi- significantly reduces reoffending rates, and
dence that lithium decreases aggressive be- that this success is probably due to MST’s
havior in children and adolescents with CD multimodal approach.
(Campbell et al., 1995; Malone, Delaney,
Luebbert, Cater, & Campbell, 2000). Evi- Although the approaches described above
dence also suggests that typical antipsychot- have evidence supporting their effectiveness,
ics are superior to placebos in treating chil- their effectiveness is typically limited. When
dren and adolescents with ODD and CD; selecting a treatment plan, service providers
should be sure to take a comprehensive ap- American Psychiatric Association (APA). (1980).
proach that takes into account the individu- Diagnostic and statistical manual of mental dis-
al factors that lead to each child’s disruptive orders (3rd ed.). Washington, DC: Author.
behaviors (Frick, 2001). American Psychiatric Association (APA). (1987).
Diagnostic and statistical manual of mental dis-
orders (3rd ed., rev.). Washington, DC: Author.
Conclusion Diagnostic and statistical manual of mental dis-
orders (4th ed., text rev.). Washington, DC: Au-
In summary, recent advances have been thor.
made in conceptualizing and understanding American Psychological Assocation Task Force on
factors that contribute to the development Promotion and Dissemination of Psychological
of aggressive behaviors, ODD, and CD in Procedures. (1993). Washington, DC: Author.
children and adolescents. Current research Anastassiou-Hadjicharalambous, X., & Warden, D.
supports a role for genetic, developmental, (2008). Physiologically-indexed and self-perceived
affective empathy in conduct-disordered children
physiological, and environmental factors,
high and low on callous-unemotional traits.
and these factors are believed to interact in Child Psychiatry and Human Development,
complex ways that lead to the onset of anti- 39(4), 503–517.
social behavior in children. The literature is Arnold, E., Goldston, D., Walsh, A., Reboussin,
replete with methodological problems, how- B. A., Daniel, S. S., Hickman, E., et al. (2005).
ever, including small sample sizes, comor- Severity of emotional and behavioral problems
bidity, differences in inclusion criteria, low among poor and typical readers. Journal of Ab-
statistical power, herterogeneity of partici- normal Child Psychology, 33, 205–217.
pants, and confounding variables. Further Baving, L., Laucht, M., & Schmidt, M. H. (2000).
research is needed to clarify the similarities Oppositional children differ from healthy chil-
dren in frontal brain activation. Journal of Ab-
and differences among boys and girls with
normal Child Psychology, 28(3), 267–275.
CD and ODD; the roles of genetic and famil- Beauchaine, T. P., Hong, J., & Marsh, P. (2008).
ial variables; and the contribution of neuro- Sex differences in autonomic correlates of con-
chemical and neuroanatomical factors to the duct problems and aggression. Journal of the
development of aggressive and antisocial be- American Academy of Child and Adolescent
haviors in children and adolescents. Advanc- Psychiatry, 47(7), 788–796.
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and treating these behaviors in children and ment at school entry cause conduct problems. So-
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Chapter 9
Gilles de la Tourette Syndrome
Alicia Hughes
Brian P. Daly
Ronald T. Brown
Gilles de la Tourette syndrome (Tourette Motor and vocal tics are classified as ei-
syndrome, or TS) is a genetic neuropsychi- ther simple or complex (APA, 2000). Simple
atric disorder consisting of chronic motor motor tics may include eye blinking, jerk-
and verbal tics that typically persist for at ing of the neck, shrugging of the shoulders,
least 1 year (American Psychiatric Associa- facial grimacing, and coughing. Typical
tion [APA], 2000). The disorder frequently complex motor tics consist of grooming be-
has its origins during middle childhood, haviors, facial gestures, touching, jumping,
with a mean age of 7 years. Typically, motor stomping feet, and smelling objects. Motor
tics precede the onset of vocal tics (Brown et tics frequently involve the head and other
al., 2008). A tic is a recurring, stereotypical, parts of the body, including the torso and
nonrhythmic vocalization or motor move- the upper and lower limbs. Simple vocal tics
ment that may occur suddenly and with- often include clearing of the throat, clicking,
out warning; it is always of short duration sniffing, grunting, snorting, and barking
(APA, 2000). Individuals frequently describe (e.g., yelps). Finally, complex vocal tics may
their tics as irresistible, although tics can be involve the repetition of words or phrases
suppressed for varying periods of time. Fre- out of context, coprolalia (use of obsceni-
quently tics are exacerbated by stress: Nu- ties or curse words), palilalia (repetition of
merous environmental factors have been one’s own sounds or words), and echolalia
associated with fluctuation of symptoms (repetition of recently heard sounds, words,
in children and adolescents with TS (Silva, or phrases) (APA, 2000). The prevalence of
Munoz, Barickman, & Friedhoff, 1995). coprolalia is actually quite low, although it
Such environmental stressors for children is frequently mentioned in connection with
and adolescents frequently include emotion- TS in the mass media.
al trauma and events causing anxiety (e.g., Core features of TS include multiple motor
social gatherings). The frequency of tics has tics and one or more vocal tics. Motor and
been observed to decrease during activities vocal tics may appear either simultaneously
that require sustained attention and concen- or separately during different periods of time
tration, as well as during sleep. Finally, the (APA, 2000). To meet diagnostic criteria for
number, frequency, severity, and type of tics TS, tics must occur many times throughout
may change over the course of time. the course of the day for a period of more
171
than 1 year. In addition, the tic symptoms severity at puberty. In fact, prevalence esti-
must be present and not absent for a period mates of TS in adolescents ages 16–17 years
of at least 3 consecutive months. Finally, the are quite similar to adult prevalence esti-
presence of the disorder must result in sig- mates (Apter et al., 1993), suggesting a rapid
nificant impairment in occupational, social, decrease in symptoms at adolescence.
or emotional functioning.
TS is conceptualized as a clinical spectrum
disorder that includes a range of functional History
impairments. Kurlan (1994) has observed
that the mildest form of TS includes largely Jean-Marc Itard recorded the first known
asymptomatic features in which only brain report of TS in the early 19th century (Hyde
morphology is affected, whereas children & Weinberger, 1995). Itard provided a case
who suffer from moderate TS evidence aca- history of a French noblewoman who dis-
demic and behavioral problems and may even played motor tics at the age of 7 years, and
require special education services at school. who subsequently developed involuntary vo-
In the most severe form of the disorder, chil- calizations consisting of screams and strange
dren with TS may require pharmacotherapy cries. Later in her life, the woman developed
so that they can function in society. coprolalia and was forced to live in seclu-
The prevalence of TS is estimated to be sion until her death. Nearly 50 years later,
between 1 and 8 cases per 1,000 males and under the supervision of the well-known
between 0.1 and 4 cases per 1,000 females neurologist Jean Martin Charcot, Gilles de
(Peterson, Pine, Cohen, & Brook, 2001). la Tourette presented a series of case stud-
Clearly, the syndrome is more prevalent in ies that detailed the history and symptoms
males than among females, with estimates of several individual patients with the same
ranging from 2:1 to 10:1 in favor of males. syndrome; the syndrome was subsequently
Variability in prevalence data has been at- named for Tourette. Early descriptions pro-
tributed to sample populations (i.e., clinic vided by Charcot included information re-
vs. community samples), the sensitivity and garding the waxing and waning of multiple
specificity of the various diagnostic instru- motor and vocal tics, the early age of onset,
ments employed, and the age distribution and the importance of genetic influences on
of the population that is sampled (Peterson the disorder (Keen-Kim & Freimer, 2006).
et al., 2001). Those epidemiological studies TS is a syndrome that has been fre-
that have employed a direct examination of quently misunderstood and underdiagnosed
individuals in outpatient clinics have yield- (Sprague & Newell, 1986). In the early
ed the highest prevalence estimates of TS, 1940s, during the psychoanalytic movement
while surveys of community populations in Europe and North America, several case
have yielded the lowest prevalence estimates. studies were offered that were interpreted
Because traditional structured diagnostic to support a psychodynamic interpretation
interviews are not sufficiently sensitive to of the tics (e.g., Mahler & Rangell, 1943).
discriminate the presence of mild tics from TS was considered a psychiatric disorder
overt TS, it is important to note that clinic- at that time, due to the patients’ ability to
based studies arte likely to overestimate the voluntarily suppress the behaviors associ-
prevalence of TS. Thus structured diagnostic ated with the syndrome and the tendency of
interviews are apt to yield a preponderance tics to be exacerbated during periods of high
of false positives, whereas community-based stress. Although the psychiatric interpreta-
investigations employing surveys for the tion of the symptoms associated with TS has
identification of TS tend to underestimate been discounted over the past several years,
the prevalence of TS due to the underreport- the relationship of tic symptoms to impor-
ing of symptoms (Peterson et al., 2001). It is tant events in individuals’ lives generally
also noteworthy that epidemiological studies suggests that these factors can influence the
of pediatric populations yield higher preva- course of TS to some extent. Nonetheless,
lence estimates than do studies that include the etiology of tic disorders is unclear: Most
their adolescent or adult counterparts. The tics are believed to have an organic etiology,
higher prevalence of TS in pediatric popula- while some are believed to be exacerbated by
tions has been attributed to a decrease in tic psychogenic factors (Mansdorf, 1995). Over
Gilles de la Tourette Syndrome 173
the past three decades, compelling evidence 10–12 years of age, prior to decreasing or
has been mounted to support an organic eti- entering full remission in most individuals
ology of TS. Advances in the study of the by early adulthood (Pappert, Goetz, Louis,
human genome, coupled with significant Blasucci, & Leurgans, 2003). The onset
developments in the neurosciences and spe- of tics is gradual, with motor tics typically
cifically in neuroimaging, have resulted in preceding vocal tics, and simple tics preced-
the reclassification of TS as a neurological ing more complex tics (Leckman & Cohen,
movement disorder (Peterson et al., 2001). 1999). For example, at about ages 6–7 years,
In support of this notion, several biologi- initial symptoms of TS include eye blinking
cal markers have been linked with TS. For and facial or head and neck tics. Following
example, the neurotransmitter dopamine these simple motor tics are the development
has been demonstrated either to precipitate of vocal tics and a rostral–caudal progres-
or to exacerbate symptoms of TS (Peterson sion of more complex multiple motor tics
et al., 2001), although the exact nature of (Brown et al., 2008).
dopamine’s effects is still being debated (see Clinically, children typically experience a
later text). Furthermore, several provocative waxing–waning course in which periods of
hypotheses have been posited suggesting sig- tic intensity are interspersed with periods of
nificant abnormal brain morphology among relative symptom stability. Risk factors as-
individuals with TS, particularly within the sociated with the exacerbation of tics dur-
basal ganglia and limbic system. These bur- ing childhood include periods of excitement,
geoning developments in the neurosciences anxiety, stress, and fatigue. In contrast, as
have resulted in valuable treatment pathways noted previously, tics decrease substantially
for pharmacological interventions. during sleep. In its most severe form, TS may
involve coprolalia; again, however, this is
relatively rare and occurs in fewer than 10%
Developmental Course of individuals diagnosed with TS.
Comorbid psychiatric conditions are
Although previous thinking suggested a common in children diagnosed with TS,
variable and unpredictable developmental particularly attention-deficit/hyperactiv-
course of symptoms associated with TS, re- ity disorder (ADHD), obsessive–compulsive
cent longitudinal studies have provided com- disorder (OCD), anxiety, depression, and
pelling evidence to indicate that TS actually learning disabilities (Freeman et al., 2000).
follows a rather common developmental Whereas comorbid attention difficulties typ-
course. Specifically, in the majority of cases, ically emerge slightly before or around the
tics associated with TS first appear in child- same time as the tics, obsessive–compulsive
hood, generally decrease in late adolescence symptoms typically emerge 3–6 years after
and young adulthood, and remain at a very the onset of tics (Bruun & Budman, 1997).
mild threshold or even in remission during Psychosocial and learning challenges also
adulthood. However, tics are described as occur in childhood, with results from a lon-
continuing from late adolescence well into gitudinal study indicating that over one-half
adulthood in a minority of cases. Although of children with TS demonstrate significant
the developmental course has some predict- social or academic problems (Pappert et al.,
ability, the clinical course of TS can be fluc- 2003).
tuating and variable. General trends in the
developmental and clinical course of TS are
Adolescence
described below.
Although tics may be particularly severe
during early adolescence, findings from lon-
Childhood
gitudinal studies indicate that approximate-
Data on the prevalence rate of TS indicate ly one-half to two-thirds of adolescents will
a 10-fold higher rate among children than experience a significant reduction, or com-
among adults (Burd, Kerbeshian, Wiken- plete remission, in tic expression by late ado-
heiser, & Fisher, 1986a, 1986b). Typically, lescence or early adulthood (Pappert et al.,
tics first appear between the ages of 5 and 2003; Peterson et al., 2001). Nonetheless,
6 years, with tic severity peaking at about adolescents with TS often experience vari-
able and unpredictable symptoms; the fluc- ter, we review the literature pertaining to the
tuations may be due to changes in hormone genetics of TS, focusing specifically on fam-
levels or noncompliance with medication. For ily genetic and twin studies.
adolescents who continue to present with se-
vere tic symptoms through late adolescence,
Family Genetic Studies
the prognosis is relatively poor (Leckman et
al., 1997). That is, late adolescents with a Family genetic studies have provided signifi-
mild presentation of symptoms will typically cant insight into the understanding of TS,
persist in having a mild presentation during with findings generally indicating that the
adulthood; those still experiencing severe disorder clearly aggregates in families and
symptoms during the late adolescence are that the majority of cases are inherited. The
likely to continue having more frequent and prevalence of TS among first-degree relatives
severe tics throughout their lives. is approximately 10–15%, while the rate of
With regard to comorbidity patterns, one other tics is about 15–20% (Hebebrand et
investigation provided data to indicate that al., 1997; Walkup et al., 1996). These rates
over 65% of late adolescents reported that are significantly higher than the rates of TS
learning difficulties and behavioral problems and tics in control participants with no fam-
(e.g., ADHD and OCD) resulted in as much ily history of the disorder. Bilineal transmis-
daily functional impairment as, or more sion occurs in up to one-quarter of families
than, the tics themselves (Erenberg, Cruse, affected by TS (Hanna, Janjua, Contant,
& Rothner, 1987). Like adolescents with & Jankovic, 1999), meaning that some in-
other chronic illnesses, adolescents with TS dividuals inherit the genetic susceptibility
may experience psychosocial challenges that from both parents. For example, McMahon,
include depression, low self-esteem, and so- Carter, Fredine, and Pauls (2003) found that
cial isolation. These adolescents may be the children with two parents affected by TS
targets of ridicule and aggression from peers; and/or OCD were three times more likely to
several studies have demonstrated that tic se- develop tics than children with only one af-
verity is inversely associated with social ac- fected parent. In a similar familial investiga-
ceptance (Boudjouk, Woods, Miltenberger, tion, 43% of young children who had a par-
& Long, 2000). ent or sibling with TS developed tic disorder
(Carter, Pauls, Leckman, & Cohen, 1994).
The results of segregation analyses of TS
Genetics and Family Patterns family data have revealed considerable vari-
ability, leaving the mode of inheritance for
Although the precise etiology of TS is un- TS uncertain and still controversial among
known, the strongest biological evidence to investigators. Early studies initially con-
date indicates a complex interaction of mul- cluded that TS results from the inheritance
tiple factors: genetics, prenatal and perinatal of a single, dominant autosomal gene with
factors, and the effects of some infections. incomplete penetrance and variable expres-
Family and twin studies support a strong ge- sion (Cohen & Leckman, 1994; Eapen,
netic component. For example, family mem- Pauls, & Robertson, 1993). However, more
bers of individuals with TS are at increased recent studies have yielded findings inter-
risk for having a tic disorder or OCD (Pauls preted to suggest a more complex multifac-
& Leckman, 1986). It is noteworthy that the torial/polygenic model with intermediate
majority of individuals who are genetically penetrance (Cavallini, Pasquale, Bellodi,
predisposed to TS experience few and very & Smeraldi, 1999; Seuchter et al., 2000;
mild symptoms, and thus rarely present to Walkup et al., 1996), or a mixed model of
health care providers for the management of genetic–environmental causes (Keen-Kim &
their symptoms. However, individuals may Freimer, 2006).
also demonstrate tics in a milder form, such According to the autosomal dominant
as transient tic disorder or chronic tic dis- model, TS is a disorder of incomplete pene-
order. Furthermore, a small percentage of trance because not all individuals who inher-
individuals with this genetic vulnerability it the genetic vulnerability will manifest the
present with the full phenotypic expression symptoms. In addition, among those family
of the syndrome. In this section of the chap- members who do show symptoms, there is
variability in symptom expression; that is, with likely involvement of the basal ganglia
different manifestations occur in various and associated cortical circuits such as the
family members. For example, family mem- corticostriatal–thalamocortical pathways
bers with the same pattern of genetic inheri- (Hoekstra, Anderson, et al., 2004; Phelps,
tance may present with differing levels or 2008; Singer & Minzer, 2003). Early re-
types of symptoms: Some may be diagnosed search findings suggested that, on average,
with chronic tic disorder, while other fam- individuals with TS have reduced volume
ily members are diagnosed with OCD (Pauls and abnormal lateralization of their basal
et al., 1990). This suggests that the expres- ganglia (Peterson, 1995). Evidence for the
sion of the gene may result in TS, a milder involvement of the basal ganglia in other
tic disorder, or even obsessive–compulsive movement disorders (e.g., Huntington disor-
symptoms with no tics at all (van de Weter- der) is well established, thereby lending sup-
ing & Heutink, 1993). Data from family port to the role of the basal ganglia in other
studies also reveal a sex-specific penetrance, movement disorders, including TS (Abbruzz-
accounting for the higher prevalence of TS ese & Berardelli, 2003). Finally, evaluation
among males; as noted earlier, estimated of the phenomenology and natural history
male-to-female ratios range between 2:1 and of tic disorders also suggests involvement of
10:1 (Marcus & Kurlan, 2001). the corticostriatal–thalamocortical circuits
(Mink, 2001).
Peterson and colleagues (2003) employed
Twin Studies
volumetric magnetic resonance imaging
Twin studies also provide strong support for (MRI) in children and adults with TS. Re-
a genetic component in the etiology of TS sults revealed significant reductions in the
(Pauls & Leckman, 1988). Studies reveal a caudate nucleus, which represents one part
concordance rate of about 60% for TS in of the basal ganglia. In a similar MRI study
monozygotic twins, while only 10% of fra- of individuals with TS, Singer (2000) report-
ternal twins demonstrate concordance for TS ed abnormalities in the caudate or lenticular
(Pauls & Leckman, 1986; van de Wetering & nuclei. Findings from a prospective study of
Heutink, 1993). For chronic motor tics, mo- children diagnosed with TS revealed signifi-
nozygotic twins demonstrate approximately cant inverse correlations between the volume
77% concordance, whereas dizygotic twins of the caudate nucleus and severity of tics in
demonstrate only 23% concordance (Price, early adulthood (Bloch, Leckman, Zhu, &
Kidd, Cohen, Pauls, & Leckman, 1985). Peterson, 2005). Specifically, the smaller the
Although researchers have examined sev- caudate nucleus in childhood, the more acute
eral candidate genes in an attempt to isolate the tics were during adulthood. Interesting-
a TS gene, results have proven inconclusive ly, there was no association with tic severity
or negative (Leckman, 2002; Rosa, Jank- at the time of the MRI scan. Findings were
ovic, & Ashizawa, 2003). Nevertheless, interpreted to support abnormalities of the
initial findings from genetic linkage stud- caudate nucleus and striatal–cortical circuits
ies suggest that several chromosome regions in individuals with TS (Bloch et al., 2005).
may contain susceptibility loci for TS (for a In their review of the literature, Hoekstra,
review, see Pauls, 2003). Anderson, and colleagues (2004) report
consistent findings between MRI studies
and positron emission tomography [PET],
Biological and single-photon emission computed tomogra-
Neuropsychological Markers phy [SPECT], and functional MRI [fMRI]
studies, thereby definitively documenting in-
Neurobiology
volvement of the basal ganglia in TS.
At the present time, the pathogenesis of tic It has been suggested that dopamine re-
disorders at a molecular and cellular level ceptor abnormalities are involved in TS.
is unknown (Hoekstra, Anderson, et al., This contention is primarily derived from
2004). In addition, the precise neurobio- the therapeutic response to neuroleptics
logical abnormality of TS remains incon- among individuals with TS. Specifically, the
clusive (Singer & Minzer, 2003); however, neuroleptic haloperidol, a dopamine recep-
TS is considered a neurobehavioral disorder, tor antagonist, has demonstrated success in
the management of TS through reduction striatal structures (for a review, see Osmon
of tics. Indeed, pharmacological agents that & Smerz, 2005).
block dopamine receptors are considered For those individuals with TS who suf-
the most effective tic-suppressing medica- fer from compromised neuropsychological
tions (Bruggerman et al., 2001). However, functioning, findings in the literature are
findings from studies of dopamine recep- generally consistent in implicating deficits in
tors are equivocal. For example, Heinz and visual processing and psychomotor difficul-
colleagues (1998) reported a correlation be- ties (Osmon & Smerz, 2005). Specifically,
tween dopamine receptor binding and tic se- the most common deficits appear to be in
verity, whereas findings from another inves- visual processing, including difficulties with
tigation demonstrated no difference between visual–motor and visual–spatial integra-
individuals with TS and those receiving pla- tion. It is noteworthy, however, that most
cebo controls (Wong et al., 1997). Another individuals with TS do not demonstrate any
research team employed SPECT to evaluate difficulty with visual processing abilities
dopamine receptor capacity in five monozy- (Schultz et al., 1998). Deficits in psychomo-
gotic twin pairs with TS. Findings revealed tor abilities frequently include impairments
greater dopamine receptor capacity in the in fine motor skills (Como, 2001) and speedy
caudate nucleus for the more severely affect- execution of movement (Georgiu, Bradshaw,
ed cotwin in each pair (Wolf et al., 1996). Phillips, Bradshaw, & Chiu, 1995).
In contrast, D2 and D3 dopamine receptor Attention and executive function problems
availability has remained unaltered in PET also occur among some individuals with TS.
(Turjanski et al., 1994) and SPECT (George In a study of evoked potential response, Jo-
et al., 1994) studies. Taken together, these hannes and colleagues (1997) demonstrated
findings suggest the lack of a unified dop- that individuals with TS struggled on more
aminergic hypothesis in TS (Hoekstra, An- complex attention tasks. Nonetheless, cur-
derson, et al., 2004). rent research on attention problems in in-
dividuals with TS suggests that these dif-
ficulties are associated with comorbidity
Neuropsychological Characteristics
of specific disorders and not with TS per
Individuals with TS do not exhibit any se. Furthermore, the evidence for executive
impairment in general intellectual ability functioning deficits is equivocal. For exam-
(Como, 2001). Furthermore, neuropsycho- ple, whereas Harris and colleagues (1995)
logical function for the majority of chil- found evidence of deficits in executive func-
dren with TS has been demonstrated to be tion, another investigation that examined
within normal limits when compared to that TS in monozygotic twins found no evidence
of age-matched peers (Yeates & Bornstein, of executive dysfunction (Randolph, Hyde,
1996). However, some individuals with TS Gold, Goldberg, & Weinberger, 1993).
do exhibit impairment in neuropsychologi-
cal functioning (Bornstein, 1990). What is
less clear, however, is whether the impair- Risk Factors
ment results from pathology associated with for Phenotypic Expression
comorbidities (e.g., ADHD, OCD, learning
disabilities) or from dysfunction in the fron- Because there is a less than 100% concor-
tostriatal area of the brain that is associat- dance rate for TS and/or tics in monozygotic
ed with pure TS (Osmon & Smerz, 2005). twins, nongenetic influences such as envi-
Certainly individuals with TS demonstrate ronmental prenatal and postnatal factors
high prevalence rates of comorbid learn- must also play a role in TS. Research evi-
ing disabilities (Burd, Freeman, Klug, & dence further indicates that environmental
Kerbeshian, 2006), as well as ADHD and factors contribute to the development and
OCD (Alsobrook & Pauls, 1997; Freeman, phenotypic expression of TS (e.g., Leckman
1997). Alternatively, some evidence suggests et al., 1987; Pauls, 2003; Price et al., 1985).
that impairment may be associated with However, the role of environmental factors
neuroanatomical and neurophysiological in TS has received far less empirical atten-
abnormalities, such as pathology in fronto- tion than the role of genetics. In this section,
we briefly review findings from studies that s ectional and longitudinal studies have sug-
have examined risk factors posited in the de- gested that TS is sensitive to psychosocial
velopment and phenotypic expression of TS stress (e.g., Findley et al., 2003; Hoekstra,
in children and adolescents. Steenhuis, Kallenberg, & Minderaa, 2004;
The role of adverse pre- and perinatal Silva et al., 1995). For example, data from
events in the development and phenotypic a recent longitudinal study of children and
expression of TS and tic disorders has prob- adolescents with TS and/or OCD revealed
ably received the most research attention that current levels of psychosocial stress pre-
to date. Increased risk for TS has been as- dicted future tic severity (Lin et al., 2007).
sociated with (1) parental age (Burd et al., The use of stimulant medication remains
1999), (2) low birthweight (Leckman et al., of concern as a possible risk for tics and TS
1987), (3) lower Apgar scores (Burd et al., (Walkup, 2001). Findings from studies ex-
1999), and (4) birth/obstetrical complica- amining the impact of stimulant medication
tions (Leckman et al., 1990). For example, suggest that there is no clear and consistent
Leckman and colleagues (1990) found that relationship between tic severity and stimu-
obstetrical complications were more com- lant medication in children with tics and
mon in individuals who developed TS than ADHD (Gadow, Sverd, & Sprafkin, 1999;
in individuals from the population at large. Nolan, Gadow, & Sprafkin, 1999). Howev-
Obstetrical complications that cause injury er, it remains unclear whether some children
to the basal ganglia and hypoxia, resulting who take stimulant medication may be at
in ischemia to vulnerable parts of the brain, increased risk of developing or exacerbating
have been implicated in the development tics.
of TS (Peterson, Riddle, Gore, Cohen, & The association between infections, es-
Leckman, 1994). Tic severity has been as- pecially streptococcal infections, and TS is
sociated with (1) maternal prenatal smoking somewhat controversial. The term pediatric
(Mathews et al., 2006), (2) low birthweight autoimmune neuropsychiatric disorder as-
(Hyde, Aaronson, Randolph, Rickler, & sociated with streptococcal infection (PAN-
Weinberger, 1992; Leckman et al., 1987), DAS) was coined on the basis of findings from
and (3) birth complications (Leckman et al., a retrospective study that reported the sud-
1990). In addition, maternal stress during den onset of tics and obsessive–compulsive
pregnancy and severe nausea or vomiting symptoms temporally associated with strep-
during the first trimester of pregnancy have tococcal infection in a sample of children
been found to be associated with tic severity (Swedo et al., 1998). It is hypothesized that
(Leckman et al., 1990). It has been posited cross-reactive antibodies induced by group
that environmental stressors may alter dop- A streptococcal infection bind to basal gan-
amine levels in the central nervous system, glia antigens and thereby result in TS symp-
which may result in a teratogenic effect on toms and PANDAS. In such cases, TS symp-
the fetus (Fredhoff, 1986). With respect to toms begin suddenly following streptococcal
comorbid disorders, maternal use of coffee, infection, but then follow a typical course.
alcohol, and tobacco has been associated However, findings from studies examining
with OCD in patients with TS (Santangelo the association between streptococcal in-
et al., 1994). For example, Mathews and col- fections and TS have been mixed. For ex-
leagues (2006) examined the association be- ample, data from a recent study of children
tween prenatal/perinatal adverse events and and adults indicated that individuals with
tic severity in a large sample of individuals TS had higher rates of group A streptococ-
with TS. Findings from this investigation re- cal and anti-basal-ganglia antibodies, com-
vealed that prenatal maternal smoking was pared to a healthy comparison control group
associated with increased tic severity and (Church, Dale, Lees, Giovannoni, & Rob-
with the presence of OCD. ertson, 2003). However, several prospective
A number of other environmental risk fac- studies have not revealed differences in an-
tors, such as psychosocial stressors, use of tistreptococcal antibodies among children
stimulant medications, and infections, have with TS (Loiselle, Wendtlandt, Rohde, &
been posited to influence the course and Singer, 2003; Luo et al., 2004; Perrin et al.,
severity of TS. Findings from both cross- 2004). Thus it seems unlikely from the re-
search evidence that streptococcal infection ship between tic severity and a comorbid di-
is a specific risk factor for the development agnosis of ADHD (Burd et al., 2006).
or phenotypic expression of TS, except in a With respect to adjustment, research sug-
few rare cases (Phelps, 2008). gests that children with TS and comorbid
ADHD exhibit poorer functioning com-
pared to those with TS alone and to their
Psychological Factors Related to normally developing counterparts (Bawden,
Symptomatology and Adjustment Stokes, Camfield, Camfield, & Salisbury,
1998; Carter et al., 2000; Spitzer, Williams,
The extant literature demonstrates that TS is Gibbon, & First, 1990). Specifically, find-
a stress-sensitive condition (Shapiro & Sha- ings indicate that children with TS who have
piro, 1998). As noted earlier, findings from a comorbid diagnosis of ADHD exhibit
cross-sectional and longitudinal studies have more internalizing and externalizing behav-
consistently demonstrated that TS is sensitive ioral problems and poorer social adaptation
to psychosocial stress (Findley et al., 2003; (Carter et al., 2000), as well as more aggres-
Hoekstra, Steenhuis, et al., 2004; Silva et sive behavior problems (Bawden et al., 1998)
al., 1995). In a recent prospective longitudi- and poorer global functioning (Spitzer et al.,
nal study, Lin and colleagues (2007) found 1990), than children with TS alone do. Cart-
that current levels of stress and depression er and colleagues (2000) found that children
independently predicted future tic severity in with TS alone were not significantly differ-
children and adolescents with TS and OCD. ent in terms of externalizing and social prob-
Stressful life events such as beginning a new lems compared to normal controls, but did
school year, waiting for test results, family exhibit a higher frequency of internalizing
conflict, and moving to a new residence are problems. Thus these findings may be inter-
also associated with an increase in tic sever- preted to suggest that some social-emotional
ity (Malatesta, 1990). and behavior adjustment difficulties may
Research studies examining emotional specifically be results of ADHD symptoms
distress or disorders have also found asso- as opposed to TS.
ciations with tic severity (Burd et al., 2006).
For example, in a study of children and
adolescents with TS, anxiety was the most Assessment
commonly reported factor associated with
tic severity (Silva et al., 1995). In addition, An assessment process that includes multiple
findings from a recent study indicate that methods and perspectives is frequently pro-
comorbid OCD, other anxiety disorders, moted as the best evidence-based assessment
mood disorders, and anger control problems strategy in the child and adolescent health
are all associated with increased tic severity and mental health literature. Assessment in-
(Burd et al., 2006). struments available for TS include clinician-
Several studies have indicated that sever- observer rating scales, self-report rating
ity of tics is associated with disruptive be- scales, parent rating scales, and video-based
havior problems and disorders, as well as rating scales. We provide a brief review of
with poorer social and academic competence some of the more widely used methods for
(Burd et al., 2006; Zhu, Leung, Liu, Zhou, & the assessment of TS in children and adoles-
Su, 2006). For instance, Zhu and colleagues cents. Furthermore, we discuss differential
(2006) found that delinquent behavior, diagnosis and assessment for common co-
thought problems, attention problems, and morbid conditions.
aggression were all positively associated with
tic severity; they also found that deficits in
Clinician-Observer Rating Scales
social and school competence were positive-
ly related to severity of tic symptoms. Find- Clinician-observer rating scales are used to
ings in the literature with respect to ADHD assess for the various dimensions of tic be-
are equivocal, with some results indicating havior, including type, duration, frequency,
a positive relationship between ADHD and intensity, location, complexity, suppres-
tic severity (Carter et al., 2000), while other sion, and functional impairment. These
studies have revealed no significant relation- rating scales are designed to be completed
by an experienced clinician after a clini- The HMVTS was created to provide a

cal interview. Some of the most commonly quick, simple, and accurate assessment of
used clinician-observer rating scales are the the nature of tics and the resulting degree
Shapiro Tourette’s Syndrome Severity Scale of impairment. However, similar to the
(STSSS; Shapiro & Shapiro, 1984), the Yale other two rating scales discussed here, the
Global Tic Severity Scale (YGTSS; Leckman HMVTS does not assess for other common
et al., 1989), and the Hopkins Motor and symptoms associated with TS in children
Vocal Tic Scale (HMVTS; Walkup, Rosen- and adolescents. The HMVTS consists of
berg, Brown, & Singer, 1992). a series of linear visual analogue scales on
The STSSS is an easy-to-use measure which a caregiver/parent and a physician
that consists of a composite rating scale of separately rank each tic symptom (motor and
tic severity based on five factors: the degree vocal), taking into consideration the tics’ fre-
to which the tics are noticeable to others; quency, intensity and interference with daily
whether the tics elicit comments or curios- functioning. Caregivers are instructed that
ity; whether others consider the identified the lines range from 0 (no tics) to 10 (most
patient as unusual or bizarre; whether the severe). The scales can be divided into four
tics interfere with daily functioning; and severity ranges: mild, moderate, moderately
whether the identified patient is incapaci- severe, and severe. Three final scores are de-
tated, homebound, or hospitalized because rived for both motor and vocal tics based on
of the tics. The clinician sums the ratings for the caregiver’s ratings, the clinician’s rating,
the five factors to derive a total global sever- and an overall assessment. Final scores use a
ity rating. The STSSS has demonstrated ad- 5-point rating scale ranging from 1 (no tics)
equate reliability and validity (Shapiro, Sha- to 5 (severe tics). Research reveals that the
piro, Young, & Feinberg, 1988). The STSSS HMVTS has adequate psychometric proper-
is primarily a measure of social impairment ties (Walkup et al., 1992).
associated with TS and therefore does not
provide an assessment of the tics’ character-
Self-Report and Parent
istics as experienced by the patient.
Rating Scales
The YGTSS is a semistructured clinician-
rated instrument that assesses the nature of Self-report and parent rating scales are
motor and vocal tics, as well as the function- frequently used to assess TS, due to their
al impairments associated with these tics. ease of administration and scoring. Child
The nature and severity of motor and vocal self-report rating scales may also be help-
tics are assessed on five separate dimensions: ful in obtaining a subjective impression of
number, frequency, intensity, complexity, the symptoms (Goetz & Kompoliti, 2001).
and interference. The five dimensions are In addition, parent report rating scales are
each rated on a 6-point scale for motor and important because they provide information
vocal tics, and the scores are then summed about how the child behaves in the home set-
to yield a total tic score. The YGTSS also in- ting and how the child is observed by signifi-
cludes a separate overall impairment rating cant people in her or his life.
ranging from 0 (no impairment) to 50 (se- The Motor tic, Obsessions and compul-
vere impairment). A global severity score is sions, Vocal tic, Evaluation Survey (MOVES;
derived by summing the overall impairment Gaffney, Sieg, & Hellings, 1994) is one of
rating and the total tic score. The YGTSS has the only self-report rating scales that may
demonstrated adequate reliably and validity be employed across the developmental spec-
(Storch et al., 2005), and has been shown to trum, since it has been developed for chil-
be sensitive to treatment effects (e.g., Gilbert, dren, adolescents, and adults. The MOVES
Batterson, Sethuraman, & Sallee, 2004). Al- is a brief 16-item self-report measure of TS.
though the YGTSS provides an assessment Items are self-rated on a 4-point scale from 0
of the nature and functional impairment of (never) to 3 (always). The MOVES yields five
tics and has good psychometric properties, it subscales: Motor Tics, Vocal Tics, Obses-
does not assess for other common symptoms sions, Compulsions, and Associated Symp-
associated with TS; it also takes more time toms (e.g., echolalia, echopraxia, coprolalia,
to complete than some other clinician rating and copropraxia). Scores on the subscales
scales. may be combined to form a Tic subscale
or an Obsessive–Compulsive subscale. The sitting quietly alone or in the presence of an

MOVES has demonstrated adequate psy- observer, engaging in casual conversion, or
chometric properties (e.g., Gaffney et al., performing mathematical computations or
1994). other mental tasks. The behavioral tasks can
Several parent/caregiver rating scales are be chosen to distract—or, more importantly,
commonly used to assess TS. The Tourette to provide a more relaxed environment for—
Syndrome Symptom List (TSSL; Cohen, the individual with suspected tic disorder, in
Leckman, & Shaywitz, 1985) is among the order to obtain a more accurate assessment
most commonly employed measures to assist of the nature of the patient’s tics (Goetz &
caregivers and parents in making daily or Kompoliti, 2001). Although video-based
weekly ratings of tic behavior. The TSSL is rating scales provide an objective assessment
a 29-item list of symptoms, each of which is of tics that may not always be possible to
rated on a 5-point scale from 1 (symptom not obtain by other measures, these scales can
present) to 5 (symptoms almost always pres- be time-consuming and difficult to imple-
ent); the 29 symptoms include a wide range ment outside a research setting, due to lack
of simple and complex tics and other be- of equipment or space.
havioral symptoms associated with TS (e.g.,
outbursts, defiance). Although the TSSL has
Differential Diagnosis
been used with considerable frequency, it has
among the Tic Disorders
not undergone rigorous psychometric vali-
dation and does not address the full range TS is differentiated from the other tic dis-
of symptomatology that accompanies child- orders primarily by the requirement that
hood TS (Kompoliti & Goetz, 1997). the child or adolescent must exhibit both
The Tourette’s Disorder Scale—Parent multiple motor tics and at least one vocal
Rated (TODS-PR; Shytle et al., 2003) was tic for more than 1 year. Chronic tic disor-
developed to improve upon previous TS der requires at least one motor or vocal tic,
rating scales by including the assessment but not both for 1 year. Transient tic disor-
of other clinically relevant symptoms (e.g., der requires that the tics occur many times
tics, inattention, hyperactivity, aggression, throughout the day for at least 4 weeks, but
obsessions, compulsions, and emotional less than 1 year. If the tics occur for less than
disturbance) seen in children with TS. The 4 weeks and/or do not occur for many times
TODS-PR is a 15-item parent-rated measure throughout the day, then tic disorder not
with severity ratings for each item ranging otherwise specified may be the appropriate
from 0 to 10 (0 = not at all and 10 = ex- diagnosis.
tremely). An overall total score is calculated
by summing the item scores (minimum score
Common Comorbid Conditions
= 0, maximum score = 150). The TODS-PR
has demonstrated good internal consistency, As noted earlier, TS is frequently comorbid
convergent validity, and discriminant valid- with other psychiatric disorders in children
ity, and has been shown to be sensitive to and adolescents; comorbidity estimates
treatment effects (Shytle et al., 2003; Storch range as high as 90% (Robertson, 2000).
et al., 2004). Research indicates that comorbid condi-
tions include a wide range of psychiatric
disorders, such as anxiety, mood, conduct,
Video-Based Rating Scales
and substance use disorders (Gaze, Kepley,
Video-based rating scales can be used to as- & Walkup, 2006). ADHD and OCD are
sess the nature of a patient’s tics via behav- among the most common comorbid condi-
ioral observation. This type of methodology tions reported. Given the high rates of co-
can provide objective information about morbidity in children and adolescents with
the individual’s tics that can be difficult to TS, a comprehensive assessment of psychiat-
obtain otherwise because tics are fleeting ric disorders is essential in order to minimize
in nature and because they are sometimes the impact of the comorbid condition(s) on
suppressed in the presence of a clinician. Ex- tic severity and to provide the most appro-
amples of behavioral observation tasks that priate treatment for both the TS and the co-
can be used to assess tics include reading, occurring disorder(s).
Treatment ceived empirical attention for the treatment

of TS. ERP entails exposing the individual
Therapies that have demonstrated empiri- to sensations and urges that precede the tics
cally validated evidence for the management and then preventing the tic response. The ra-
of TS include behavioral treatments, phar- tionale for ERT in managing TS is that tic
macotherapy, and their combination. reduction occurs as a result of habituation
to premonitory sensations and urges. Recent
results from a study that compared ERT to
Behavioral Treatments
HRT for the treatment of TS indicated that
Although several behavioral interventions both treatments significantly reduced tics,
have been examined for the management but that the treatment groups did not differ
of TS, habit reversal training (HRT; Azrin from each other (Verdellen, Keijsers, Cath,
& Nunn, 1973) is among the most widely & Hoogduin, 2004). Although the results
recognized and has received the most rigor- from this study are preliminary, the data do
ous empirical attention. Originally, HRT suggest that the two treatments are compa-
consisted of eight components. However, it rable in helping to reduce tic symptoms in
has since been simplified based on a com- individuals with TS.
ponent analysis, which indicated three criti-
cal components: (1) awareness training, (2)
Pharmacological Treatments
competing-response practice, and (3) social
support (Woods & Miltenberger, 1995). Research evidence suggests that neuroleptic
Awareness training has several components agents (both atypical and typical antipsy-
(i.e., response description, response detec- chotics) that block postsynaptic dopamine
tion, identifying early warning signs, and receptors are presently the most effective
identifying high-risk situations), all of which medications for the treatment of tics (Gil-
are geared toward increasing awareness bert, 2006; Phelps, 2008). Typical neurolep-
and are based on the premise that increased tic medications such as haloperidol (Haldol)
awareness of tics facilitates self-control. and pimozide (Orap) have received the most
Competing-response training occurs once rigorous empirical attention and have dem-
awareness training has been mastered. This onstrated efficacy in numerous double-blind
training entails teaching individuals with placebo-controlled studies (for a review, see
TS to produce any physical response that is Sandor, 2003). Atypical neuroleptics such
incompatible with the tic and to tense the as risperidone (Risperdal) and ziprasidone
identified tic-opposing muscles until the (Geodan) have also demonstrated efficacy
urge to produce the tic subsides. Social sup- for the management of tics (Gilbert et al.,
port involves having the individual’s caregiv- 2004; Sallee et al., 2000). For example, in
ers, family, and friends provide prompting, a recent randomized double-blind crossover
praise, and support for the individual to use study that compared risperidone to pimoz-
the newly learned skills outside of treatment. ide, risperidone was associated with signifi-
HRT is based on the rationale that tics are cantly lower tic severity scores, but greater
maintained by unawareness of their occur- weight gain. Although research suggests that
rence, excessive practice, response chaining, risperidone is associated with greater weight
and social reinforcement of the tics. A task gain, atypical neuroleptics generally tend to
force of the American Psychological As- have fewer or less severe adverse side effects
sociation published criteria for empirically than typical neuroleptics do. Adverse side
supported treatments (American Psychologi- effects associated with the typical neurolep-
cal Association Task Force, 1995), including tics, such as extrapyramidal symptoms and
criteria for describing treatments as “well es- sedation, can result in patients’ discontinu-
tablished” and “probably efficacious.” From ing the medication. Thus the atypical neuro-
a review of the literature, Carr and Chong leptics show promise in the management of
(2005) conclude that HRT meets the “prob- tics in children and adolescents.
ably efficacious” criteria. Although neuroleptic medications that
Exposure with response prevention (ERP) block postsynaptic dopamine receptors are
is a behavioral treatment that is most fre- considered the most effective medications
quently used to treat OCD, but also has re- for the treatment of tics, placebo-controlled
studies provide evidence for several alterna- Summary and Conclusions

tive pharmacological treatments for tics (for
a review, see Gilbert et al., 2006). For ex- Over the past few decades, significant ad-
ample, findings from a recent double-blind vances in empirical developments have in-
study indicated that clonidine (Catapres) creased our understanding of the assessment
was as effective at reducing tics as the atypi- and management of TS, together with the
cal neuroleptic risperidone (Gaffney et al., comorbidities that are frequently associated
2002). In addition, clonidine and gaunfacine with this disorder. In particular, neuroimag-
(Tenex) are two psychotropic agents that ing research over the past 10 years has yield-
have been shown to reduce both tics and im- ed fairly compelling evidence that TS has a
pulsivity (Scahill et al., 2001; Tourette Syn- strong biological component. Moreover, re-
drome Study Group, 2002). Thus, given that search on the role of dopamine in both the
children and adolescents with TS frequently development and the course of TS and other
have a comorbid diagnosis of ADHD or movement disorders has allowed for signifi-
demonstrate impulsivity, findings from re- cant advances in the pharmacotherapy of
search studies to date suggest that these two these disorders. Finally, it has become par-
medications may be particularly beneficial ticularly clear that TS has a strong familial
for children with TS and comorbid ADHD. and genetic component. The developments in
This is especially relevant, given the wide- human genome research that have furthered
spread concerns that stimulant medications our understanding of the genetics of TS have
typically used for the treatment of ADHD assisted in predicting those individuals who
may exacerbate tics. However, findings from are at greatest risk for the phenotypic ex-
a study comparing clonidine, methylpheni- pression of the disorder, and also provide
date (Ritalin), and placebo for the treatment promising avenues for the treatment of TS
of ADHD in children with tics indicated based on specific genetic markers.
that all treatments were superior to placebo Whereas much has been learned about
with respect to reducing both ADHD and tic the biology of TS over the past decade, im-
symptoms (Tourette Syndrome Study Group, portant progress has also been made in our
2002). Therefore, contrary to the popular understanding of the environmental factors
belief that stimulant medication exacerbates associated with the course of the disorder.
tic symptoms, results from this study suggest Clearly, a next step in research efforts will
that methylphenidate is effective at reducing be a greater understanding of how the in-
tics in children and adolescents with tics and teraction between biological factors (e.g., ge-
ADHD. However, tic exacerbation remains netics, neurotransmitters) and environmen-
possible in some susceptible individuals, and tal factors results in the expression of the
this possibility warrants careful monitoring disease, and of how both biology and envi-
during stimulant treatment. Recent findings ronment can be manipulated for the purpose
from a randomized double-blind study ex- of managing TS. Although specific biologi-
amining the nonstimulant medication atom- cal markers must clearly be present for phe-
oxetine (Strattera) indicated greater ADHD notypic expression of the disease, environ-
symptom improvement and greater reduc- mental factors may mediate or moderate the
tion in tic severity compared to placebo for phenotypic expression of the disorder. This
the treatment of ADHD in children and ado- remains an important and fruitful area for
lescents with TS (Spencer et al., 2008). research in the years to come.
Many medications have been shown to be The clinical assessment of children with
effective at treating tics in open-label studies TS is especially complex, as this disorder is
(see Gilbert, 2006, for a review). However, frequently comorbid with a number of psy-
due to the lack of control groups in these chiatric disorders, including anxiety disor-
studies, extraneous variables may have in- ders, mood disorders, ADHD, and learning
fluenced the outcome measures and led to disabilities. The impact of these comorbid
overestimates of the treatment effects. As psychiatric disorders on the symptom dis-
such, findings from these studies should be play and natural history of TS remains an
viewed with caution, and the data must be important area for future investigation.
interpreted judiciously in the management of Conversely, the impact of TS on the symp-
children and adolescents with TS. tom display and natural history of the vari-
ous comorbid psychiatric disorders is also an ship problems in children with Tourette’s disorder
important area for further study. or diabetes mellitus. Journal of Child Psychology
Finally, behavioral treatments and phar- and Psychiatry, 39, 663–668.
Bloch, M. H., Leckman, J. F., Zhu, H., & Peter-
macotherapy are the therapies of choice in
son, B. S. (2005). Caudate volumes in childhood
the management of TS because of their firm predict symptom severity in adults with Tourette
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Chap ter 10
Anxiety Disorders
Steven R. Pliszka
The last decade has seen major growth in of high arousal, such as muscle tension, poor
research on child and adolescent anxiety sleep, internal feelings of restlessness, sweat-
disorders, with new data emerging from ing, heart racing, or shortness of breath.
longitudinal, family/genetic, neuroimaging, When the symptoms of physical arousal are
and treatment studies. This has allowed in- extreme and uncontrollable, a panic attack
vestigators to develop new hypotheses about is said to occur.
the etiology of these disorders, as well as to Anxiety disorders are subdivided by the
make evidence-based recommendations to Diagnostic and Statistical Manual of Men-
clinicians regarding treatment approaches. tal Disorders, fourth edition, text revision
It is key to begin with a definition of anxi- (American Psychiatric Association, 2000)
ety. Fear can be defined as a negative brain into generalized anxiety disorder (GAD),
state brought on by the immediate presence specific phobia, agoraphobia, panic disor-
of threatening stimuli (e.g., a predator or an der, social phobia (social anxiety disorder),
oncoming car), whereas anxiety is a similar posttraumatic stress disorder (PTSD), acute
brain state “engaged when encountering sus- stress disorder, and obsessive–compulsive
tained cues that more ambiguously predict disorder (OCD). Separation anxiety disor-
threat” (Pine, Helfinstein, Bar-Haim, Nel- der (SAD) is the only anxiety disorder that is
son, & Fox, 2009, p. 213). Thus fear and required to have an onset during childhood
anxiety are differentiated by the immediacy and is not diagnosed in adults (although
of the threat, which may be physical (e.g., children with SAD are at high risk for adult
an approaching hurricane) or social (e.g., an anxiety disorders, as we shall see).
upcoming examination). Anxiety is adap-
tive if it causes an individual to take action
against a threat (e.g., evacuating the coast or T ypical Development of Anxiety
studying for the examination), but becomes
symptomatic if it is so severe that the person Klein (1994) has reviewed the developmental
is persistently in a negative state (i.e., always course of anxiety and fear in children. In in-
worrying) or needs to avoid situations to an fants, fears of loud noises or loss of support
extent that is self-defeating. Anxiety is gener- predominate. Fear of strangers arises next,
ally also associated with physical symptoms at about 8 months of age, with separation
188
Anxiety Disorders 189
anxiety apparent at about 12–15 months. the anxiety scores. Children with the highest
Fears of imaginary creatures arise dur- anxiety scores showed lower achievement in
ing early childhood, and as children enter mathematics and reading. Interestingly, self-
primary school, fears about performance, ratings of anxiety did not predict peer or
health, and personal harm become more teacher nominations for shyness. Although
pronounced. Silverman, La Greca, and Was- none of the children in the study underwent
serstein (1995) extensively studied the wor- a structured interview for psychiatric dis-
ries of 272 elementary school children ages order, the findings with regard to achieve-
7–12 years. Children were given a structured ment are not consistent with the notion that
interview that assessed worries in 14 areas: anxiety in childhood is a benign phenom-
school, performance, classmates, friends, enon. Also, the studies reviewed above show
war, disasters, money, health, future events, that children can reliably rate their anxious
personal harm, “little things,” appearance, symptoms and articulate their worries; thus
family, and “other.” The children were asked greater confidence can be placed in stud-
whether they worried about each broad cat- ies that base the diagnosis of anxiety on a
egory, and, if so, were then asked to list spe- child’s report.
cific worries within that area. Children next The experience of anxiety is closely re-
rated the intensity of their worry and filled lated to emotional regulation, defined as a
out a number of standardized anxiety rat- “voluntary and goal directed process aimed
ing forms. One-week test–retest reliability at modifying emotional state to achieve so-
of the interview was very good, suggesting cial and biological adaptation, as well as in-
that children in this age group are reliable dividual goals” (Hannesdottir & Ollendick,
reporters of their worries, at least over the 2007, p. 276). For instance, a child may be
short term. The average child reported about afraid of water, but may work to consciously
8 worries, spanning an average of 6 of the suppress the fear when peers are watching.
14 areas. The most common worries were Success or failure of emotional regulation
about school, health, and personal harm, may lead to an adaptive response (e.g., jump-
with friends and appearance ranked the lowing in the pool and discovering that there is
est. European American and Hispanic girls nothing to be worried about) or a maladap-
reported more worries than boys, but Afri- tive one (e.g., refusing to go to a pool party).
can American boys had as many worries as Some children with anxiety disorders may
girls. The number of worries reported by a not differ from typically developing children
child correlated highly with the child’s self- in terms of the fear or anxiety experienced
rating on anxiety scales. internally, but in their ability to regulate
Muris, Meesters, Merckelbach, Sermon, their emotions. Deficits in emotional regula-
and Zwakhalen (1998) examined anxiety tion occur with other emotional states (i.e.,
in 193 nonreferred children. Sixty (31%) anger, elation) and thus are not specific to
of the sample stated that they never wor- anxiety disorders. Indeed, some parents may
ried at all. The other children reported that identify general “negative affect” as anxiety
they worried two to three times per week, in some situations, particularly in children
with the most common worries being about with disruptive behavior disorders; this
school, dying, getting sick, or being teased. may complicate the interpretation of both
Girls worried more than boys. Other stud- research and treatment outcome findings
ies have examined anxiety in an unreferred (March et al., 2000).
population of children (Ialongo, Edelsohn,
Werthamer-Larsson, Crockett, & Kellam,
1994). Over 1,000 first-grade children filled Epidemiology and Comorbidity
out the Revised Children’s Manifest Anxi-
ety Scale (RCMAS). Teacher ratings of class- Epidemiological studies of the anxiety disor-
room adaptive behavior, peer ratings, and ders in children and adolescents have yield-
achievement measures were also obtained. ed broadly similar results and are shown in
About 400 of these children filled out the Table 10.1. Anxiety disorders as a group are
RCMAS again 4 months later; the intraclass the most common forms of mental disorders
correlation coefficients were .64 for boys in children and adolescents. The National
and .42 for girls, showing good stability of Comorbidity Survey Replication Adolescent
Supplement (NCS-A) involved face-to-face an anxiety disorder, with SAD being the
interviews with nearly 10,000 adolescents most prevalent (Kovacs, Gatsonis, Paulaus-
ages 12–17 from 2001 to 2004; a lay in- kas, & Richards, 1989). In most cases, the
terview for psychiatric disorders was used. anxiety disorder predated the first episode
Information from parents was also obtained of MDD and persisted after the remission
(Kessler, Avenevoli, Costello, et al., 2009). of the depression; this suggested that the
The full results of the NCS-A are yet to be depression and anxiety were clearly distinct
published at this writing, but data are avail- from each other, rather than that the anxi-
able from a subsample of 347 adolescents ety was an epiphenomenon of the depres-
that were administered both the lay inter- sion. Angold and Costello (1993) reviewed
view and the Schedule for Affective Disor- nine epidemiological studies of childhood
ders and Schizophrenia for School-Age Chil- mental disorder where at least some of the
dren (K-SADS) (Kessler, Avenevoli, Green, data were obtained from the children them-
et al., 2009). The lay interview showed good selves. They examined the rates of depres-
concordance with the K-SADS. In this sub- sive comorbidity with the anxiety disorders,
sample, the lifetime prevalence on the K- which ranged from a low of 6.6% to a high
SADS for any anxiety disorders was 25%, of 69%. In most of the studies, however,
with specific phobia being most common only about 10–20% of the anxious children
(12.7%), followed by social phobia (9.2%). were depressed. The overlap of depression
GAD (3.3%), PTSD (4.2%), and panic dis- and anxiety is thus asymmetrical: Whereas
order (2.1%) were less common. Clearly, approximately a quarter of anxious children
many adolescents had more than one anxi- are depressed, well over half and sometimes
ety disorder—a finding consistent with older up to 75% of children with depressive disor-
research. Half of children with DSM-III-R ders have comorbid anxiety disorders.
overanxious disorder were also found to have There is also a well-studied overlap of anx-
SAD, particularly younger patients (Strauss, iety and disruptive behavior disorders. Chil-
Lease, Last, & Francis, 1988). Over a quar- dren with anxiety disorders have been found to
ter of patients with SAD also have phobias have higher than expected rates of attention-
(Benjamin, Costello, & Warren, 1990). deficit/hyperactivity disorder (ADHD) and
Anxiety disorders are comorbid with other oppositional defiant disorder (ODD) (Strauss
mental disorders as well. In a population of et al., 1988). Chavira, Garland, Daley, and
104 prepubertal children with major depres- Hough (2008) examined mental disorders in
sive disorder (MDD), 41% met criteria for a subset of 1,715 participants ages 6–18 years
TABLE 10.1. Epidemiology of Anxiety Disorders in Children and Adolescents

Prevalences of anxiety
diagnoses (%)
Specific Any
Age group (simple) Social anxiety
Study (years) Comment SAD GADa phobia phobia disorder
Anderson et al. (1987) 11 3.5 2.9 2.4 — —
Bird et al. (1988) 4–16 CGAS < 61 4.7 — 2.6 — —
CGAS = 61–70 2.1 1.3
Costello (1989) 7–11 CGAS < 70 4.1 4.6 9.2 1.0 —
Shaffer et al. (1996) 9–17 Parent Youth 1.4 1.9 0.7 2.8 5.3
Combinedb 1.6 2.6 1.6 2.3 7.1
3.9 5.7 2.6 5.4 13.0
Kessler et al. (2009b) 12–18 K-SADS NA 3.3 12.7 9.2 25.0
Note. CGAS, Children’s Global Assessment Scale; K-SADS, Schedule for Affective Disorders and Schizophrenia for
School-Age Children.
a Includes DSM-III/DSM-III-R overanxious disorder.
bUsed “either–or” method.
who received care in a public sector, such as (2001) found a clear dose–response relation-
child welfare or juvenile justice. They com- ship between the number of anxiety disor-
pared participants (mean age ~14 years) with ders in childhood and the likelihood of later
anxiety disorders to those with an anxiety adult anxiety disorders. It is also clear that
disorder and a physical illness to those with anxiety disorders predict MDD (Gregory et
a physical illness alone or no physical illness. al., 2007); this indicates that anxiety disor-
There was no control group of children not ders of childhood are not benign conditions
treated in the public health sector. Children that resolve with maturity.
with anxiety disorders had very significant
rates of depressive disorders (28.4%), disrup-
tive disorders (59.2%), and substance use dis- Genetics and Family Patterns
orders (21.4%). The additional comorbidity
of a physical illness further increased psychi- Studies performed over the last decade have
atric comorbidity. Conversely, up to 25–33% confirmed that parents with anxiety disor-
of children with ADHD or other disruptive ders have elevated rates of anxiety disorders
behavior disorders will meet criteria for an among their children. Hirshfeld-B ecker and
anxiety disorder (Angold, Costello, & Er- colleagues (2008) combined results from 14
kanli, 1999; Pliszka, Carlson, & Swanson, studies examining the rates of anxiety disor-
1999). ders in children of parents who themselves
had anxiety disorders compared to control
parents. These studies involved 1,371 par-
Longitudinal Course ticipants; the 465 children of parents with
anxiety disorders had a rate of anxiety
Of 14 prospective, long-term epidemiologi- disorders of 37%, compared with a rate of
cal follow-up studies reviewed by Hirshfeld- 15% among children of control parents (p <
Becker, Micco, Simoes, and Henin (2008), 13 .0001). In general, if a parent has a particu-
showed that childhood anxiety disorders are lar anxiety disorder, a child is at risk for the
associated with an increased rate of anxiety full range of anxiety disorders, not just the
disorders in adulthood. Table 10.2 shows se- anxiety disorder afflicting the parent. Paren-
lected results from several of the larger stud- tal MDD and bipolar disorder also increase
ies. Of interest, Woodward and Fergusson the risk for childhood anxiety disorders
TABLE 10.2. Selected Prospective Studies Examining Long-Term Outcome of Childhood

Anxiety Disorders
Study Sample Results at follow-up
Newman et al. 961 children assessed at ages 11, Among those with anxiety disorder at age 21,
(1996) 13, 15, 18, and 21 61.5% had a childhood disorder.
Pine et al. (1998) 776 children ages 9–19 years, Those with an early anxiety disorder were
assessed at ages 14, 16, and 22 2.5–3.8 times more likely to have the disorder
years at follow-up.
Woodward and 964 children in birth cohort, ages Rates of anxiety disorder at follow-up:
Fergusson (2001) 15–16 years, followed for 1–5 years ≥ 3 anxiety disorders at baseline: 77%
2 anxiety disorders at baseline: 46%
1 anxiety disorder at baseline: 42%
No anxiety disorder at baseline: 13%
Kim-Cohen et al. 1,037 in birth cohort, ages 11–26 Anxiety disorder before age 15 predicted
(2003) years, assessed over 15 years anxiety disorder in adulthood (odds ratio = 2.9).
Gregory et al. 963 children in birth cohort, Adults with a variety of anxiety disorders had
(2007) assessed at ages 11–32 years elevated rates of anxiety disorders in childhood,
as well as higher rates of MDD. Adults with
PTSD had elevated rates of disruptive behavior
disorders.
(Grigoroiu-Serbanescu et al., 1989; Weiss- over, as indicated above, these fascinating

man et al., 2006). Last, Hersen, Kazdin, advances in the neurobiology of anxiety
Orvaschel, and Perrin (1991) interviewed should not blind us to equally impressive
the first- and second-degree relatives of 94 work on family and environmental factors
children with anxiety disorders, as well as in anxiety (reviewed in the next section).
the relatives of 58 children with ADHD and
87 controls. There was a significantly higher
Animal Models
rate of anxiety disorders in the relatives of
the anxious children (35%), compared to the Serotonin (5-HT) has long been implicated
relatives of children with ADHD (24%) or in the pathophysiology of many psychiatric
normal controls (16%). disorders, particularly anxiety and depres-
Family studies such as those reviewed sive disorders. Mice genetically engineered
above cannot tell us whether genetic or en- to lack the 5-HT1A autoreceptor show in-
vironmental factors (or a combination of creased anxiety in a variety of tasks (Kle-
both) are involved in the transmission of the menhagen, Gordon, David, Hen, & Gross,
disorder. There have been very few adoption 2006). If the 5-HT1A receptor is functional
studies of anxiety disorders. Twin studies during the first 15 days of life, the mice do
have found that about 30–40% of the vari- not develop levels of anxiety higher than
ability of anxiety symptoms can be attrib- wild-type mice, but if the 5-HT1A receptor
uted to genetics (i.e., heritability = 0.3–0.4) is disabled in mice at birth, then the mice are
(Hettema, Neale, & Kendler, 2001; Smoller more anxious even if the receptor is enabled
& Tsuang, 1998). Hettema, Prescott, Myers, after day 21 of life (Gross et al., 2002; San-
Neale, and Kendler (2005) examined data tarelli et al., 2003). Similar effects are found
from more than 5,000 twin pairs to look at if mice have the 5-HT transporter (5-HTT)
the role of genes and environment in six dif- knocked out in postnatal days 4–21 (Leon-
ferent anxiety disorders. Since the different ardo & Hen, 2008). These models suggest
anxiety disorders were highly comorbid in that excessive 5-HT in early life may enhance
the sample, Hettema and colleagues sought anxiety; this is paradoxical, considering that
to determine whether there were unique or specific serotonin reuptake inhibitors (SSRIs)
shared genes or environmental factors for enhance the availability of serotonin acutely,
each disorder. The heritability of six anxiety though it is highly likely that chronic effects
disorders ranged from 0.2 to 0.3, but two of SSRIs are more complex and may lead to
different genetic factors were found: one a diminution of 5-HT influence.
shared by GAD, panic disorder, and agora- Recent studies in rodents have shown that
phobia; the other by three phobic disorders epigenetic events (i.e., environmental influ-
(social, animal, and situational). Shared en- ences on gene expression) may be key in anx-
vironmental factors did not exceed 0.11 for ious behaviors. Rat pups raised by mothers
any anxiety disorder. Nonshared environ- that do not engage in the normal amount of
ment accounted for 62–79% of the variance. licking and grooming develop a highly reac-
There was a common nonshared environ- tive hypothalamic–pituitary–adrenocortical
mental factor for each of the six disorders, axis (HPA) with high levels of corticotropin-
but each disorder had a specific environmen- releasing hormone (CRH), adrenocorticotro-
tal factor as well. pin, and plasma cortisol in response to stress
(Meaney, 2001; Ogren & Lombroso, 2008).
The behavior of the maternal rats appears
Biological Markers to be mediated through a complex process
wherein tactile stimulation causes increased
There has been a major expansion of hy- release of thyroid hormone. This, combined
potheses about the biological nature of the with activation of the 5-HT system, leads to
genetic diathesis to anxiety disorders, fu- activation of genes that control the expres-
eled by the technical revolutions in genetics sion of nerve growth factor. Tactile stimula-
and neuroimaging. Despite these advances, tion also leads to demethylation of the DNA
the complex etiology of anxiety disorders that controls the transcription of glucocorti-
remains a mystery, and there are no genetic coid receptors; this allows the nerve growth
clinical applications at this writing. More- factor to activate glucocorticoid receptor
transcription in the hippocampus. This ap- than infants with other genotypes did to ap-
pears to be the step that down-regulates proach of a novel stimulus. Infants who had
the HPA axis, and these effects are lifelong the 7-repeat DRD4 allele and who were ho-
(Kaffman & Meaney, 2007). mozygous for the s allele showed more anxi-
ety and resistance to a stranger’s initiation
of interaction (Lakatos et al., 2003). Inter-
Human Genetic Studies
estingly, these two polymorphisms were not
As noted, one-third of the variance in child- related to maternal ratings of infant tem-
hood anxiety disorders can be attributed to perament. Smoller and Tsuang (1998) found
genetics (Jang, 2005). Lesch and colleagues an association between an allele of the CRH
(1996) first identified a common functional gene and behavioral inhibition (BI) in young
polymorphism in the 5-HTT gene (SLC6A4). children, with the association being more
The 5-HTT-linked polymorphic region marked in children of parents with panic
(5-HTTLPR) can have two elements: a short disorder. The association of CRH and BI is
(s) allele consisting of a 14-base-pair repeat, intriguing, given the animal data reviewed
and a long (l) allele consisting of a 16-base- above and the association of BI with the de-
pair repeat. The s allele has been associated velopment of anxiety disorders.
with half the reuptake of 5-HT in vitro than
the l allele, but whether this translates into
Behavioral Inhibition
more 5-HT transmission in humans carry-
ing an s allele is unclear (Hariri & Holmes, Kagan and colleagues (Kagan, Reznick,
2006). Furthermore, the l allele exists in Clarke, & Snidman, 1984; Kagan, Reznick,
two forms (la and lg), with the lg allele also & Snidman, 1988) initially described the
showing lower levels of 5-HTT (Parsey et phenomena of BI in children. Children were
al., 2006). A very large number of studies brought to a playroom where they interacted
now show that persons carrying an s allele with an unfamiliar person or objects. About
exhibit higher levels of anxiety, depression, 15% of the sample showed behavioral inhi-
and other forms of negative affect than do bition, defined as a long latency to speak,
persons homozygous for the l allele (Lesch play, or interact with a stranger, as well as
et al., 1996; Schinka, Busch, & Robichaux- maintenance of increased proximity to the
Keene, 2004; Sen, Burmeister, & Ghosh, mother. Such a pattern of behavior is highly
2004). In children, however, the picture has stable over time (Reznick et al., 1986). High
been more mixed: The s allele was associated rates of motor activity and crying in infants
in one study with shyness (Battaglia et al., as young as 4 months predict BI at ages 9
2005); the opposite finding (l allele related and 14 months (Kagan & Snidman, 1991).
to shyness) was obtained in another (Arbelle In utero heart rates may also be a predictor
et al., 2003); and still other studies showed of BI (Snidman, Kagan, & Riordan, 1995).
no relationship of the s allele to shyness, Inhibited children show increased heart rate,
anxiety, or depression in children (Schmidt, pupillary dilation, salivary cortisol, and uri-
Fox, Rubin, Hu, & Hamer, 2002; Young, nary norepinephrine during stressful tasks,
Smolen, Stallings, Corley, & Hewitt, 2003). compared to uninhibited children (Kagan,
Persons carrying the s allele are more prone Reznick, & Snidman, 1987; Kagan et al.,
to depression if exposed to environmental 1988; Snidman et al., 1995). Inhibited chil-
stressors (Caspi et al., 2003; Kendler, Kuhn, dren also show less secure attachments to
Vittum, Prescott, & Riley, 2005), though it their mothers as assessed by the Strange Sit-
is unclear whether this relationship holds for uation, and are rated higher than uninhib-
anxiety disorders. As reviewed below, the ited children on the Child Behavior Check-
greatest interest of 5-HTTLPR may be in list Internalizing scale (Manassis, Bradley,
relationship to neuroimaging findings (Mu- Goldberg, Hood, & Swinson, 1995).
nafo, Brown, & Hariri, 2008). A number of studies have shown a rela-
Several other genes have been studied tionship between BI and both adult and
in childhood anxiety but findings are very child anxiety disorders (Biederman et al.,
preliminary. Infants with at least one copy 1990; Hirshfeld et al., 1992; Rosenbaum et
of both the 7-repeat DRD4 allele and the al., 1988, 1992). Children of parents with
l allele of 5-HTTLPR showed less anxiety panic disorder and agoraphobia had sig-
nificantly higher rates of BI than children of ing memory tasks under reward conditions
controls or children of parents with MDD (Pizzagalli, Sherwood, Henriques, & David-
(Rosenbaum et al., 1988). Conversely, chil- son, 2005). Infants show greater right-sided
dren who were identified as having BI had activation when a bad-tasting substance is
an increased risk of anxiety disorders (Bie- placed on their tongues, whereas a good-
derman et al., 1990), as did their parents tasting substance elicits left-sided EEG acti-
(Rosenbaum et al., 1992). At a 3-year follow- vation (Fox & Davidson, 1986). At age 10
up, children who showed the most consistent months, infants watching a film of an actress
BI had the greatest likelihood of having an crying or laughing showed right or left acti-
anxiety disorder; these children were also vation of the anterior EEG, respectively (Da-
more likely to show multiple anxiety disor- vidson & Fox, 1982). Left frontal activation
ders (Biederman et al., 1990; Hirshfeld et is found when 10-month-olds observe the
al., 1992). Hirshfeld-B ecker and colleagues approach of their mothers, while right acti-
(2008) found that 22% of preschoolers with vation is noted when a stranger approaches
BI showed an anxiety disorder by age 10, (Fox & Davidson, 1988). Using the criteria
compared to only 8% of children without of Kagan and colleagues (1984), Davidson
BI, even after the investigators controlled for (1992) classified 31-month-olds into three
parental diagnosis. It should be emphasized groups of 28 subjects: inhibited, uninhibited,
that not all children with BI go on to devel- and a middle group. When the children were
op anxiety disorders; the above-cited studies 38 months of age, EEG recordings were ob-
found that about 40–60% of the inhibited tained both at rest and during several tasks.
children were free of anxiety disorders, de- The inhibited children showed significantly
pending on the time of follow-up. more right-sided activation in the midfrontal
electrodes than did the middle or uninhib-
ited children. Uninhibited children, in con-
EEG Frontal Asymmetry
trast, showed greater left-sided activation
Frontal lobe “power” can be assessed by than either of these groups.
quantifying the relative amounts of alpha, More recent studies have suggested that
beta, and other wavelengths obtained from the left–right hemispheric distinction is re-
various frontal electroencephalographic lated to the approach–withdrawal distinc-
(EEG) leads. Greater alpha power is asso- tion rather than to a positive–negative affect
ciated with reduced activation and lower discrimination. Left-sided activation has
cerebral blood flow (Cook, O’Hara, Uijt- been shown to be related to anger as well
dehaage, Mandelkern, & Leuchter, 1998; as positive affect (Harmon-Jones, Lueck,
Goldman, Stern, Engel, & Cohen, 2000). Fearn, & Harmon-Jones, 2006), and deacti-
Davidson (1992) first used this finding to vation of the left anterior cortex by transcor-
explore the neurobiological basis of nega- tical magnetic stimulation interferes with the
tive affect, using EEG measures of frontal processing of anger (van Honk & Schutter,
lobe activation. In adults, left anterior cere- 2006). In this variation of Davidson’s model,
bral hemisphere activation was associated both anger and happiness are viewed as “ap-
with positive affect, whereas right anterior proach” emotions, as anger might lead an
hemisphere activation was more associated organism to be aggressive against a poten-
with negative affect. Davidson hypothesized tial foe. Family history complicates the in-
that the left frontal areas of the cerebrum terpretation of this straightforward analysis,
are part of an “approach” system, whereas however. Forbes and colleagues (2006) as-
the right frontal areas mediate “withdraw- sessed frontal asymmetry in 74 children, 44
al.” Adults who consistently show left-sided of whom had mothers with childhood-onset
activation in the resting state report more depression. Whereas right frontal asymme-
positive emotional responses to a pleasant try was associated with depression/anxiety
film. In contrast, adults with greater right- in children of nondepressed mothers, anxi-
sided activation report more intense negative ety/depression was associated with left fron-
feelings to a film with fearful or disgusting tal asymmetry in the children of mothers
stimuli (Wheeler, Davidson, & Tomarken, with a history of depression. Gender effects
1993). Left-sided activation is more likely to were found as well, with only boys showing
be shown when individuals perform work- a relationship of left frontal asymmetry with
aggression. Gender effects were also found cused on specific aspects of the parent–child
for frontal EEG asymmetry in an adult twin relationship that might be related to the de-
study; furthermore, EEG asymmetry was velopment of anxiety.
only heritable in young adults (Smit, Post-
huma, Boomsma, & De Geus, 2007). This
Emotional Dysregulation/
suggests that as people age, environment
Information Processing
and experience may shape this “biological”
trait. If an emotion is experienced as overwhelm-
ing or noxious, an individual must find a
way to regulate it, and there is evidence that
Anxiety Sensitivity
anxious children have major difficulties in
Anxiety sensitivity is the tendency to experi- this regard (Hannesdottir & Ollendick,
ence any state of high arousal as harmful, 2007). Anxious children have less ability
unpleasant, and portending harmful physi- than controls to hide their emotions in order
cal or psychological consequences (McNal- to obtain an interpersonal goal (Southam-
ly, 2002). High rates of anxiety sensitivity Gerow & Kendall, 2000). Like adults with
(assessed by questionnaire) in high school anxiety, anxious children tend to give high-
students predicts the onset of panic disor- er priority to the processing of threatening
der, even after comorbid depression is con- information than nonanxious subjects do
trolled for (Hayward, Killen, Kraemer, & (Vasey & MacLeod, 2001). Hadwin, Gar-
Taylor, 2000). Adolescents who rate them- ner, and Perez-Olivas (2006) extensively re-
selves as chronically anxious are more likely viewed the data on information processing
to have acute anxiety attack in response to in anxious children. There is good evidence
hyperventilation (Leen-Feldner, Reardon, to suggest that anxious children show clear
& Zvolensky, 2007). Anxious children are attentional biases to threatening stimuli and
more sensitive to bodily cues that antici- are more likely to interpret ambiguous situ-
pate negative emotions (Thompson, 2001). ations as threatening. Although adults show
Thus persons at risk for anxiety disorders memory biases for negative past events, this
may experience a normal increase in physi- finding is not as well replicated in children.
ological arousal after a stressor as intoler- Pine and colleagues (2009) reviewed three
able, leading to avoidance of situations that developmental models of information pro-
are not ordinarily threatening. Consistent cessing in anxiety disorders of childhood: (1)
with this, offspring of parents with anxiety Such biases may emerge very early in devel-
disorders show increased heart rates under opment as a possible neurobiological factor;
stress (Battaglia et al., 1997), elevated sali- (2) information-processing biases are a late
vary cortisol (Warren et al., 2003), and an feature, and perhaps an actual consequence,
increased startle reflex (Grillon, Dierker, & of the anxiety disorder; and (3) these biases
Merikangas, 1997). emerge from interactions between a child
and a caretaker. With regard to the third
model, it is clear that biases to threatening
Risk Factors stimuli can be induced by training in indi-
for Phenotypic Expression viduals who do not have anxiety disorders.
Given the relatively low amount of the vari-

Parenting Behaviors
ance in anxiety disorders that is attributable
to genetics, a substantial amount of the re- McLeod, Wood, and Weisz (2007), examin-
maining variance must be attributed to ening how the characteristics of parental behav-
vironmental factors. For the most part, pro- ior are related to childhood anxiety behav-
spective studies show a relationship between iors, reviewed 47 studies involving 12,879
health problems, divorce, abuse, and paren- subjects. Overall, parenting behaviors ac-
tal loss in early childhood on the one hand, counted for 4% of the variance in anxiety
and later anxiety disorders on the other symptoms, but the effect size was larger for
(Kroes et al., 2002). As these variables may diagnosed anxiety disorders (0.35). More
be associated with a variety of psychiatric specifically, parental rejection and parental
disorders, a wide body of research has fo- control accounted for 4% and 6% of the
variation in anxiety, respectively. Parental happy) faces, so a brief summary of what is

autonomy granting has the largest relation- known about recognition of facial emotion is
ship with anxiety, accounting for 18% of the in order (see Vuilleumier & Pourtois, 2007,
variance. Fisak and Grills-Taquechel (2007) for a review). Recognition of facial features
reviewed studies related specifically to the and emotion strongly involves the facial fusi-
role of parental modeling in the develop- form area (FFA) in the ventral temporal cor-
ment of childhood anxiety. Social referenc- tex. Visual stimuli reach this area by travel-
ing is the process by which young children ing from the retina to the lateral geniculate
use their parents’ reaction to stimuli to form nucleus and then on to the primary visual
their own emotional reaction to the same areas in the occipital cortex; from there it is
event. In one study, mothers of toddlers were processed in various secondary visual areas,
coached to make either anxious or nonanx- including the FFA. The FFA responds more
ious responses to the appearance of a toy spi- strongly to faces than to other objects. This
der or snake (Gerull & Rapee, 2002). Tod- pathway is relatively “slow.” There is also
dlers who were shown their mothers reacting a direct pathway to the amygdala that by-
fearfully to a toy were more likely to avoid the passes the lateral geniculate; furthermore,
toy. The effect was particularly pronounced the amygdala will respond to fairly coarse
in girls. A similar effect was found when features of facial expression. The amygdala
mothers were coached to respond anxiously responds more strongly to angry/threatening
to a stranger in the laboratory (de Rosnay, faces than to neutral/happy faces. From an
Cooper, Tsigaras, & Murray, 2006). Thus evolutionary perspective, this may allow so-
parents with anxiety disorders may model cial mammals to respond rapidly to a threat
anxious responses to events, which toddlers from a peer—ultimately by either withdraw-
and young children use to determine their ing or approaching.
own emotional responses. Retrospective A now well-replicated finding is that anx-
studies show that anxious adults report that ious individuals have an attention bias to
their parents reinforced their anxious behav- angry faces; that is, they take longer than
iors (e.g., allowing them to stay home from controls to disengage from focusing on an
school) (Ehlers, 1993). Parents of anxious angry face in order to respond to a probe
children have been shown to deliver a larger (Bar-Haim, Lamy, Pergamin, Bakermans-
number of messages conveying dangerous- K ranenburg, & van IJzendoorn, 2007). This
ness of the environment than parents of task is easily adapted to an fMRI paradigm.
typically developing children do (Beidel & The blood-oxygen-level-dependent signal (a
Turner, 1997). In summary, there is evidence measure of the flow of oxygenated blood to
to support the hypothesis that parents may an active brain region) is assessed in vari-
transmit anxiety to children by not granting ous brain regions during the presentation
age-appropriate autonomy, modeling (social of an angry face relative to a neutral face.
referencing), reinforcing anxious behaviors, The magnitude of this contrast can then be
and transferring information that the world compared between anxious and nonanxious
is dangerous. Further prospective studies are subjects, or it can be correlated with subjects’
needed to determine to what degree child response on an anxiety rating scale. Monk
temperament influences parenting style. and colleagues (2008) found that anxious
adolescents showed greater activation of the
amygdala than controls when the faces were
Neuroimaging presented for only 17 milliseconds; such acti-
vation was correlated with the reaction time
Some of the most exciting work in under- to disengage from the faces and respond to
standing the pathophysiology of anxiety in the probe. In a second study (Monk et al.,
the last decade has come from the integration 2006), the subjects were exposed to the faces
of genetic and neuroimaging studies, partic- for 500 milliseconds. At the longer exposure,
ularly functional magnetic resonance imag- the controls and anxious subjects had equal
ing (fMRI) (Munafo et al., 2008; Pine et al., activation of the amygdala; however, now
2009). Most of this work has focused on the the anxious subjects had greater activity in
neural processing of angry versus neutral (or the ventrolateral prefrontal cortex (PFC).
Reaction time on the task was now corre- carriers had. In contrast, patients homozy-
lated negatively with the degree of this ac- gous for the la genotype had greater activa-
tivity. Pine and colleagues (2009) suggested tion of the amygdala than patients who were
that when a threat is briefly presented, anx- s/lg carriers had.
ious adolescents have abnormally increased As exciting as neuroimaging and genetics
acute activity of the amygdala (which may are, the Lau and colleagues study shows the
be related to arousal or physical discomfort). need for caution in interpreting results. The
Once the amygdala is activated, ventrolater- 5-HTTLPR s/l findings may at best relate to
al PFC processing comes online to cope with an underlying endophenotype of emotional
the anxiety, and this secondary process is reactivity, rather than to anxiety/mood dis-
disturbed in anxious individuals. orders per se (Hariri & Holmes, 2006). This
Social interactions in humans go well be- endophenotype may be influenced by many
yond reading facial expression. Guyer and other genes (most unknown at this point)
colleagues (2008) asked anxious adolescents and by environmental interactions. As we
and controls to look at pictures of teenag- shall see below, neuroimaging findings can
ers and rate how much they would like to be altered by both psychosocial and psy-
interact with them in an online chat ses- chopharmacological treatments; thus they
sion. They were told that the people in the should not be viewed as “hard-wired” into
picture would be rating them. They then the brain.
viewed the pictures during the fMRI scan;
anxious adolescents had greater amygdala
activation than controls when viewing peers Assessment
they had negatively evaluated (even though
the peers were pictured smiling). A measure Despite advances in genetics and neuroim-
of ventrolateral PFC–amygdala connectivity aging, diagnosis of anxiety disorders in
correlated positively with baseline anxiety children is based on clinical interview. The
ratings; anxious subjects showed greater clinician should obtain data from the pri-
connectivity than controls. This again sug- mary caregiver(s); from the child; and (when
gests that anxious subjects tend to have their appropriate and possible) from other adults
attention captured by negatively perceived who interact with the child, such as teach-
social stimuli; perhaps the aberrant frontal– ers or day care workers. The clinician should
amygdala connections lead to perseveration screen for anxiety disorders regardless of the
on the anxiety-provoking stimulus. chief complaint that has brought the child to
Genetic studies are increasingly being the evaluation. In the research arena, both
combined with neuroimaging to yield great- the K-SADS (Kaufman et al., 1997) and the
er understanding of these brain–behavior Diagnostic Interview Schedule for Children,
relationships. Increased activation of the Version IV (Shaffer, Fisher, Lucas, Dulcan,
amygdala in response to fearful faces is & Schwab-Stone, 2000) contain extensive
related not only to diagnostic status, but sections covering all the DSM-IV/DSM-IV-
to an individual’s underlying genotype. A TR anxiety disorders. In a regular clinical
meta-analysis of 14 fMRI studies compar- setting, the practitioner should ask ques-
ing carriers of the s allele of the 5-HTTLPR tions covering each of these disorders. It is
genotype to homozygous l carriers showed most convenient to begin with GAD, asking
the s carriers to have greater activation of whether the child worries excessively about
the amygdala to angry faces (p < .001), either past behavior or upcoming events;
though genotype explained only 10% of the the clinician must be certain that the parent
variance on the task. In adolescents, the re- does not mistakenly perceive fear of pun-
lationship between 5-HTTLPR genotype ishment for misbehavior or oppositionality
and diagnosis has proved complex. No dif- about future tasks as anxiety (see the caveat
ference was found in 5-HTTLPR genotype regarding negative affect, below). Does the
distribution between adolescents with GAD child have unrealistic fears about events in
or MDD and controls (Lau et al., 2009). In the world (e.g., a tornado hitting the house,
healthy controls, s or lg carriers had greater wars starting, earthquakes)? Does he or she
amygdala activation to fearful faces than la feel stressed about an event for which the
child is clearly capable and prepared? GAD scales for anxiety, shown in Table 10.3. Care-
also requires some physiological symptoms ful attention to a child’s reading level and
(e.g., insomnia, restlessness, muscle tension). attention span is required for the use of self-
From these questions, it is a logical segue report scales; young children should not be
into questions about social anxiety (e.g., asked to fill out ratings unsupervised. Rating
the child’s fears that people don’t like him scales should be used as screening tools or
or her, avoiding parties due to fears of in- as part of a mental health assessment. Lack
teracting with others). Social anxiety should of concordance between parent and child
be distinguished from avoidant personality reports of anxiety (whether symptoms are
disorder, as in the latter the child does not elicited by rating scale or by clinical inter-
desire to interact with others. If a child has view) is a common problem (Bird, Gould, &
separation difficulties (e.g., school refusal, Staghezza, 1992). Parents may be unaware
not sleeping alone, unable to stay with sitter of the child’s symptoms. In contrast, if a par-
or relatives), the clinician should ask about ent reports that the child is anxious while
the full range of SAD symptoms, followed the child denies all symptoms, careful re-
by questions about panic attacks. Finally, view is needed. If a child’s nonverbal behav-
specific phobia and OCD can be covered. ior is highly suggestive of anxiety) (fearful
Parents sometimes report excessive interest facial expression, apparent muscle tension,
in video games or other pleasurable activi- low voice volume), or if other adults beside
ties as “obsessive”; therefore, the clinician the parent report objective signs of anxiety
should be certain to determine whether the (e.g., teacher reports child is afraid to go out
obsessions or compulsions are repetitive, rit- at recess), the parent’s report is validated in
ualistic, irrational, and generally unwanted spite of the child’s denial of anxiety.
by the child. As ADHD and depression are frequently
The clinical interview can be supplement- comorbid with anxiety disorders, question-
ed by a wide range of parent and child rating ing about these diagnoses is necessary. Clini-
TABLE 10.3. Selected Rating Scales Used in the Assessment of Child and Adolescent
Anxiety Disorders
Instrument Description
Revised Children’s Manifest Recently updated anxiety scale measuring the level and nature of
Anxiety Scale: Second Edition anxiety as experienced by children, using a yes–no response format.
(RCMAS-2) Age-stratified norms based on a national sample of more than 2,300
children and teens. Scale has 49 items covering Physiological Anxiety,
Worry, Social Anxiety, Defensiveness, and Inconsistent Responding
(Reynolds & Richmond, 2008).
Screen for Child Anxiety Related A 38-item scale with parent and child forms. Subject responds to each
Emotional Disorders (SCARED) item with 0 (not true), 1 (sometimes true), or 2 (often true). Yields
five factors: Somatic/Panic, General Anxiety, Separation Anxiety,
Social Phobia, and School Phobia. Discriminates depressed/anxious
children from those with disruptive behavior disorders; no norms as yet
(Birmaher et al., 1997).
Multidimensional Anxiety Scale A 39-item scale with four factors: Physical Symptoms, Social Anxiety,
for Children (MASC) Separation Anxiety, and Harm Avoidance. Fourth-grade reading level
(March, Parker, Sullivan, Stallings, & Conners, 1997).
Pediatric Anxiety Rating Scale A clinician-rated, 50-item symptom checklist with items grouped into
(PARS) the following categories: Social Interactions or Performance Situations
(9 items), Separation (10 items), Generalized (8 items), Specific Phobia
(4 items), Physical Signs and Symptoms (13 items), and Other (6 items).
Each symptom is scored by the interviewing clinician as present or
absent (yes–no) during the previous week (Research Unit on Pediatric
Psychopharmacology Anxiety Study Group, 2002).
cians should not attribute hyperactivity and for 12 weeks. The sertraline dose range was
impulsivity to psychodynamically driven 25–200 mg, with a mean daily dose of 170
anxiety. Children with ADHD, ODD, de- mg. The Children’s Yale–Brown Obsessive–
pression, or anxiety can more broadly show Compulsive Scale was the primary outcome
excessive “negative affect” (March et al., measure. Results indicated a statistically sig-
2000). This consists of whining, crying, stub- nificant advantage for CBT alone (p = .003),
bornness, or temper tantrums in response to sertraline alone (p = .007), and combined
stressors. It should be distinguished from treatment (p = .001) compared with placebo.
anxiety per se; its presence alone should not Combined treatment also proved superior to
lead to a diagnosis of anxiety disorder if the CBT alone (p = .008) and to sertraline alone
child does not also meet the criteria for one (p = .006), which did not differ from each
of the DSM-IV-TR anxiety disorders dis- other. The response rates for the four groups
cussed above. were 53.5% for the combined group, 39.3%
for the CBT group, 21.4% for the sertraline
group, and 3.6% for the placebo group. It is
Treatment not clear why the sertraline group response
rate was so much lower in the POTS study
Over the last two decades, both psychophar- than the 53% response rate in the earlier
macological and psychosocial interventions study (March et al., 1998). It should be also
(particularly cognitive-behavioral therapy noted that the placebo group response rate
[CBT]) have been the focus of large-scale, was substantially lower in this study than in
well-designed randomized controlled trials all the others. There were site differences in
(RCTs) in children and adolescents. These terms of the CBT response rate; that is, CBT
studies have extensively documented their ef- was more efficacious in some localities than
ficacy relative to placebo or waiting-list con- in others, suggesting differences in culture
trols, giving the modern clinician a potent or therapist characteristics that affected the
armamentarium to treat these disorders. outcome. A meta-analysis of 12 studies of
SSRIs in OCD showed a highly significant
difference between drug and placebo (Geller
Selective Serotonin
et al., 2003b), with no difference among the
Reuptake Inhibitors
various SSRIs.
The SSRIs fluoxetine, sertraline, fluvoxam- SSRIs have also been studied in non-OCD
ine, and paroxetine have all been the foci of anxiety disorders, though controlled stud-
large-scale RCTs in the treatment of child ies are less numerous than for OCD. In a
and adolescent OCD (Reinblatt & Riddle, large-sample study, children and adolescents
2007). March and colleagues (1998) ran- with GAD were randomly assigned to either
domly assigned 187 children or adolescents fluvoxamine or placebo for 8 weeks; the ac-
to placebo or sertraline (mean daily dose tive drug was found to be markedly supe-
167 mg) and found that 53% responded to rior to placebo (76% vs. 29%) (Walkup et
sertraline versus 37% to placebo. Fluoxetine al., 2001). Birmaher and colleagues (2003)
was superior to placebo (49% vs. 25% at a found 20 mg/day of fluoxetine superior to
mean dose of 25 mg/day) in adolescents with placebo in 74 children with a variety of non-
OCD (Geller et al., 2001). In another study, OCD diagnoses (61% vs. 35%). Ninety per-
Liebowitz and colleagues (2002) found that cent of children and adolescents with GAD
57% of subjects with OCD responded to flu- randomly assigned to sertraline responded,
oxetine versus 32% to placebo. Fluvoxamine compared with a mere 10% in the placebo
(mean dose 165 mg/day) was superior to pla- group (Rynn, Siqueland, & Rickels, 2001).
cebo (42% vs. 26%) in a 10-week RCT (Rid- Wagner and colleagues (2004) found par-
dle et al., 2001). Paroxetine was the subject of oxetine superior to placebo in subjects ages
two large RCTs (Geller et al., 2003a, 2004); 8–17 years who had social phobia. Most re-
both showed the superiority of the active cently, a major study randomly assigned 488
drug to placebo. The Pediatric OCD Treat- children with a variety of anxiety disorders
ment Study (POTS) Team (2004) randomly to treatment with sertraline, CBT, combined
assigned 112 subjects to CBT alone, sertra- treatment, or placebo (Walkup et al., 2008).
line alone, combination treatment, or placebo The proportions of responders were 80.7%
for combination therapy, 59.7% for CBT, the possibility of increased thoughts of self-
and 54.9% for sertraline, with all therapies harm before the patients are started on any
being superior to placebo (23.7%). Combi- antidepressant (see “Individualizing Treat-
nation therapy was superior to both mono- ment,” below).
therapies.
The number needed to treat (NNT) is the
Cognitive-Behavioral Treatment
number of patients who need to be treated
in order to prevent one additional bad out- Kendall (1993) theorized that childhood
come (95% chance that at least one patient anxiety is based on cognitive distortions:
has responded above the placebo rate). In “Anxious children seem preoccupied with
the above-reviewed studies, the NNT was concerns about evaluations by self and oth-
2–6, indicating significant efficacy. All these ers and the likelihood of severe negative con-
studies reported side effects of agitation, in- sequences. They seem to misperceive charac-
somnia, gastrointestinal upset, and suicidal teristically the demands of the environment
ideation. In a meta-analysis examining the and routinely add stress to a variety of
effects of antidepressants in both anxious situations” (p. 239). CBT promotes chang-
and depressed children and adolescents, ing negative cognitions in conjunction with
Bridge and colleagues (2007) found that using behavior therapy techniques known to
the SSRIs had better-established efficacy in decrease anxiety. Kendall’s CBT approach,
non-OCD anxiety disorders, with interme- which requires 16–20 sessions, is summa-
diate efficacy for OCD, whereas the efficacy rized in Table 10.4. CBT has become the best-
for MDD was more limited. In terms of sui- validated psychosocial intervention for the
cidal ideation, the number needed to harm treatment of child and adolescent anxiety; it
(NNH, the opposite of NNT) was 143, has been the focus of several meta-analyses
clearly showing that the cost–benefit ratio is and reviews in the last decade (Cartwright-
in favor of treating anxiety disorders with Hatton, Roberts, Chitsabesan, Fothergill, &
SSRIs. Nonetheless, in line with the Food Harrington, 2004; James, Soler, & Weath-
and Drug Administration’s boxed warning erall, 2005; Munoz-Solomando, Kendall,
in the package inserts of all antidepressants, & Whittington, 2008). In non-OCD, non-
parents and patients should be warned about phobic anxiety, the pooled response rate
TABLE 10.4. Cognitive-Behavioral Therapy (CBT) According to Kendall’s Model

Session 1 Build rapport; collect information on situations that promote anxiety and on how the
child responds to the anxiety.
Session 2 Teach child to identify different types of feelings.
Session 3 Rank-order anxiety-provoking situations. Help child distinguish anxiety response from
other types of emotions.
Session 4 Relaxation training; give child personalized audiocassette for use outside of sessions.
Session 5 Teach child to modify self-talk (replace negative with positive) and use self-talk to reduce
anxiety.
Session 6 Emphasize coping self-talk and verbal self-redirection.
Session 7 Teach child to self-evaluate and self-reward positive, nonanxious coping responses.
Session 8 Review all of the skills above.
Session 9 Have child practice skills and watch therapist model handling anxiety; use role playing to
rehearse handling anxiety-provoking situations.
Sessions 10–15 Expose child to real and imagined anxiety-provoking situations. Continue practice.
Session 16 Termination issues; discuss therapy experience; encourage the child to consider how to
use new coping skills in everyday life.
to CBT was 56.5% compared to 34.8% in alone, whereas CBT and medication alone
no-treatment controls (Cartwright-Hatton appear to have equal efficacy (Walkup et al.,
et al., 2004). Similar results (56% for CBT, 2008). Thus clinicians have a great deal of
28.2% for controls) were found in a sub- flexibility in determining a treatment plan,
sequent meta-analysis (James et al., 2005). and family preferences can be taken into ac-
Four controlled studies (N = 222 subjects) count. It is perfectly reasonable for a clini-
using CBT for treatment of OCD were in- cian to choose CBT alone if the family does
cluded in a meta-analysis, but the POTS not wish to have their child on medication.
results reviewed earlier were viewed as the Conversely, some families and children find
best estimate for the effect size of this mo- CBT difficult or do not have the resources to
dality (O’Kearney, Anstey, & von Sanden, pursue it regularly, and medication alone is
2006). The response rates of anxiety disor- a good treatment option in such situations.
ders of childhood and adolescents are com- Also, when a child has spontaneous panic at-
parable to those for SSRIs, and the studies tacks or separation anxiety with physiologi-
reviewed above also favor the superiority of cal arousal, medication treatment is some-
combined medication and CBT over either times necessary as a first step just to stabilize
modality alone. the child so that the therapist can work with
When CBT was compared to education him or her. If a child has not responded to
support for youth with school refusal (sepa- 6–10 weeks of monotherapy with either CBT
ration anxiety), both treatments were equally or an SSRI, then combined therapy should
efficacious (Last, Hansen, & Franco, 1998). be strongly considered.
Silverman and colleagues (1999) random-
ly assigned 81 children with phobia to an
Neuroimaging Effects of Treatment
exposure-based contingency management
treatment condition, an exposure-based One of the more exciting recent developments
cognitive self-control treatment condition, has been work showing how the brain chang-
or an education support control condition. es both anatomically and physiologically in
Whereas both exposure-based treatments response to either pharmacotherapy or CBT.
were superior to education support at the end CBT and paroxetine appear to have differ-
of the 10-week intervention, all the groups ent effects on brain functioning in children
were equally improved at the 3-, 6-, and 12- and adolescents with OCD. Twelve weeks
month follow-ups. This raises the issue as to of paroxetine reduced glutamate/glutamine
whether CBT is in fact superior to other psy- caudate concentrations as well as thalamic
chosocial interventions or nonspecific social volume to levels seen in controls (Gilbert
support. Recently, Hudson and colleagues et al., 2000; Rosenberg, McMaster, et al.,
(2009) randomly assigned 112 children with 2000)—effects not seen in a separate sample
anxiety disorders (ages 7–16 years) to either of children treated with OCD with cogni-
group CBT or an attention control group for tive therapy alone, despite an equally good
10 sessions. Parents attended the groups as response of symptoms (Benazon, Moore, &
well. CBT was superior to the control group Rosenberg, 2003; Rosenberg, Benazon, Gil-
in reducing anxiety at follow-up; 6 months bert, Sullivan, & Moore, 2000). Thus the
after treatment, the children receiving CBT brain changes were associated with response
had a remission rate of 69% (vs. 45% of in one form of treatment but not in another,
those who received the attention control), suggesting different biological routes to re-
suggesting that CBT yields specific benefits covery. Paroxetine has been shown to alter
over supportive therapy. CBT has also been amygdala volume symmetry (Szeszko et al.,
provided in school-based and family contexts 2004). In another study, patients with OCD
(Bernstein, Bernat, Victor, & Layne, 2008; had less gray matter bilaterally in the PFC
Creswell & Cartwright-Hatton, 2007). at baseline than controls did, but after 6
months of paroxetine treatment, there was a
trend for gray matter volume to be increased
Individualizing Treatment
in the patient group (Lazaro et al., 2006). In
The studies reviewed above suggest that the future, such studies may lead to a better
combining CBT with medication yields a understanding of why some patients do not
success rate better than either modality respond to treatment.
Conclusion and nonanxious individuals: A meta-analytic

study. Psychological Bulletin, 133, 1–24.
Our understanding of the nature and treat- Battaglia, M., Bajo, S., Strambi, L. F., Brambilla, F.,
ment of anxiety disorders in children and Castronovo, C., Vanni, G., et al. (1997). Physi-
ological and behavioral responses to minor stres-
adolescents has increased greatly in the last sors in offspring of patients with panic disorder.
decade. Genetic factors account for about Journal of Psychiatric Research, 31, 365–376.
one-third of the variance in anxiety symp- Battaglia, M., Ogliari, A., Zanoni, A., Citterio, A.,
toms, but multiple genes are likely to be in- Pozzoli, U., Giorda, R., et al. (2005). Influence
volved. Furthermore, these genes most likely of the serotonin transporter promoter gene and
exert their effects through endophenotypes, shyness on children’s cerebral responses to facial
such as emotional dysregulation, attention expressions. Archives of General Psychiatry, 62,
bias to threatening stimuli, or BI. Thus en- 85–94.
vironmental factors can exert their effects in Beidel, D. C., & Turner, S. M. (1997). At risk for
anxiety: I. Psychopathology in the offspring of
the development of the endophenotype itself,
anxious parents. Journal of the American Acad-
and then again in combining with the endo- emy of Child and Adolescent Psychiatry, 36,
phenotype to bring about the full disorder. 918–924.
Most encouraging has been the development Benazon, N. R., Moore, G. J., & Rosenberg, D.
of evidence-based treatments such as CBT R. (2003). Neurochemical analyses in pediatric
and SSRIs. Intriguingly, in children and obsessive–compulsive disorder in patients treated
adolescents, the evidence for the efficacy of with cognitive-behavioral therapy. Journal of the
SSRIs is stronger in anxiety disorders than in American Academy of Child and Adolescent Psy-
depressive disorders. Nonetheless, caution is chiatry, 42, 1279–1285.
warranted in treating anxious children and Benjamin, R. S., Costello, E. J., & Warren, M.
(1990). Anxiety disorders in a pediatric sample.
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patients and their families. Future advances Layne, A. E. (2008). School-based interventions
in genetics and neuroimaging may lead to for anxious children: 3-, 6-, and 12-month follow-
even more effective pharmacological and ups. Journal of the American Academy of Child
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lescent Psychiatry, 42, 814–825. Young, S. E., Smolen, A., Stallings, M. C., Corley,
Weissman, M. M., Wickramaratne, P., Nomura, Y., R. P., & Hewitt, J. K. (2003). Sibling-based as-
Warner, V., Pilowsky, D., & Verdeli, H. (2006). sociation analyses of the serotonin transporter
Offspring of depressed parents: 20 years later. polymorphism and internalizing behavior prob-
American Journal of Psychiatry, 163, 1001– lems in children. Journal of Child Psychology
1008. and Psychiatry, 44, 961–967.
C h a p t e r 11
Mood Disorders
Susan M. Swearer
Cixin Wang
Jami Givens
Brandi Berry
Dawn Reinemann
According to the Diagnostic and Statisti- interest or pleasure almost all the time, over
cal Manual of Mental Disorders, fourth at least 2 weeks of time. For children and ad-
edition, text revision (DSM-IV-TR; Ameri- olescents, their mood can be irritable rather
can Psychiatric Association [APA], 2000), than depressed. Children and adolescents
mood disorders are predominantly charac- must also experience at least four additional
terized by disturbances in affect, including symptoms to meet the criteria, including sig-
depressed and/or manic states. Depressive nificant weight loss, insomnia or hypersom-
disorders include major depressive disor- nia, psychomotor agitation or retardation,
der (MDD), dysthymic disorder (DD), and loss of energy, feelings of worthlessness or
depressive disorder not otherwise specified excessive guilt, inability to concentrate, and
(DDNOS). These three depressive disorders suicidal ideation. Symptoms of DD are less
differ in the number of symptoms required severe than those of MDD; however, symp-
to meet the diagnostic criteria, as well as toms must exist over a longer period of time
the severity and duration of the symptoms (at least 1 year for children and adolescents,
(APA, 2000; Reinemann & Swearer, 2005). and 2 years for adults). DD is characterized
Bipolar disorders include full-blown bipo- by chronic and persistent mood disturbance,
lar disorder (bipolar I) and the milder and including depressed mood (or irritable mood
perhaps more common forms of bipolar dis- for children and adolescents) and at least
order (bipolar II, cyclothymic disorder, and two additional depressive symptoms. For
bipolar disorder NOS) (Akiskal & Mallya, children and adolescents, any symptom-free
1987). period during the 1-year period of dysthy-
mic symptoms should be no longer than 2
months and should be free of MDEs. When
Background and History some symptoms of mood disturbance exist,
but the youth does not meet the criteria for
Diagnostic Criteria
MDD or DD, a diagnosis of DDNOS may
MDD is characterized by one or more major be used (APA, 2000; Stark, Sander, et al.,
depressive episodes (MDEs) without a histo- 2006).
ry of manic, mixed, or hypomanic episodes Bipolar disorders are characterized by the
(APA, 2000). The main features of MDEs occurrence of manic or mixed episodes (bi-
are the presence of depressed mood or loss of polar I) or hypomanic episodes (bipolar II)
209
in addition to MDEs (APA, 2000). The main (Kessler, 2002); different compositions of
features of manic episodes include persis- the samples (e.g., in terms of age and ethnic-
tently elevated, expansive, or irritable mood ity); and different time intervals examined.
for at least a week, and three or more other Studies using point prevalence and a shorter
symptoms, including grandiosity, pressure to interval, such as a 3-month interval, usually
talk, decreased need for sleep, flight of ideas, show lower prevalence rates than studies
distractibility, increase in goal-directed be- using longer intervals (12 months or more)
havior, and excessive involvement in pleasur- (Costello, Egger, & Angold, 2004). Studies
able activities with high risk for painful con- on point prevalence of MDD have shown
sequences. Hypomanic erpisodes are shorter that the current rates of depression are usual-
(at least 4 days) and less severe than manic ly less than 1% among children (reviewed by
episodes. If children present with hypoman- Merikangas & Angst, 1995), and vary from
ic symptoms and depressive symptoms, but 1.2% to 6% among adolescents (reviewed by
these are not sufficient or severe enough to Kessler, Avenevoli, & Merikangas, 2001).
meet full criteria for a manic episode or an The Methods for Epidemiology of Child and
MDE, a diagnosis of cyclothymic disorder Adolescent Mental Disorders Study found
may be given (if other criteria are also met). that the current prevalence rate of major
If children present with bipolar features but depression among youths ages 9 through 17
do not meet criteria for any bipolar disorder, years was 4.8% (Lahey et al., 1996). Studies
a diagnosis of bipolar disorder NOS may on adolescents from clinic samples usually
be used. The diagnosis of bipolar disorders show higher prevalence rates of depression,
among children and adolescents is difficult ranging from 13% to 61% (e.g., Hodge &
because bipolar disorders in youth present in Siegel, 1985; Peterson et al., 1993).
a very different way from the classic cycles According to DSM-IV-TR (APA, 2000),
of manic and depressive episodes often seen the lifetime prevalence rates for bipolar
among adults (Geller & DelBello, 2003). disorders in the general population are as
Children and adolescents usually experience follows: from 0.4% to 1.6% for bipolar I
rapid mood changes (e.g., mood and energy disorder, approximately 0.5% for bipolar II
shifts as frequent as several times within a disorder, and from 0.4% to 1% for cyclothy-
day). As a result, most children do not meet mic disorder. Most epidemiological studies
the duration criteria (4–7 days) for bipolar I have focused on adults, and fewer studies
or bipolar II disorder in DSM-IV-TR (Bir- have been conducted with younger popu-
maher, 2007). lations. Most epidemiological studies also
rely on youth self-reports instead of clinical
interviews, which may lead to an underesti-
Prevalence mation of the prevalence of bipolar disorders
(Youngstrom, Findling, Youngstrom, & Ca-
The results on the prevalence rates of child- labrese, 2005). Studies using clinical inter-
hood and adolescent depression vary (see views among children and adolescents have
Table 11.1). Angold, Costello, and Erkanli shown that the prevalence of bipolar I disor-
(1999) conducted a review of 21 popula- der ranges from approximately 1% to 1.5%
tion-based studies published between 1987 (Kashani et al., 1987; Lewinsohn, Klein, &
and 1997 on children and adolescents, and Seeley, 1995, 2000) in community samples.
found that the prevalence rate (3-month to The prevalence of bipolar I disorder is higher
12-month) of depressive disorders (including (6–22%) among clinical samples and incar-
MDD and DD) varied from 0.3% to 8%. cerated adolescents (Biederman et al., 1996;
Other recent studies suggest that rates of de- Pliszka, Sherman, Barrow, & Irick, 2000).
pressive disorders among adolescents range
from 2.6% to 24% (Costello, Mustillo,
Erkanli, Keeler, & Angold, 2003; Garber, Developmental Course
2000; Lewinsohn, Clarke, Seeley, & Rohde,
1994; Riolo, Nguyen, Greden, & King, 2005; The age of onset for an initial MDE varies
Rushton, Forcier, & Schectman, 2002). The across studies (Merikangas & Angst, 1995).
large variation in prevalence rates may be The age of onset for MDD varies from child-
due to different assessment methods used hood to adulthood, with an average age in
Mood Disorders 211
TABLE 11.1 Prevalence Rates of Youth Mood and Depressive Disorders

Bipolar
Ages of MDD DD disorders
Authors youth Diagnostic prevalence prevalence prevalence
Study (date) (years) Source criteria % % %
NCS Kessler et 15–18 National DSM-III-R/ 14.1 lifetime
al. (1994) UM-CIDI1
NHANES III Jonas et al. 17–19 National DSM-III/ 7.2 lifetime 4.7
(2003) DIS (MDE) lifetime
MECA Lahey et al. 9–17 National DSM-III-R 4.8 point

(1996)
Whitaker et 14–17 High DSM-III, 4.0 lifetime 4.9
al. (1990) school clinical lifetime
interview
Lewinsohn 14–18 High DSM-III-R, 18.4 lifetime 3.2
et al. (1991) school K-SADS-E 2.9 point lifetime
Lewinsohn 14–18 High DSM-III-R, 2.57 point 0.53 point
et al. (1993) (grades school K-SADS-E, 3.12 point 0.13 point
9–12) LIFE 18.48 3.22
lifetime lifetime
24.01 2.98
lifetime lifetime
Lewinsohn 14–18 DSM-III-R, 18.49 0.53–0.64
et al. (1995) K-SADS lifetime point;
0.94–0.95
lifetime
Lewinsohn 15–18 DSM-IV, 18.25 1.12
et al. (2000) K-SADS-PL lifetime lifetime
Note. The studies are selected if structured diagnostic interviews were used and if the studies were published between
1989 and 2009. NCS, National Comorbidity Survey; DSM-III-R/UM-CIDI, diagnosis based on DSM-III-R criteria and
made with a modified version of the Composite International Diagnostic Interview; NHANES III, Third National Health
and Nutrition Examination Survey; DSM-III/DIS, diagnosis based on DSM-III criteria and made with the Diagnostic
Interview Schedule; MECA, Methods for Epidemiology of Child and Adolescent Mental Disorders Study; K-SADS-E,
Schedule for Affective Disorders and Schizophrenia for School-Age Children, Epidemiologic Version (Chambers et al.,
1985); K-SADS-PL, Present and Lifetime Version of the K-SADS; LIFE, Longitudinal Interval Follow-Up Evaluation
(Shapiro & Keller, 1979).
the mid-20s. DD tends to have an earlier polar disorders is related to increased fre-
onset (APA, 2000). In general, depression is quency of mood swings, longer duration of
very rare during childhood, but after age 12 illness (Suppes et al., 2001), and lower global
the prevalence rate increases (Merikangas functioning (Wozniak et al., 1995).
& Angst, 1995). This is discussed further The average length of MDD among ado-
below. lescents is about 8–9 months, and the length
Evidence has shown that bipolar disorders of DD ranges from 3 to 4 years (Stark,
may first occur during childhood or adoles- Sander, et al., 2006). Patients with untreated
cence. Retrospective studies show that most MDD can remain symptomatic for up to 24
adults with bipolar disorders (20–65.3%) months (Ingram, Miranda, & Segal, 1998).
reported experiencing symptoms during Most children and adolescents do not meet
childhood and adolescence. In a community the criteria for depressive disorders after 1 or
sample, the mean age of onset for the first 2 years (Kendall, 1993). However, not meet-
episode was 11.75 years for children with ing the criteria for depressive disorders does
bipolar disorders (Lewinsohn et al., 1995). not mean the absence of depressive symp-
Some studies suggest that early onset of bi- toms, and adolescents may continue to show
some symptoms of depression. Research has children who have early-onset depression
reported that recurrence of depressive symp- with other comorbid disorders (see Kessler
toms is common among adolescents (Rein- et al., 2001, for a review). However, only
emann & Swearer, 2005). In one study, ado- a small portion (9%) of those children and
lescents with bipolar disorders had longer adolescents who experienced MDD during
symptom duration and more mixed cycling their early years continue to experience it as
episodes than adults with these disorders adults (Lewinsohn, Rohde, Seeley, Klein, &
had (Birmaher et al., 2006). Another study Gotlib, 2000).
showed that the duration of bipolar disor-
ders ranged from 0.7 to 125 months, with
a mean of 50 months (Lewinsohn et al., Genetics and Family Patterns
1995). Studies show that between 37% and
70% of adolescents with bipolar disorders Evidence suggests that family influences,
recover from the initial episode after 1–2 such as maternal depression, may contribute
years (Birmaher et al., 2006; Geller, Craney, to the development of depression via genetic
et al., 2001; Geller et al., 2002); however, as well as environmental factors (Burge &
the relapse rates are also high, ranging from Hammen, 1991). Similar findings suggest
approximately 23% to 80% (Birmaher et that genetic influences as well as environ-
al., 2006; Geller, Craney, et al., 2001; Geller mental factors appear to contribute to risk
et al., 2002; Pavuluri, Birmaher, & Naylor, for developing bipolar disorders (Du Rocher
2005). Schudlich, Youngstrom, Calabrese, & Fin-
Researchers suggest that the basic charac- dling, 2008). Thus, in the quest to identify
teristics of depression are similar in children, factors and events that may cause or contrib-
adolescents, and adults (e.g., APA, 2000; ute to the development of mood disorders,
Stark, Sander, et al., 2006), but that the fre- both genetic and environmental factors must
quency of the common depressive symptoms be explored.
changes with age. Adolescents typically dis- Some identified risk factors appear to be
play more anhedonia, hopelessness, hyper- largely environmental. Maternal stress as
somnia, and weight change; children report well as harsh parenting and discipline, for
more somatic complaints and agitation, and instance, were found to be risk factors for
present with a depressive appearance (Kend- both internalizing and externalizing prob-
all, 1993; Nurcombe, 1992). lems in children (Bayer, Hiscock, Ukomune,
Studies have also shown that the prevalence Price, & Wake, 2008). Furthermore, having
rate of depressive disorders increases during a single parent and/or experiencing parental
adolescence (Cantwell, 1990; Costello et al., conflict also predicted children’s develop-
2003; Hankin et al., 1998; Lewinsohn et al., ment of internalizing problems. In addition,
1994; Reinemann & Swearer, 2005). Using a review of the literature by Wells, Deykin,
a structured diagnostic interview in a lon- and Klermin (1985) concluded that parental
gitudinal study, researchers found that the loss through death or separation was also a
lifetime prevalence of depressive disorders salient risk factor for depression. Endrass
increased from 1.07% to 5.66% during ages and colleagues (2007) found that a his-
11–15, and then jumped to 20.67% at age tory of problematic social behavior, such as
18. The peak (lifetime prevalence of depres- truancy and running away from home, in-
sion and new onset of depression) occurred creased one’s risk of developing bipolar II
between ages 15 and 18 (Hankin et al., disorder—perhaps by increasing one’s expo-
1998), which was hypothesized to coincide sure to stressful life events such as negative
with pubertal changes. Similarly, in a ran- consequences for those behaviors. Low pa-
domly selected sample of 1,710 high school rental financial status was also found to be a
students, researchers found that older ado- risk factor for the development of bipolar II
lescents were more likely than younger ado- disorder, increasing risk by over 90%.
lescents to have a diagnosis of DD (Lewin- Other risk factors for the development of
sohn, Hops, Roberts, Seeley, & Andrews, mood disorders appear to stem predomi-
1993). nantly from genetic factors. In one study, a
Longitudinal studies have shown conti- family history of depression was found to be
nuity in depression over time, especially in a risk factor for the development of depres-
Mood Disorders 213
sion (Angst, Gamma, & Endrass, 2003). In environmental contributions of specific dis-
fact, following the conclusion of a literature orders. Thus, both are usually necessary to
review on depression, Wells and colleagues determine whether a disorder is heritable,
(1985) identified parental mental illness and/ and if so, to what extent it is being passed
or alcoholism as the strongest risk factors on via genetic versus environmental factors.
for depression. In addition, parents’ mood One family study interviewed probands
disorders have been found to be significantly with and without a diagnosis of DD, chronic
related to their children’s development of bi- MDD, or episodic MDD, as well as one or
polar disorders, depression, and/or opposi- more relatives, across three time periods to
tional defiant disorder (Du Rocher Schudlich screen for psychopathology (Klein, Shank-
et al., 2008). Furthermore, family histories man, Lewinsohn, Rohde, & Seeley, 2004).
of bipolar disorders as well as generalized The relatives of probands with either type
anxiety disorder were found to predict bipo- of depression exhibited significantly high-
lar II disorder (Endrass et al., 2007). er rates of MDD than did the relatives of
It has been noted that familial psychopa- probands without a diagnosis of a mood
thology may be the result of genetic influenc- disorder. Relatives of probands with chronic
es, environmental factors, or both (Althoff, MDD or DD were 40% more likely to exhib-
Faraone, Rettew, Morley, & Hudziak, it MDD than were the relatives of probands
2005). In fact, genetic factors may influence with episodic MDD. Thus it appears that de-
one’s environment, and the environment pression, especially chronic forms of depres-
may have an impact on physiology. Reiss sion, is familial.
(2008) has described three potential ways in Bipolar I disorder also appears to be fa-
which parental depression may be transmit- milial, given one study’s finding that a mo-
ted to children. First, the parent may pass on nozygotic twin of a proband with bipolar I
genes that cause or contribute to depression disorder was 60 times more likely to develop
in the child. However, a parent’s depression bipolar I disorder than members of the gen-
may also undermine his or her parenting eral population were (Craddock, Khodel,
style, thus affecting the child’s environment. Van, & Reich, 1995, as cited in Potash &
Finally, a depressed mother may expose her DePaulo, 2000). First-degree relatives of a
fetus to high levels of cortisol, affecting proband with bipolar I disorder were 7 times
the fetus’s hypothalamic–pituitary–adrenal more likely to develop bipolar I disorder
axis. Thus stressful environmental factors than were members of the general popula-
may affect a mother’s cortisol levels, which tion. Both of these findings suggest a strong
may then have an impact on her fetus. In ad- degree of family factors for bipolar I disor-
dition to these three possibilities, a parent’s der. As previously discussed, however, stud-
genetic makeup may affect the way that par- ies on family influences yield little informa-
ent behaves, which may influence the child’s tion on the contributions of genetic versus
environment. This dynamic appeared in Du environmental factors; thus adoption stud-
Rocher Schudlich and colleagues’ (2008) ies are necessary to tease apart these effects
study, which found that parents’ mood dis- more clearly.
orders were correlated with increased con- An adoption study that explored environ-
flict and impaired family functioning, which mental contributions to the development
then contributed to children’s development of adolescent depression involved admin-
of bipolar disorders. Thus separating genetic istering clinical interviews to 568 adopted
and environmental contributors is a difficult adolescents, 416 nonadopted adolescents,
and complicated process. and their parents (Tully, Iacono, & McGue,
To begin teasing these factors apart, family 2008). These interviews assessed lifetime
and adoption studies have been conducted to diagnoses of MDD. For both sets of adoles-
investigate genetic as well as environmental cents, maternal but not paternal depression
influences of risk. As Althoff and colleagues was associated with a higher risk of develop-
(2005) describe, family studies may help ing MDD and disruptive behavior disorders.
determine whether a disorder is heritable, Thus Tully and colleagues (2008) concluded
but they yield little information on genetic that environmental factors elevate the risk
effects. Adoption studies yield clearer infor- that adolescents will develop MDD and/
mation on the magnitude of genetic versus or disruptive behavior disorders in families
with depressed mothers, whether or not the amine the link between frontal asymmetry
mothers are biologically related to the ado- of EEG alpha power (FA) and risk for the de-
lescents. velopment of depression and anxiety (Smit,
Contrary to Tully and colleagues (2008), Posthuma, Boomsma, & De Geus, 2006).
who found powerful evidence for the con- The results showed that FA was only herita-
tribution of environmental factors in the ble during young adulthood and was higher
development of depression, Mendlewicz for females than for males. A gender differ-
and Rainer (1977) found evidence sug- ence was also found in the link between FA
gesting that genetics play a powerful role and depression/anxiety; that is, a significant
in the transmission of bipolar disorder. In relationship was only found for females.
this study, biological and adoptive parents Thus, FA may be a valid endophenotype for
of adoptees with manic–depressive disor- females in young adulthood.
der, now known as bipolar disorder, were In yet another study, a genome-wide link-
interviewed. The investigators found that age scan explored chromosomes that may
the biological parents showed higher rates contain genes that contributing to the de-
of psychiatric illness than the adoptive par- velopment of early-onset, recurrent MDD
ents did. However, as Althoff and colleagues (Holmans et al., 2007). The results of the
(2005) noted, there have been few adoption evidence gathered from 656 families with
studies of any mood disorder, and there have two or more such cases showed that regions
been no adoption studies of pediatric bipolar of 8p, 15q, and 17p may contain such genes.
disorders. Some of the studies that have been A similar study done by Levinson and col-
undertaken have become quite dated, while leagues (2007) examined DNA markers
others still struggle to separate the effects of on chromosomes 15q25–26 for 631 fami-
genetic versus environmental factors. Thus, lies, and found modestly positive evidence
more research is clearly needed to identify in favor of a link between genes in these
the extent to which genetic and environmen- chromosomal regions and susceptibility to
tal factors contribute to the development of MDD.
mood disorders in children and adolescents. Similar studies have been conducted to
explore biological and neuropsychological
markers of bipolar disorders. Frampton,
Biological and Allen, and Cross (2008) used a variety of
Neuropsychological Markers tests to assess the neurocognitive functioning
of three groups of participants: those with
The etiology of mood disorders is largely first-degree relatives with bipolar disorders
unknown (Zhang, Hauser, Conty, Emrich, who also had diagnoses of bipolar disorder
& Dietrich, 2007). To yield more informa- (referred to in this study as the BP group);
tion on potential contributors to depression, those with first-degree relatives with bipolar
Zhang and colleagues (2007) assessed the disorder who did not have the disorder them-
behavioral and electrophysiological char- selves (who composed the FD group); and in-
acteristics of healthy individuals with and dividuals without bipolar disorder or a fam-
without familial risk for depression. Those ily history of it (who made up the NC group).
with high risk for depression due to family Though this finding was not significant, the
history showed greater accuracy but slower NC group generally tended to perform better
speed than individuals at lower risk due to than the FD group, who in turn performed
lack of family history did. High-risk individ- better than the BP group. Even after the in-
uals also showed significantly reduced P3b vestigators controlled for mood symptoms,
amplitudes over left temporal areas, com- the NC group outperformed the BP and FD
pared to low-risk individuals. Thus P3b, a groups on the visual–spatial/constructional
component of event-related potentials, may domain, which was assessed via tests such as
be a neurocognitive marker of vulnerability the Wechsler Block Design subtest and the
for the development of depression. Judgment of Line Orientation test. Further-
Another study exploring markers of de- more, the BP group performed significantly
pression involved administering electroen- worse than the FD and NC groups on the
cephalograms (EEGs) and questionnaires Wechsler Digit Symbol subtest. Thus deficits
to assess for depression and anxiety in 732 on these neuropsychological tests may be en-
twins and nontwin siblings, in order to ex- dophenotypes for bipolar disorder.
Mood Disorders 215
In another study, a genome-wide linkage certain cultures, depressive symptoms may

scan was conducted to explore genes that be demonstrated in terms of somatic com-
may contribute to susceptibility to the de- plaints instead of depressed mood. Depres-
velopment of bipolar disorders (Zandi et al., sive experiences may be expressed in terms
2007). Participants with or without a major of an “imbalance” of internal energy in Chi-
mood disorder were genotyped, and evi- nese and some Asian cultures, headaches in
dence showed that chromosomes 2q24 and Hispanic and Mediterranean cultures, and
3q28 may contain such genes; however, the problems of the “heart” in Middle Eastern
findings were not significant. A review of the cultures (APA, 2000). The prevalence of de-
literature led Althoff and colleagues (2005) pressive disorders may be different among
to identify chromosomes 12p, 14q, and 15q cultures as well. Some Asian cultures, such
as potentially containing genes that contrib- as China, Japan, and Taiwan, have been
ute to early-onset bipolar disorder. Althoff found to have lower prevalence rates of de-
and colleagues concluded that an early onset pressive disorders than those in Western
of bipolar disorder may be connected with cultures among adults (Bland, 1997; Hwu,
greater familial risk to relatives. Further- Chang, Yeh, Chang, & Yeh, 1996; Simon,
more, it was hypothesized that early-onset Von Korff, Picvinelli, Fullerton, & Ormel,
bipolar disorder may be a more severe form 1999), as well as among adolescents (Doi,
or separate form of bipolar disorder. Roberts, Takeuchi, & Suzuki, 2001).
There is some evidence that adolescents
from ethnic minority groups may experi-
Risk Factors ence more depressive symptoms than Eu-
for Phenotypic Expression ropean American adolescents do (Rush-
ton et al., 2002). Studies on mental health
Gender
outcomes among children and adolescents
Research has found no gender differences in have shown that African American youth
depression between boys and girls before the (Brown, Meadows, & Elder¸ 2007; Gore
onset of puberty (e.g., Speier, Sherak, Hirsch, & Aseltine, 2003) and Hispanic American
& Cantwell, 1995). However, during adoles- youth reported more depressive symptoms
cence, more girls are diagnosed with depres- than European Americans did (Brown et
sive disorders than boys (Cantwell, 1990; al., 2007; Gore & Aseltine, 2003; Siegal,
Hankin et al., 1998; Lewinsohn et al., 1993, Aneshensel, Taub, Driscoll, & Cantwell,
1994; McGee, Feehan, Williams, & Ander- 1998). Epidemiological studies have also
son, 1992; Reinemann & Swearer, 2005). shown that the prevalence of MDD is higher
The gender difference seems to emerge be- among African American youth (Doi et al.,
tween ages 13 and 15 (Ge, Conger, & Elder, 2001) and Hispanic American youth (Doi
2001; Hankin et al., 1998). This gender dif- et al., 2001) than among European Ameri-
ference continues into adulthood, with the can youth. Some researchers suggest that
prevalence of depression being twice as high the ethnicity differences may be attributable
among women as among men. For bipolar to the socioeconomic differences among
disorders, gender differences have been less different ethnic groups. In one study, the
studied, and no clear gender difference in the significant association between adolescent
prevalence of bipolar I has been document- depression and ethnicity disappeared after
ed (APA, 2000). Bipolar II disorder may be the investigators controlled for sociodemo-
more common in women than in men (APA, graphic variables such as family income and
2000); however, there is no empirical sup- parental education (Doi et al., 2001). How-
port for this difference among children and ever, another study showed that the ethnic
adolescents. difference between Hispanic Americans
and European Americans still existed even
after the researchers controlled for socio-
Ethnic, Cultural,
economic differences (Siegel et al., 1998). It
and Socioeconomic Differences
is possible that higher depressive symptoms
Recent studies have shown that the ex- among minority groups reflect their greater
perience and interpretation of depressive exposure to challenging social conditions,
symptoms are likely to be different among such as ongoing stressors, above and beyond
different cultural and ethnic groups. In the common measure of socioeconomic sta-
tus (Siegal et al., 1998). Limited epidemio- The assessment of pediatric bipolar disor-
logical data from community samples do ders is less well defined. Psychology as a field
not support significant racial differences in has been skeptical of diagnosing children and
the prevalence of bipolar disorders among adolescents with bipolar disorders, and this
children and adolescents (Lewinsohn et al., skepticism has probably decreased efforts
1995; Lewinsohn, Klein, & Seeley, 2000). to establish accurate assessment strategies.
The effects of socioeconomic factors, such However, these disorders can only be cor-
as family income and parental educational rectly diagnosed through careful assessment,
level, on adolescent depression have also which will in turn decrease the risk of over-
been documented (Doi et al., 2001; Siegal diagnosing disorders that appear to be recent
et al., 1998). Children and adolescents from “trendy” conditions. A differential diagno-
low-income families are at greater risk for sis is also difficult, as few assessment strat-
experiencing stressful life events, which may egies for the diagnosis of pediatric bipolar
lead to higher rates of mood disorders (Rein- disorders have been designed (Youngstrom,
herz, Giaconia, Lefkowitz, Pakiz, & Frost, 2007). Diagnosis is further complicated by
1993; Siegal et al., 1998). symptom overlap between these disorders
and other disorders (e.g., overlap between
manic and ADHD symptoms), high rates of
Assessment comorbidity, and mood changes inherent to
bipolar disorders (Youngstrom et al., 2005).
The primary purpose of assessing psycho- Youngstrom and colleagues (2005) sug-
logical disorders in children and adolescents gest a provisional evidence-based approach
is to gather sufficient information to make a to pediatric bipolar disorder assessment.
diagnosis, determine prognosis, guide treat- The authors suggest gathering four types
ment, and monitor and evaluate treatment of information from multiple sources. First,
goals (Klein, Dougherty, & Olino, 2005). due to the heritability of bipolar disorders,
A complete assessment determines whether it is important to gather detailed informa-
the level of intervention should target the tion regarding any family history of mood
individual, the environment, or both (Stark, disorders. It is also suggested that clinicians
1990). Assessment of depression evaluates assess symptoms that are specific to bipolar
the symptoms, severity, and syndrome of disorders (Youngstrom et al., 2005), such
depression (Chrisman, Egger, Compton, as increased energy and grandiosity (see
Curry, & Goldston, 2006). During the first Youngstrom, Birmaher, & Findling, 2008).
phase of assessment, a preliminary diagnosis Symptoms such as irritability and aggressive
is made. The therapist determines whether behaviors are certainly common in bipolar
the diagnosis of MDD or DD is met, and disorders; however, they are not exclusive
rules out other diagnoses (e.g., bipolar dis- to a bipolar diagnosis and may be found in
orders, depression due to a medical condi- other childhood and adolescent disorders
tion or substance). Case conceptualization (Youngstrom et al., 2005, 2008). Clinicians
begins, and symptoms that may guide or should also gather evidence regarding mood
influence treatment are evaluated (e.g., sui- functioning changes over time, as informa-
cidal ideation, psychotic symptoms; Klein tion and documentation about mood cycling
et al., 2005). The chronology and course of will aid in bipolar disorder diagnosis. Fi-
depressive symptoms are evaluated (Chris- nally, the gathering of assessment informa-
man et al., 2006), as well as the prior his- tion should be extended beyond the initial
tory of depression, comorbidity with other meeting, as a diagnosis of a bipolar disorder
disorders, functional impairment, and en- should stem from more than a single assess-
vironmental stressors. When treatment for ment period (Youngstrom et al., 2005).
depression begins, assessment continues in Common to all psychological assess-
order to monitor the change in depressive ments is a multimethod evaluation, includ-
symptoms and determine whether the treating reports from multiple informants. Such
ment needs to be continued, changed, or reports aid in diagnosis, as children often
terminated. Assessment information should lack the ability to describe their emotions
be gathered through multiple informants, and experiences (Smith & Handler, 2007).
including the child, parents, and teachers Approaches used in the assessment of mood
(Klein et al., 2005). disorders include behavior checklists and
Mood Disorders 217
rating scales, clinical interviews, and obser- Diagnostic Interview for Children and Ado-
vational information. lescents (DICA: Reich, 2000); and the Child
and Adolescent Psychiatric Assessment
(CAPA; Angold & Costello, 1995, 2000;
Behavior Checklists
Angold et al., 1995).
and Rating Scales
Rating scales are standardized lists of ques-
Observation
tions based on cumulative experience with
youth. Such scales rely on quantifiable in- Observational tools are capable of address-
formation as a means of determining devi- ing limitations inherent in self-report data,
ance from normative behaviors (Piacentini, including children’s and adolescents’ limited
1993). A rating scale can either be adminis- capacity for self-reflection (Rudolph & Lam-
tered by a clinician or completed by a youth, bert, 2007). When developing a treatment
a parent, or a teacher. Self-report measures plan for depression, a therapist observes a
are more relevant for reporting the covert child’s behavior to determine whether this
nature of depressive symptoms (Klein et al., behavior is playing a role in maladaptive
2005), but are less useful in diagnosing bi- family interactions. Maladaptive messages
polar disorders, as youth are less likely to be and covert family rules are observed within
knowledgeable about or even aware of their the context of the family, in order to estab-
manic symptoms (Youngstrom, 2007). It is lish the behaviors and communications that
generally recommended that a combination may be maintaining the youth’s depressive
of a clinical interview and self-report mea- cognitions (Stark, 1990). Information from
sures (see Table 11.2) be used in order to direct observation of the youth and caregiv-
gather the information needed for diagnosis er during the clinical interview can be incor-
and treatment. Repeated administration of porated into the multimethod assessment.
rating scales is also a useful way to monitor Observation records are also useful for
treatment gains (Piacentini, 1993). monitoring mood highs and lows, allowing
the clinician to differentiate between bipolar
disorders and unipolar depressive disorders
Clinical Interviews
(Youngstrom, 2007).
Both structured and semistructured inter-
views have been established to assess psy-
chological disorders in youth. The benefits of Treatment and Prognosis
structured interviews include their systemat-
Pharmacotherapy
ic, comprehensive nature and high interrater
reliability (Klein et al., 2005). Although Although medication is typically reserved
structured interviews have some limitations, for severely impaired children and adoles-
including a lack of flexibility (Klein et al., cents, or for use when other treatments have
2005) and lengthy administration times, not been effective (Brown, Carpenter, &
they may aid in the assessment of mood dis- Simerly, 2005), the number of prescriptions
orders in youth, as young children are often written for children and adolescents in the
not able to provide detailed answers or re- United States is growing (Deveaugh-Geiss
spond well to open-ended questions (Stark, et al., 2006). In fact, psychopharmacologi-
1990). Some clinical interviews used to di- cal treatments are likely to be the first treat-
agnose depressive and/or bipolar disorders ments for pediatric bipolar disorders (Feeny,
in children and adolescents include the Na- Danielson, Schwartz, Youngstrom, & Find-
tional Institute of Mental Health Diagnos- ling, 2006). Unlike children with depressive
tic Interview Schedule for Children, Version disorders, children diagnosed with bipolar
IV (NIMH DISC-IV; Shaffer, Fisher, Lucas, disorders almost always require pharma-
Dulcan, & Schwab-Stone, 2000); the Sched- cological treatment (Brown et al., 2005). A
ule for Affective Disorders and Schizophre- study by Moreno, Arango, Parellada, Shaf-
nia for School-Age Children, also referred to fer, and Bird (2007) examined the psycho-
as the Kiddie-SADS (K-SADS; Puig-A ntich tropic medications given to youth referred to
& Chambers, 1978); The Washington Uni- outpatient physicians for bipolar disorders
versity in St. Louis K-SADS (WASH-U-K- from 1999 to 2003 and found that 90.6%
SADS; Geller, Zimerman, et al., 2001; the received psychotropic medication (N = 154).
TABLE 11.2. Mood Disorder Rating Scales Published in the Mental Measurements

Yearbook (MMY)
Author(s) and Original publisher
Scale name MMY date and date Ages; number of items
Adolescent Reynolds (2003) Psychological Assessment Ages 12–19; 346 items
Psychopathology Scale Resources (1998)
(APS)
Adolescent Symptom Gadow & Sprafkin Checkmate Plus (1998) Ages 12–18; teacher form
Inventory–4 (ASI-4) (2003a) (106 items), parent form
(120 items)
Beck Depression Beck et al. (2001) Psychological Corporation Ages 13–adult; 21 items
Inventory–II (BDI-II) (1996)
Children’s Depression Kovacs (1992) Multi-Health Systems Ages 7–17; forms: long (21
Inventory (CDI) items), short (10 items),
parent (17 items), teacher
(12 items)
Clinical Assessment of Bracken & Howell Psychological Assessment Ages 8–79; 50 items
Depression (CAD) (2004) Resources (2004)
Hilson Adolescent Profile Inwald et al. Hilson Research (1992) Ages 10–19; 310 items
(HAP) (1992)
Internalizing Symptoms Merrell & Walters PRO-ED (1998) Ages 8–13; 48 items
Scale for Children (ISSC) (2001)
Millon Clinical Multiaxial Millon et al. National Computer Ages 18–adult; 175 items
Inventory–III (MCMI-III) (2001) Systems (1997)
Multiscore Depression Berndt (1992) Western Psychological Ages 13–adult; 118 items
Inventory (MDI) Services (1986)
Multiscore Depression Berndt & Kaiser Western Psychological Ages 8–17; 79 items
Inventory for Children (2001) Services (1996)
(MDI-C)
Reynolds Adolescent Reynolds (2005) Psychological Assessment Ages 11–20; 30 items

Depression Scale–2nd Resources (2002)
Edition (RADS-2)
Reynolds Child Reynolds (1992) Psychological Assessment Ages 8–12; 30 items

Depression Scale Resources (1989)
State–Trait Depression Lubin (1998) Psychological Assessment Ages 14–adult; forms

Adjective Checklists Resources (1994) A–D, 108 adjectives
(ST-DACL)
Weinberg Depression Weinberg et al. PRO-ED (1998) Fourth-grade reading

Scale for Children and (2001) level; 56 items
Adolescents (WDSCA)
Youth’s Inventory–4 Gadow & Sprafkin Checkmate Plus (1999) Ages 12–18; 118 items
(YI-4) (2003b)
Mood Disorders 219
Many psychopharmacological treatments lescents. Further research is needed to de-

for mood disorders have demonstrated effec- termine whether the medications described
tiveness with the adult population, but the ef- above are indeed efficacious treatments for
fectiveness with children is in need of future children and adolescents. Studies have been
research. Four major classes of antidepres- limited and methodologically flawed in some
sants exist, with selective serotonin reuptake cases (Moreno, Laje, et al., 2007). However,
inhibitors (SSRIs) being the most commonly controlled studies have indicated favorable
prescribed for depressive disorders (Ben- outcomes in the treatment of depressive dis-
nett, Teeling, & Feely, 2005; Brown et al., orders with SSRIs (Emslie et al., 1997, 2002;
2005). SSRIs prevent the reabsorption of se- Keller et al., 2001; Treatment for Adoles-
rotonin, making more serotonin available to cents with Depression Study [TADS] Team,
the brain. SSRIs have fewer side effects than 2004). Studies comparing medication and
the other antidepressants, but the benefits placebo have found both paroxetine (Keller
of SSRIs may take 4–8 weeks to take effect et al., 2001) and fluoxetine (TADS Team,
(Brown et al., 2005). Tricyclic antidepres- 2004) to be significantly more effective than
sants (TCAs) also target the neurotransmit- placebo. The TADS Team (2007) also found
ters in the brain; however, their side effects that fluoxetine accelerated treatment im-
are usually harsh, making TCAs a second or provements measured at 12 weeks.
third choice for treatment in most cases. The The efficacy of medication use with chil-
risk of overdose is also higher, so TCAs are dren and adolescents diagnosed with bipo-
not typically prescribed without the assur- lar disorders is also emerging through con-
ance of prudent supervision (Brown et al., trolled and uncontrolled studies. Studies
2005; Fombonne & Zinck, 2008). Mono- using open-label treatment have yielded pre-
amine oxidase inhibitors are also rarely used liminary results for the efficacy of lithium
in children and adolescents because of the (e.g., Kafantaris, Coletti, Dicker, Padula, &
significant dietary restrictions they require. Kane, 2003) and other medications, includ-
Psychopharmacological treatments for bi- ing ziprasidone (Biederman et al., 2007).
polar disorders in children and adolescents Geller and colleagues (1998) conducted a
most often include lithium. In fact, lithium randomized controlled treatment study of
(also widely used for adult bipolar disor- adolescents (N = 25) with comorbid bipolar
ders) is the only medication for the treat- I disorder and substance abuse. Adolescents
ment of acute mania and bipolar I disorder assigned to the lithium group showed sig-
in adolescents that has been approved by the nificantly greater improvement in both bi-
U.S. Food and Drug Administration (FDA) polar and substance abuse symptoms than
for youth 12 years and older (Hamrin & those assigned to the placebo group did. It
Pachler, 2007). Lithium affects neurotrans- is less clear how children and adolescents
mitters in the brain, including norepineph- respond to mood stabilizers and anticonvul-
rine, dopamine, and serotonin. It has several sants compared to lithium; at least one study
negative side effects, however; these include detected no significant differences between
nausea, vomiting, tremor, sleepiness, weight these treatments (Kowatch et al., 2000).
gain, and damage to the kidneys. Mood sta-
bilizers are also prescribed for youth diag-
Black-Box Warnings
nosed with bipolar disorders. Mood stabiliz-
ers also have negative side effects, and both Safety concerns regarding the use of antide-
lithium and mood stabilizers require blood pressants in youth arose following a report
level monitoring (Brown et al., 2005). For by the Medicine and Healthcare Products
medication treatment guidelines for children Regulatory Agency in the United Kingdom
and adolescents diagnosed with bipolar disin 2003 (Fombonne & Zinck, 2008). Fol-
orders, see Kowatch and colleagues (2005). lowing these concerns, the U.S. FDA con-
ducted an investigation examining the use
of SSRIs. The FDA found that SSRIs had
Medication Use for Children
a significant risk for youth, in that taking
and Adolescents
these medications might increase the risk of
Much debate has risen about the use of psy- suicidal events; however, no deaths due to
chotropic medications for children and ado- SSRIs were discovered (Fombonne & Zinck,
2008). The FDA has placed “black-box” years. This small-group CBT interven-
label warnings on SSRIs to warn that SSRIs tion is structured according to a therapist’s
have been linked to depression and suicide manual, contains workbooks for the girls
attempts in some children. Fluoxetine is the and their parents, and is conducted in the
only medication that the FDA has approved school environment. A self-control model is
for use by children (Brown et al., 2005), as the basis for the treatment program, which
its use has proven effective in at least two includes affective education, coping skills
studies. training, problem-solving training, and cog-
nitive restructuring. The girls in the group
are taught to use coping skills through the
Psychosocial Treatments
cognitive-behavioral model (Stark et al.,
Cognitive-behavioral therapy (CBT) has 2008). Parent training is implemented con-
been effective in treating unipolar depression currently, with the aim to teach parents the
and meets the criteria for a well-established same skills their children are learning and to
treatment for depressive disorders (Comp- help them reinforce and support their chil-
ton et al., 2004). We briefly describe three dren’s skill acquisition (Stark, Sander, Har-
treatment programs based on CBT and in- grave, et al., 2006). Stark, Sander, Hauser,
terpersonal process, with empirical support and colleagues (2006) obtained preliminary
for their effectiveness in treating childhood results suggesting that 70% of girls no longer
and adolescent depression. The ACTION experienced depressive symptoms following
program (Stark, Schnoebelen, et al., 2007, the ACTION program.
Stark, Simpson, Schnoebelen, et al., 2007;
Stark et al., 2008; Stark, Simpson, Yancy, &
Adolescent Coping with Depression Course
Molnar, 2007), the Adolescent Coping with
Depression course (CWD-A; Lewinsohn, The CWD-A (Lewinsohn et al., 1990) is
Clarke, Hops, & Andrews, 1990), and inter- based on the assumption that depressed
personal psychotherapy for depressed ado- youth do not receive reinforcement, do not
lescents (IPT-A; Mufson, Dorta, Moreau, & engage in pleasant activities, and behave in
Weissman, 2004) all have evidence for their a way that contributes to a loss of support.
effectiveness with youth. This program incorporates pleasant events
Compared to the literature on depression, and reinforcement while addressing negative
less attention has been given to psychosocial cognitions and deficits in interpersonal skills.
interventions for pediatric bipolar disorders, The CWD-A teaches adolescents how to use
leaving many psychologists unprepared for coping skills and problem solving (Rohde,
the rising numbers of referrals for these dis- Lewinsohn, Clarke, Hops, & Seeley, 2005).
orders (Youngstrom, 2007). In fact, there are The program also integrates a parallel parent
no proven efficacious or effective treatments component (Lewinsohn et al., 1990; Rohde
for bipolar disorders in youth (Youngstrom et et al., 2005). CWD-A administered either
al., 2005). However, psychoeducation, CBT, on an individual basis or with a parent has
and family therapy have all shown promise. proven effective in the treatment of adoles-
Preliminary effectiveness has been indicat- cent depression: Lewinsohn and colleagues
ed for CBT (Feeny et al., 2006), child- and (1990) found that participants in both these
family-focused CBT (CFF-CBT; Pavuluri et forms of active treatment had significantly
al., 2004), and multifamily psychoeducation improved depression scores, which were
groups (Goldberg-A rnold & Fristad, 2003). maintained 2 years after treatment.
The first and second of these are also briefly
described.
Interpersonal Psychotherapy
for Depressed Adolescents
The ACTION Program
IPT-A (Mufson, Dorta, Moreau, & Weiss-
The ACTION program (Stark et al., 2008; man, 2004) is a brief, manualized treatment
Stark, Schnoebelen, et al., 2007; Stark, that addresses common adolescent issues
Simpson, Schnoebelen, et al., 2007; Stark, through focusing on decreasing depres-
Simpson, Yancy, et al., 2007) is a group sive symptoms and increasing interpersonal
treatment for depressed girls ages 9–13 functions. Mufson and colleagues developed
Mood Disorders 221
IPT-A with the assumption that depression in disruptive family environments (Stark &
is maintained in an environment involv- Brookman, 1992). Family involvement is
ing interpersonal and social difficulties. often implemented as a parallel process to
Parents are involved in the initial session, individual treatment of depression. Parents
and are asked for further involvement dur- attend therapy sessions in order to promote
ing treatment if a clinician and adolescent the acquisition of their children’s newly
believe that this would be helpful (Mufson, learned skills, enhance communication, and
Dorta, Moreau, & Weissman, 2004; Young become educated about their children’s de-
& Mufson, 2008). IPT-A has proven to be pression. For example, parallel family thera-
an efficacious treatment for depression. A py is seen in the ACTION program (Stark et
study by Mufson, Dorta, Wickramaratne, al., 2008; Stark, Schnoebelen, et al., 2007;
and colleagues (2004) found that IPT-A was Stark, Simpson, Schnoebelen, et al., 2007)
superior to treatment as usual in reducing and the CWD-A (Lewinsohn et al., 1990).
depressive symptoms and improving overall Parents are included, but to a lesser extent,
functioning. A 1994 study by Mufson and in IPT-A (Mufson, Dorta, Moreau, & Weiss-
colleagues determined that following the man, 2004; Young & Mufson, 2008).
course of IPT-A treatment, none of the 12- Family therapy for bipolar disorders has
to 18-year-olds previously diagnosed with recently been extended to the treatment of
MDD met the diagnostic criteria. children and adolescents. CFF-CBT (Pavu-
luri et al., 2004) was adapted from an adult
family-focused treatment (Miklowitz &
CBT for Bipolar Disorders
Goldstein, 1997). CFF-CBT was designed
There is less research on psychotherapy for to be used in conjunction with medication
children and adolescents with bipolar disor- and to specifically address the developmen-
ders, as noted above. However, pilot studies tal needs of children, adolescents, and their
have indicated that CBT and psychoeduca- families. This technique combines CBT with
tional treatments are effective at reducing interpersonal therapy techniques. Other
and managing bipolar symptoms (Geller & characteristics of CFF-CBT include address-
DelBello, 2003). On the basis of research ing rapid cycling through psychoeducation,
indicating that CBT techniques are effective mood monitoring, and affect regulation
for adults diagnosed with bipolar disorders, techniques. Interpersonal problem-solving
Feeny and colleagues (2006) created a man- strategies are implemented to address ir-
ualized form of CBT for adolescents, mod- ritability as well as mixed episodes. A pre-
eled after the TADS treatment and substance liminary exploratory study using CFF-CBT
abuse work. Each session followed the same found that participants’ functioning signifi-
format: (1) reviewing symptoms; (2) review- cantly improved following treatment (Pavu-
ing the previous session’s homework; (3) set- luri et al., 2004).
ting an agenda (e.g., a fight with the family);
(4) teaching a new skill (e.g., problem solv-
ing); (5) applying the new skill to the agenda Summary
item; and (6) assigning homework for the
next session. After 12 sessions, adolescents In this chapter, the literature on the diag-
in a pilot study (N = 16; ages 10–17 years) nostic criteria; prevalence; developmental
who received CBT (plus medication) had course; genetics and family patterns; bio-
fewer manic and depressive symptoms as es- logical and neuropsychological markers;
tablished by parent report than the control and risk factors (with gender and ethnic/
group (medication only). cultural/socioeconomic differences) in juve-
nile mood disorders has been reviewed. The
importance of multimethod assessment has
Family Involvement in Therapy
been described, and promising treatments
For the most part, families have not been infor depressive and bipolar disorders in youth
volved in the treatment of depressed youth. have been briefly reviewed. Congruent with
In fact, only 32% of treatments include par- a risk reduction model (Mrazek & Hag-
ents (Sander & McCarty, 2005), despite the gerty, 1994) of mental health disorders, it is
findings that depressed youth are involved important for clinicians working with youth
and their families to view prevention, treat- yearbook [Electronic version]. Retrieved June 4,
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dren and adolescents. Biederman, J., Faraone, S., Mick, E., Wozniak, J.,
Ghen, L., Ouellette, G., et al. (1996). Attention-
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C h a p t e r 12
Autism Spectrum Disorders
Blythe Corbett
Joan Gunther
Although it does not represent an official di- ner (1943) identified early infantile autism as
agnostic category, the term autism spectrum consisting of symptoms including social def-
disorders (ASDs) has become an increasingly icits, language peculiarities, and insistence
familiar label for the pervasive developmen- on sameness.
tal disorders (PDDs) found in the Diagnostic At almost the same time a physician in Vi-
and Statistical Manual of Mental Disorders, enna, Austria, named Hans Asperger made
fourth edition, text revision (DSM-IV-TR; use of Bleuler’s term in a paper he titled “Au-
American Psychiatric Association [APA], tistic Psychopathy in Childhood” (Asperger,
2000). The ASDs include autistic disorder, 1991). The paper, originally published in
Asperger’s disorder (Asperger syndrome), 1944, portrayed a group of children Asperger
and PDD not otherwise specified (PDD- described as possessing such characteristics
NOS); two rare PDDs, Retts disorder (Rett as abnormal nonverbal behaviors, emotional
syndrome) and childhood disintegrative dis- peculiarities, social challenges, and circum-
order, are also included (APA, 2000). In this scribed interests (Hippler & Klicpera, 2003).
chapter, we first provide a brief historical Although Kanner’s and Asperger’s observed
framework, and then highlight some of the symptoms still constitute many of the basic
most recent conceptualizations and findings criteria for the ASDs, ideas about their di-
related to these complex disorders. agnoses, prevalence, theory, and treatment
The term autistic, first used in 1911 by a approaches have evolved throughout the
Swiss psychiatrist named Bleuler, originated years.
from the Greek word meaning “self.” Bleul- Various behaviors associated with autism
er used it to depict the tendency observed may be observed in infancy; however, impair-
in individuals with schizophrenia to isolate ments in one of the three core domains (re-
themselves socially and focus their attention ciprocal social interaction, language used as
on their “inner life” (Parnas, Bovet, & Za- social communication, and symbolic/imagi-
havi, 2002). Leo Kanner is credited with the native play) must be apparent before 3 years
original account of the disorder of autism. of age (Filipek et al., 2000). Autistic disorder,
His keen observations led to his description often referred to as classic autism, is marked
of common features among 11 children seen by impairment across all three areas: deficits
in his Baltimore, Maryland clinic in 1943. in social functioning; impaired verbal and
Making use of Bleuler’s word autistic, Kan- nonverbal communication; and a repertoire
228
Autism Spectrum Disorders 229
of repetitive, restricted, and stereotyped be- A subgroup of roughly 30% of individu-

haviors (APA, 2000). PDD-NOS, also known als with autism have a developmental profile
as atypical autism, is a condition in which known as autistic regression, which is char-
impairment in all three domains exists, but acterized by a period of typical development
the full diagnostic criteria for a specific PDD or mild autistic traits followed by deterio-
are not met. Asperger syndrome is character- ration, usually between the ages of 2 and 3
ized by social impairments and stereotyped years (Davidovitch, Glick, Holtzman, Tiro-
patterns of behavior, interests, or activities; sh, & Safir, 2000). The lost skills most com-
however, there is no cognitive impairment or monly include language ability, but losses in
clinically significant delay in language devel- social behavior, motor skills, and play may
opment (APA, 1994). Rett syndrome is a ge- also occur, along with the onset of repetitive
netic malady that primarily affects girls and and stereotyped behavior. Autistic regression
is characterized by a decline in functioning differs from childhood disintegrative disor-
across several domains after a period of nor- der in that children with the latter disorder
mal functioning. Deficits include problems demonstrate typical development until at
with social interaction, motor coordina- least the age of 2, followed by a sharp decline
tion, and receptive and expressive language in skills before the age of 10 (APA, 2000).
development. In addition, purposeful hand Although screening instruments such as
movements are replaced with nonpurpose- the Social Communication Questionnaire
ful movements resembling hand washing or (SCQ) (Berument, Rutter, Lord, Pickles, &
hand wringing. (For a complete discussion Bailey, 1999) may indicate a need for further
of Rett syndrome, see R. T. Brown & Mc- evaluation, a diagnosis of an ASD requires a
Millan, Chapter 22, this volume.) Similarly, comprehensive evaluation, including cogni-
childhood disintegrative disorder is distin- tive and language testing. A thorough diag-
guished by significant behavioral, cognitive, nostic evaluation frequently includes instru-
and language regression following at least ments designed exclusively for supporting
2 years of typical development. Significant the diagnosis of autism, such as the Autism
impairment is noted in at least two of the Diagnostic Observation Schedule (ADOS—
following domains: receptive or expressive Gotham, Risi, Pickles, & Lord, 2007; Lord,
language, social skills, adaptive skills, bowel Rutter, DiLavore, & Risi, 1999), the Autism
or bladder control, play skills, or motor skills Diagnostic Interview—Revised (ADI-R—
(APA, 2000). Le Couteur, Rutter, Lord, & Rios, 1989;
Subgroups of individuals with autism are Lord, Rutter, & Le Couteur, 1994), or the
frequently categorized as “low-functioning” Childhood Autism Rating Scale (CARS—
or “high-functioning.” Not only are these Schopler, Reichler, DeVellis, & Daly, 1980).
labels unofficial diagnoses, but they lack An inclusive evaluation also often incorpo-
agreed-upon definitions. Some research re- rates neurological and genetic assessments
fers to individuals with autism of normal (Filipek et al., 2000).
intelligence as “high-functioning” (Allik, Research conducted in the United States
Larsson, & Smedje, 2006); therefore, in- determined that although parents noticed
dividuals referred to as “low-functioning” symptoms of autism in children as young
possess below-average intelligence. It is cur- as 6 months of age, diagnoses were not
rently estimated that nearly 70% of indi- made until 3 or 4 years of age (Planche,
viduals with autism have IQs in the range Lazartigues, & Lemonnier, 2004). A United
of mental retardation/intellectual disability Kingdom study estimated the average age at
(Shattuck et al., 2007). An extensive review an ASD diagnosis as 6 years, although most
of 215 articles published between 1937 and families noted some characteristics of au-
2003 indicates that the prevalence rates of tism as early as 18 months of age (Howlin
mental retardation in autism were not em- & Moore, 1997). Some studies have distin-
pirically derived and did not consider the guished the average ages of diagnosis for dif-
impact of autism on the assessment measure ferent ASDs. For instance, Mandell, Novak,
scores. Consideration of such evidence sug- and Zubritsky (2005) indicated that the aver-
gests that the prevalence rates of intellectual age ages of diagnosis for autism, PDD-NOS,
disability may actually fall somewhere be- and Asperger syndrome were 3.1 years, 3.9
tween 40% and 55% (Edelson, 2006). years, and 7.2 years, respectively.
Gender R atios, Prevalence, viduals with autism, refers to cases in which

and Incidence an environmental toxin or genetic abnor-
mality can be identified. Idiopathic autism,
Numerous researchers have published data or autism with unknown etiology, makes up
estimating the occurrence of autism based the remaining 85% of cases. Of these indi-
on demographic factors, such as gender viduals, approximately 30% have complex
and intelligence. It is generally believed that autism, which is delineated by dysmorphic
the ratio of males to females with an ASD features or other structural or brain abnor-
is approximately 4:1 (Gillberg & Wing, malities (www.genome.gov). The other 70%
1999; Tidmarsh & Volkmar, 2003; Wing & or so of these individuals have essential au-
Gould, 1979). Although this gender propor- tism, which is demarcated by a lack of physi-
tion holds true for persons of average IQ, the cal abnormalities (www.genome.gov; Miles
proportion significantly changes to a male– et al., 2005).
female ratio of approximately 2:1 for those
with intellectual disability (Ehlers & Gill-
Psychoanalytic Theory
berg, 1993: Wing & Gould, 1979). A large
U.S. study showed that the male–female Numerous theories regarding the etiology of
ratio decreased as the level of intellectual im- autism have been presented over the last sev-
pairment reciprocally increased from mild to eral decades. Kanner (1943) maintained that
profound (Yeargin-A llsopp et al., 2003). the autistic characteristics of the children
The prevalence of autism refers to the pro- he studied might have been attributable to
portion of individuals in a population that their parents’ lack of warmth and affection.
have autism at any stated time, whereas the This view continued into the 1960s with the
incidence refers to the number of new diag- “refrigerator mother” hypothesis of autism,
noses in a population throughout a period of suggesting that “cold” styles of mothering
time. The Centers for Disease Control and led to a child’s autism. Genetic, biological,
Prevention’s 2009 Surveillance Summaries and neuroanatomical findings since then
detailed the 2006 reporting period of 11 sites have provided compelling evidence to refute
in the United States and determined that ap- these early notions.
proximately 1 in 110 children age 8 in the
United States were characterized as having
Genetics
an ASD. In an excellent review, Fombonne
(2005) summarizes several studies finding The first strong evidence for a genetic role in
the prevalence of classic autism to be ap- the etiology of autism emerged from a twin
proximately 13 per 10,000 individuals, that study published in the 1970s in England
of PDD-NOS to be 20.8 per 10,000 individu- (Folstein & Rutter, 1977b). It is now well
als, and that of Asperger syndrome to be 2.6 accepted that ASDs have a strong genetic
per 10,000. Taken together, the estimated component: The concordance rate in mo-
prevalence for all PDDs was at least 36.4 per nozygotic twins (60% autism, 90% broader
10,000 individuals. Although a genuine in- phenotype) is much higher than that in dizy-
crease in the number of children developing gotic twins (3%), and the sibling recurrence
ASD cannot be ruled out, the incidence and risk ratio is 5–10 times that for the general
prevalence of autism may be partially due population (Bailey, Phillips, & Rutter, 1996;
to broadened criteria, health care providers’ Folstein & Rutter, 1977a, 1977b; Skaar et
increased familiarity with ASD symptoms, al., 2005). In general, it is thought that ge-
greater public awareness, and improved case netic and chromosomal abnormalities ac-
finding (Fombonne, 2005; Gernsbacher, count for approximately 90% of ASDs (Fre-
Dawson, & Goldsmith, 2005). itag, 2007).
Since a single gene or group of genes has
not been unequivocally linked to autism, it
Etiology has been suggested that the broad ASD phe-
notypes are likely to be polygenetic, with up-
The causes of autism are referred to as either wards of 15 interacting genes (Risch et al.,
idiopathic or secondary. Secondary autism, 1999). Studies have located various genetic
accounting for approximately 15% of indi- loci related to autism; however, only a few of
these regions have been confirmed. A num- lation of a list of possible genes associated
ber of methods are used to identify possible with autism. For a recent comprehensive re-
relevant genome regions. view, see Abrahams and Geschwind (2008).
Linkage Studies Findings from Related Genetic Syndromes

and Medical Disorders
Linkage studies attempt to identify particular
genes or sequences of genes that are passed Autism candidate genes have also been iden-
from parent to child. Autism linkage studies tified through the study of genetic syndromes
have met with minimal success. However, with a co-occurring ASD. Examples include
regions on 17q11–21, 7q, and 2q24–31 have Rett syndrome, which is the only ASD cur-
been sufficiently replicated and are now con- rently shown to have a genetic cause. Rett
sidered suggestive of linkage (Cantor et al., syndrome is most commonly caused by de
2005; Kumar & Christian, 2009). novo mutations or deletions of the meth-
yl-CpG-binding protein 2 (MECP2) gene
(Amir et al., 1999). Additional syndromes
Cytogenetic Studies
of interest include tuberous sclerosis (e.g.,
Cytogenetic studies attempt to identify in- Smalley, 1998), Angelman syndrome (e.g.,
herited chromosomal abnormalities. These Peters et al., 2004; Trillingsgaard & Øster-
studies initially identify relatively large gaard, 2004), 22q deletion (Manning et al.,
chromosomal regions, with identification of 2004), Joubert syndrome (Holroyd, Reiss,
particular genes requiring further analysis. & Bryan, 1991; Ozonoff, Williams, Gale,
For example, it is estimated that abnormali- & Miller, 1999), Potocki–Lupski syndrome
ties in the region 15q11–13 account for ap- (Potocki et al., 2007), Smith–L emili–Opitz
proximately 1–2% of cases of autism (Cook, syndrome (Bukelis, Porter, Zimmerman, &
Lindgren, et al., 1997; Matsuura et al., 1997; Tierney, 2007), Timothy syndrome (Barrett
Peters, Beaudet, Madduri, & Bacino, 2004). & Tsien, 2008), and fragile X syndrome
Studies of this region indicate deficiencies (Hagerman et al., 1986; Rogers, Wehner,
of the UBE3 (Samaco, Hogart, & LaSalle, & Hagerman, 2001). Significant knowledge
2005) and GABRB3 (Fatemi, Reutiman, can be gained by studying these related syn-
Folsom, & Thuras, 2009) genes in ASDs. dromes.
The UBE3A gene directs the production of Studies of fragile X and Rett syndromes
the enzyme ubiquitin protein ligase E3A, implicate synaptic dysfunction as an etiolog-
which helps to regulate neuronal activity by ical factor for autism, whereas studies of tu-
breaking down proteins within the cell (Sutc- berous sclerosis implicate common pathways
liffe, 2008), and has been implicated in both ostensibly giving rise to ASDs. The autism
autism and Angelman syndrome (Samaco et presentation found in fragile X often meets
al., 2005). The GABRB3 gene is a receptor full diagnostic criteria; therefore, the fragile
for gamma-aminobutyric acid (GABA), the X FMR1 gene mutation may be considered
major inhibitory transmitter of the central a cause of autism (Hagerman, Rivera, &
nervous system (CNS). It is approximated Hagerman, 2008). Even so, it is estimated
that all cytogenetic abnormalities account that only 2% of children with autism have a
for 6–7% of ASD cases in which there is no full mutation of the fragile X mental retar-
dysmorphia or intellectual disability, with dation protein (FMR1) (Reddy, 2005). Due
higher percentages in the populations that to the high male preponderance in ASDs and
have these characteristics (Marshall et al., the association with fragile X syndrome, one
2008). might be inclined to conclude that autism is
an X-linked disorder. However, because of
male-to-male transmissions (Hallmayer et
Association Studies
al., 1996) and chromosomal abnormalities
Association studies attempt to identify spe- resulting from maternal transmission (Simic
cific variations in the human DNA to evalu- & Turk, 2004), it is unlikely that autism is a
ate candidate genes and pathways believed prominently X-linked disorder.
to be associated with particular conditions. Known medical disorders give rise to eti-
These investigations have led to the compi- ological hypotheses as well. For example,
epilepsy is associated with autism in an esti- and by-products that may be related to ge-
mated 30% of cases (Gubbay, Lobascher, & netic alterations associated with autism and
Kingerlee, 1970). Therefore, some forms of other genetic disorders (Junaid & Pullarkat,
ASD may be associated with aberrant neural 2001). A proteomic approach was used to
conduction and transmission. Nevertheless, quantify 6,348 peptides in a comprehensive
even when taken together, the syndromes investigation of serum from young children
and known medical disorders are thought to with high-functioning (n = 35) and low-
account for fewer than 10% of ASD cases functioning (n = 34) autism, matched in gen-
(Chakrabarti & Fombonne, 2005; Hertz- der and age to a cohort of typically develop-
Picciotto et al., 2006). ing (n = 35) children (Corbett et al., 2007).
Corbett and colleagues used statistical and
protein-matching methods to identify four
Advanced Technology Findings
known proteins (which included apolipopro-
Higher-resolution technologies, including teins and complement proteins) that differ-
microarray analysis, have dramatically in- entiated the children with autism from the
creased detection of promising genetic leads. neurotypical children. Such findings con-
Again, Abrahams and Gechwind’s (2008) tribute to a growing body of evidence that
exemplary review cites microarray studies immune factors may be implicated in the
that reveal approximately 900 genes (many neuropathology of ASDs in a subset of chil-
found on the 15q chromosome) and numer- dren (see below).
ous pathways appearing to be dysregulated
in ASDs. In addition, copy number varia-
Environmental Factors
tions (CNVs) have recently been found. A
CNV is a segment of DNA wherein differ- The increasing incidence rates of ASDs have
ences in copy numbers are found when the directed attention toward possible contribu-
genomes of different individuals are com- tory factors in the environment. Suspected
pared. A repeatedly occurring de novo dele- environmental factors are numerous and in-
tion was found on approximately 30 genes clude prenatal infections, perinatal insults,
on chromosomal region 16p11 (Kumar et viral infections, heavy metals, mercury,
al., 2008). CNV research suggests that the pesticides, polychlorinated biphenyls, and
incidence of autism ascribed to the structur- childhood vaccines containing thimerosal
al variation of chromosomes may be much (Fatemi, 2008b; Muhle et al., 2004; Szpir,
higher than the 6–7% that were identified by 2006). The vaccine controversy is discussed
traditional cytogenetic approaches. Clearly, later in this chapter (see “Controversial Top-
much knowledge can be gained from deter- ics,” below).
mining the function of the individual genes, A breakthrough study (Nelson et al.,
as well as from understanding the repeated 2001) analyzed the blood of newborns col-
duplications. For comprehensive reviews, lected via heel stick; it revealed that several
see Abrahams and Geschwind (2008) and neuropeptides, such as vasoactive intestinal
Muhle, Trentacoste, and Rapin (2004). The peptide (VIP) and brain-derived neurotropic
tremendous advances in genetic technology, factor (BDNF), were elevated in children
and the still unanswered questions regard- who were later diagnosed with autism or
ing the causes of ASDs, draw attention to mental retardation. Importantly, the identi-
the complexity of the ASDs and the need for fied peptides were not elevated in children
larger sample sizes. with cerebral palsy or with typical develop-
ment. These findings suggest detectable dif-
ferences in peripheral neonatal blood at the
Proteomics
time of birth between the children with au-
The search for potential biomarkers in ASDs tism and mental retardation and those with-
is a critical pursuit that has led to novel out such disorders.
methods of molecular profiling for system- A number of studies indicate that several
atic and unbiased biomarker discovery. Pro- well-known teratogens may be related to
teomics uses separation and mass spectrom- autism, including maternal rubella infec-
etry methods that support ongoing genetic tion, ethanol, valproic acid, and thalido-
approaches by identifying aberrant proteins mide. A large study by Chess (1977) found
an increased rate of autism in children who & Rivas, 2004; Vargas, Nascimbene, Krish-
were prenatally exposed to rubella. Another nan, Zimmerman, & Pardo, 2005; Wills et
study reported a cohort of children exposed al., 2009; Zimmerman et al., 2007). The
to ethanol before birth that were identi- presence of inflammation within the brain
fied as exhibiting not only the dysmorphic and cerebrospinal fluid (CSF) of individuals
facial features of fetal alcohol syndrome with autism, indicating innate neuroimmune
(FAS), but also the behavioral symptoms of system activation, provides compelling evi-
autism (Nanson, 1992). Additional studies dence of immunopathogenic mechanisms in
have reported similarities between children at least a subset of these individuals (Vargas
exposed to valproic acid and those with au- et al., 2005).
tism, including posterior rotation of the ears A growing body of research supports the
(Christianson, Chesler, & Kromberg, 1994; hypothesis that aberrant maternal immune
Williams & Hersh, 1997). Finally, various response may be associated with the patho-
reports have shown an association with au- genesis of some cases of autism (e.g., Croen
tism in cases of thalidomide embryopathy Matevia, Yoshida, & Grether, 2008; Lee et
(Miller, 1991; Stromland & Miller, 1993), al., 2006; Nelson et al., 2006; Zimmerman
specifically suggesting exposure between the et al., 2007). In a relatively recent investiga-
20th and 24th days of gestation. tion, neonatal blood from children later di-
agnosed with autism was compared to blood
from children with Down syndrome and with
Immunological Considerations
neurotypical development; the comparison
An increase in the frequency of autoimmune revealed distinct developmental trajectories
disorders has been reported in the families and concentrations across the groups. The
of persons with autism (Comi, Zimmerman, findings suggest that intrauterine inflamma-
Frye, Law, & Peeden, 1999; Croen, Grether, tion may be an etiological pathogenic mech-
Yoshida, Odouli, & Van de Water, 2005). It anism in autism (Nelson et al., 2006). Other
is interesting to note that several genes in au- investigations using various animal models
tism relate to immune regulation and func- and analyzing the serum of mothers have
tion; these include genes for human leukocyte provided evidence for prenatal maternal im-
antigen (HLA) presentation molecules and mune responses and autoantibodies in some
various components of the complement pro- cases (Croen, Braunschweig, et al., 2008;
tein system (e.g., Ferrante et al., 2000; Odell Martin et al., 2008; Singer et al., 2008;
et al., 2005; Purcell, Jeon, Zimmerman, Blue, Zimmerman et al., 2007). Despite a lack of
& Pevsner, 2001; Torres, Maciulis, & Odell, consistent findings, the preponderance of
2001; Torres, Maciulis, Stubbs, Cutler, & evidence from cellular to neuroanatomical
Odell, 2002; van Gent, Heijnen, & Treffers, findings strongly supports a prenatal or very
1997; Warren et al., 1996). Abnormalities of early postnatal etiology in autism, under-
various cytokines and chemokines have been scoring the need to continue to pursue the
reported, including interleukin-12 (IL-12), influential role of maternal immunological
IL-10, tumor necrosis factor-alpha (TNF- factors in the heterogeneous ASDs. There is
a), TNF receptor II, and interferon-gamma also evidence that developmental parental
(IFN-g). It has been suggested that alterations factors, such as age, play into the complex-
in cytokine levels may be associated with ity of prenatal effects in autism (Durkin et
different clinical phenotypes within autism al., 2008; Saha et al., 2009; Tsuchiya et al.,
(e.g., Ashwood & Van de Water, 2004; De- 2008).
Felice et al., 2003; Jyonouchi, Geng, Ruby,
Reddy, & Zimmerman-Bier, 2005; Molloy
et al., 2006; Singh, 1996; Zimmerman et al., Neural Mechanisms
2005). Additional alterations linked to the
immune system include autoantibodies in In recent years, considerable efforts have
the blood, which have been speculated to be been made to identify the neural substrates
directed to CNS or brain antigens (e.g., Ash- of autism by using a variety of neuroscientif-
wood & Van de Water, 2004; Croen, Braun- ic methods, such as human pathology, ani-
schweig, et al., 2008; Pessah et al., 2008; mal models, positron emission tomography
Silva et al., 2004; Singer et al., 2008; Singh (PET), magnetic resonance imaging (MRI),
functional MRI (fMRI), and electroen- Andreasen, 1996). It may be reasoned that
cephalography (EEG). Some of the notable some of the inconsistencies across studies
advances in these areas are briefly outlined are attributable to differences in methodol-
below. We focus on the brain regions and ogy, inclusion criteria, and developmental
structures most consistently implicated in factors. Although the precise time trajectory
the neuropathology of autism. may be argued, a convergence of data im-
plicates a period of aberrant brain growth
as a neural precursor for the anatomical and
Cerebrum and Total
biobehavioral manifestation of autism.
Cerebral Volume
Postmortem investigations allow the careful
Minicolumns
study of neurobiological substrates that may
be related to gross or functional brain ab- Another leading theory involves atypical
normalities. To date, fewer than 100 cases development of the neuronal architecture,
of individuals with autism have been investi- specifically the minicolumnar structure.
gated via neuropathological techniques, and Minicolumns have been described as a self-
many of these cases have been potentially contained system of afferent, efferent, and
confounded by comorbid conditions such interneuronal connections (Casanova, Bux-
as mental retardation or seizures (Amaral, hoeveden, & Gomez, 2003). Cassanova
Schumann, & Nordahl, 2008). Bauman and colleagues investigated the notion of in-
and Kemper were among the first to utilize creased cell-packing density to explain cere-
pathological techniques through a series of bral enlargement in the brains of individuals
influential qualitative studies on six brains (5–28 years of age) diagnosed with autism,
of individuals with autism (Bauman & Kem- compared to the brains of control subjects.
per, 1985; Kemper & Bauman, 1993). The The investigations revealed that within the
primary cortical features that distinguished group with autism there was altered organi-
these brains were described as small neu- zation, resulting in an increase in the number
ronal cell size and increased cell-packing of minicolumns and reduced cells within the
density in the anterior cingulate (Kemper & columns in the frontal and temporal lobes
Bauman, 1993). Subsequently, Bailey and (Casanova, Buxhoeveden, Switala, & Roy,
colleagues (1998) examined six cases of au- 2002a, 2002b). Subsequent investigations
tism revealing different patterns of pathol- supported and extended the findings to re-
ogy, including megalenencephaly, cortical veal that minicolumnopathy consisting of a
dysgenesis, and increased neuronal density. greater number of minicolumns contributed
A relatively consistent neuroanatomical to plausible differences in brain size, distinc-
finding, based on retrospective and longitudi- tions in the gray and white matter ratios,
nal head circumference (a proxy for cerebral and interareal connectivity in persons with
volume) and MRI data, has been an enlarged autism (e.g., Casanova, 2006; Casanova et
total cerebral volume in children with autism al., 2006).
(Aylward, Minshew, Field, Sparks, & Singh,
2002; Courchesne, Carper, & Akshoomoff,
Amygdala
2003; Courchesne et al., 2001; Hazlett et
al., 2005; Sparks et al., 2002). Specifically, Individuals with autism often exhibit dif-
enlarged cortical gray and cerebellar and ficulty with emotion and face processing
cerebral white matter volumes have been re- (e.g., Adolphs, Sears, & Piven, 2001; Ash-
ported at 2–3 years of age, but not in older win, Wheelwright, & Baron-Cohen, 2006;
children with autism (Aylward et al., 2002). Baron-Cohen et al., 1999; Critchley et al.,
Courchesne and colleagues (2001) hypothe- 2000; Macdonald et al., 1989; Schultz et
sized that abnormal brain growth regulation al., 2000) and increased stress and anxiety
results in premature overgrowth resulting in (Amaral & Corbett, 2003; Corbett, Men-
brain enlargement, followed by a period of doza, Abdullah, Wegelin, & Levine, 2006;
protracted growth. In addition to develop- Muris, Steerneman, Merckelbach, Hol-
mental factors, distinctions based on gender drinet, & Meesters, 1998) as part of their
have been demonstrated, with males but symptom profile. Thus the amygdala, which
not females with autism showing increased is involved in these processes, has been im-
total brain volume (Piven, Arndt, Bailey, & plicated in the neuropathology of autism.
Baron-Cohen and colleagues (2000) specu- whether or not the participant is looking
lated that early dysfunction of this key brain in the eyes, may help determine whether or
structure may be largely responsible for im- not the amygdala is recruited (Dalton et al.,
paired social and emotional functioning, in 2005; Spezio, Huang, Castelli, & Adolphs,
the often-referred-to “amygdala theory of 2007). Also, as noted above, the level of
autism.” social impairment (Nacewicz et al., 2006)
Early neuropathological case series re- anxiety (Corbett, Carmean, et al., 2009; Ju-
vealed clusters of small, tightly packed neu- ranek et al., 2006) or of restricted/repetitive
rons in the medial nuclei of the amygdaloid behavior (Dziobek et al., 2006) appears to
complex of persons with autism (Bauman play a role in the structure and function of
& Kemper, 1985; Kemper & Bauman, the amygdala.
1998). More recently, a quantitative inves-
tigation using stereological analysis showed
Hippocampus
fewer neurons in the amygdala overall and
in the lateral nucleus, despite a lack of dif- Another part of the limbic system, the
ference in overall volume of the amygdala, hippocampus—located in the medial tem-
individual subdivisions, or cell size (Schu- poral lobe of the brain, and critical in the
mann & Amaral, 2006). Volumetric studies formation of long-term memory—has been
using MRI have revealed increased (Abell et shown to be enlarged in children and adoles-
al., 1999; Howard et al., 2000), decreased cents with autism as compared to neurotypi-
(Aylward et al., 1999; Pierce & Courchesne, cal peers (Schumann et al., 2004). This brain
2000), or inconclusive amygdala differences structure was also shown in early pathologi-
in subjects with autism (Corbett, Carmean, cal reports to contain smaller neurons and
et al., 2009; Palmen, Durston, Nederveen, increased cell-packing density (Kemper &
& Van Engeland, 2006). The discrepancies Bauman, 1993). However, this finding is not
across these studies may be the results of consistently observed (Bailey et al., 1998).
differences in developmental factors (Cor- Differences in the shape of the hippocampus
bett, Carmean, et al., 2009; Schumann et have also been recently reported (Dager et
al., 2004; Sparks et al., 2002), level of social al., 2007; Nicolson et al., 2006), and such
impairment (Munson et al., 2006; Nace- alterations may be associated with the sever-
wicz et al., 2006), comorbid features such ity of cognitive and neuropsychological im-
as anxiety (Corbett, Carmean, et al., 2009), pairment (Dager et al., 2007).
or restricted/repetitive behavior (Dziobek,
Fleck, Rogers, Wolf, & Convit, 2006)—all
Cerebellum
of which ostensibly play pivotal roles in the
structure (and presumably the function) of Still another key brain region showing ab-
the amygdala. normalities associated with autism at both
In addition, suggestive evidence for a the microscopic and macroscopic levels is
role of the amygdala in autism comes from the cerebellum, a brain structure often re-
a variety of functional imaging studies ferred to as “the little brain.” It is located
(e.g., Ashwin, Baron-Cohen, Wheelwright, at the base of the brain and is involved in
O’Riordan, & Bullmore, 2007; Baron- motor coordination/control and integration
Cohen et al., 1999). In general, individu- of sensory perception. Research in autism
als with ASDs show reduced or differential has revealed reduced size and number of
activation of the amygdala and the “social Purkinje neurons located in the vermis and
brain” network, amidst increased activity cerebral hemisphere, as well as atypical cer-
and greater reliance on other brain regions ebellar volumes (Bailey et al., 1998; Bauman
(e.g., superior temporal cortex and anterior & Kemper, 1985; Ritvo et al., 1986). The
cingulate cortex) (Ashwin et al., 2006; Bar- speed of growth has been shown to be more
on-Cohen et al., 1999; Corbett, Carmean, rapid, and both hypoplasia and hyperplasia
et al., 2009; Critchley et al., 2000; Schultz have been reported, ostensibly dependent on
et al., 2003; Wang, Dapretto, Hariri, Sig- the age of the cases and the region studied
man, & Bookheimer, 2004). However, it is (Courchesne et al., 1994; Hardan, Minshew,
important to note that other factors, such Harenski, & Keshavan, 2001; Hashimoto et
as the familiarity of the stimulus (Pierce, al., 1995). Since the cerebellum is involved
Haist, Sedaghat, & Courchesne, 2004) and in many brain processes, such as motor
planning, language processing, sequencing, superior parietal lobe (Iacoboni et al., 1999).
and imagery, abnormalities in structure and Human mirror neurons not only allow us to
function of the cerebellum may affect many understand and imitate actions; they also
areas of functioning related to some of the appear to be involved in understanding the
core deficits in ASDs (Bauman & Kemper, intentions of others (Iacoboni et al., 2005).
2003). Moreover, mirror neurons allow us to expe-
rience the emotions of others, thus serving
as the foundation of empathy and intention-
Neural Networks
ality (Gallese, 2003; Gallese, Keysers, &
It is apparent that early brain overgrowth Rizzolatti, 2004).
and differences in neuronal architecture set In a study using fMRI, children with ASDs
the stage for a cascade of atypical biologi- showed a lack of mirror neuron activity in
cal events and connections contributing to the pars opercularis of the inferior frontal
broad limitations in perceptual and cogni- gyrus, which was negatively correlated with
tive processes. Complementing this idea, one social impairment (Dapretto et al., 2006).
of the current leading hypotheses conceptu- Similar findings have been reported in stud-
alizes ASDs as resulting from developmental ies using event-related potentials, thereby
disconnection between key highly evolved supporting the hypothesis that the mirror
neural structures (Frith, 2004; Geschwind neuron system may be dysfunctional in au-
& Levitt, 2007). Converging evidence from tism (Oberman et al., 2005). Furthermore,
widespread disturbances in circuitry, cyto- reduction in gray matter in the mirror neu-
architecture, brain structure, and function ron region has been reported in individuals
suggest that higher-order association areas with ASDs (Hadjikhani, Joseph, Snyder, &
are disturbed (e.g., Bauman & Kemper, Tager-Flusberg, 2006), as have atypical acti-
2005; Carper & Courchesne, 2005; Just, vation patterns associated with face process-
Cherkassky, Keller, Kana, & Minshew, ing (Hadjikhani, Joseph, Snyder, & Tager-
2007; Koshino et al., 2008), and that such Flusberg, 2007).
disturbances are likely to be results of early
disruption in distributed networks. It is ap-
parent that combining neuroscientific ap- Neurobiology
proaches in hypothesis-driven theoretical
ways may provide complementary informa- Many neurochemical investigations of au-
tion and significantly advance our under- tism have been conducted. The identifica-
standing of ASDs. tion of biological markers has the potential
to facilitate the early and accurate diagnosis
of ASDs, to provide direction for biologi-
Mirror Neurons
cally based treatments, and to facilitate the
In addition, the synthesis of single-cell inves- identification of subgroups or phenotypes
tigations and animal studies may hold the within the spectrum. The more promising
key to aberrant neural substrates important pursuits involve serotonin (5-HT), oxytocin
in perspective taking, imitation, and em- (OT), acetylcholine, cortisol, glutamate, and
pathy in ASDs. In the early 1990s, several GABA; research on these is briefly reviewed.
Italian scientists led by Giacomo Rizzolatti Studies of dopamine, norepinephrine, and
were using single-cell recording to study the endogenous opioids have been less fruitful.
neurons involved in grasping when they ob-
served that the same nerve fired when a mon-
Serotonin
key reached to pick up an object or when the
monkey simply viewed a human picking up 5-HT is arguably the most studied neuro-
the object (Fogassi et al., 1992). The discov- biological candidate. 5-HT is derived from
ery of these so-called “mirror neurons” pro- the fatty acid tryptophan. Serotonergic neu-
vides a simple mechanism for understanding ron cell bodies are primarily distributed in
the actions of others by experiencing the clusters in the raphe nuclei of the medulla,
action passively in one’s mind. In humans, pons, and midbrain. The behavioral effects
fMRI studies have localized a mirror neuron of 5-HT are vast and complex; they include
system to the inferior frontal cortex and the the regulation of mood, arousal, hormone
release, pain sensitivity, eating, sexual be- interactions among the hypothalamus, the
havior, and temperature. One of the more pituitary gland, and the adrenal glands. The
consistent early biological findings in autism LHPA axis is involved in the regulation of
relates to hyperserotonemia, which occurs in many biological processes involving mood
approximately one-third of individuals with and emotions, energy metabolism, digestion,
autism (e.g., Anderson et al., 1987; McBride immune functioning, and sexual behavior.
et al., 1998; Ritvo et al., 1970; Schain & The responsiveness of the LHPA axis is af-
Freedman, 1961) as well as family members, fected by specific psychological and social
suggesting a genetic susceptibility (Cook, factors, which can enhance or diminish the
Leventhal, & Freedman, 1988; Cook et al., stress response (e.g., Levine, 2000; Levine
1990; Leventhal, Cook, Morford, Ravitz, & Mody, 2003).
& Freedman, 1990). It has since been de- A growing body of research has focused
termined that the majority of whole-blood on the functioning of the LHPA axis in
5-HT resides in the platelets, which is the terms of the diurnal regulation, stress re-
factor contributing to the elevated levels sponsiveness, and feedback mechanisms of
of 5-HT in autism (Anderson et al., 1987; key regulatory hormones. Some early stud-
Cook et al., 1988). However, research has ies reported dysfunction of the tonic regu-
shown that the prevalence of hyperserotone- lation of the LHPA axis in autism (Nir et
mia within autism is influenced by pubertal al., 1995; Yamazaki, Saito, Okada, Fujieda,
status (lower 5-HT in postpubertal youth) & Yamashita, 1975) as well as alterations
and race (European American youth show in the normal circadian rhythm (Aihara &
lower 5-HT than Hispanic or African Amer- Hashimoto, 1989; Hill, Wagner, Shedlarski,
ican youth), emphasizing the importance of & Sears, 1977; Hoshino et al., 1984), which
controlling for these potential confounds in appeared more prominent in low-functioning
neurobiological research (McBride et al., children with autism. Nevertheless, other
1998). In addition, the measurement of pe- investigations have failed to replicate such
ripheral 5-HT makes it challenging to form findings (Richdale & Prior, 1992; Tordjman
assumptions about central effects. Thus the et al., 1997), instead suggesting that amidst
primary metabolite of 5-HT, 5-hydroxyin- normal temporal placement of the diurnal
doleacetic acid (5-HIAA), investigated via rhythm, elevations in cortisol during the
CSF, PET, and treatment studies, has led day may reflect enhanced stress (Richdale &
to the notion that developmental regulation Prior, 1992). Differences in concentration of
of 5-HT synthesis is dysregulated in autism adrenocorticotropic hormone have also been
(Whitaker-A zmitia, 2005). In fact, two reported (Curin et al., 2003). An important
polymorphisms have been reported for the confounding factor in some of the the ear-
serotonin transporter gene (SLC6A4) (e.g., lier studies relates to the potential stressful
Cook, Courchesne, et al., 1997; Tordjman et effects of venipuncture; this confound has
al., 2001; Yirmiya et al., 2001). The afore- been minimized with the advent of salivary
mentioned literature of a plausible “sero- cortisol as a valid and reliable index of the
tonin hypothesis” of autism has contributed unbound hormone in blood (Kirschbaum &
to the pursuit of pharmaceutical treatment. Hellhammer, 1994). Thus the majority of re-
Importantly, selective serotonin reuptake cent investigations evaluate cortisol, one of
inhibitors (SSRIs) are among the most fre- the primary glucocorticoid hormones in hu-
quently prescribed psychotropic medications mans. Cortisol follows a circadian rhythm:
for individuals with autism (Langworthy- high concentrations in the morning, a decline
Lam, Aman, & Van Bourgondien, 2002). throughout the day, and the lowest levels in
the evening. Response to stress in salivary
cortisol can be detected approximately 20
The Limbic–Hypothalamic–Pituitary–
minutes after presentation of a stressor.
Adrenal Axis and Cortisol
Recent work has shown that children
In addition to being a key regulatory sys- with high-functioning autism demonstrate
tem of stress, the limbic–hypothalamic– notable variability in diurnal rhythmicity,
pituitary–adrenocortical (LHPA) axis is a higher evening cortisol, and alterations in
major part of the neuroendocrine system. As morning cortisol over time (Corbett et al.,
its name indicates, it involves a network of 2006; Corbett, Mendoza, Wegelin, Car-
mean, & Levine, 2008). Importantly, the early reports suggest that administration of
variability in the cortisol rhythm of persons OT may improve the ability of adults with
with autism may be related to such factors ASDs to determine the emotional signifi-
as sensory sensitivity and cumulative stress cance of speech (Hollander et al., 2007) and
associated with changes in routine through- may reduce repetitive behaviors (Hollander
out the day (Corbett, Schupp, Levine, & et al., 2003). Most recently, genetic associa-
Mendoza, 2009). In addition, several studies tions have been reported between the OT
have shown an exaggerated stress response receptor gene (OXTR) and autism (Jacob et
to various medical and environmental events al., 2007; Wu et al., 2005; Ylisaukko-oja et
(Corbett et al., 2006; Maher, Harper, Ma- al., 2006).
cleay, & King, 1975; Richdale & Prior, 1992;
Tordjman et al., 1997), although individual
Melatonin
and group differences exist (Corbett, Men-
doza, et al., 2008). These findings emphasize The sleep patterns of individuals with
the notable heterogeneity in ASDs not only ASDs have been reported to be disturbed
in behavioral profile, but in underlying bio- to varying degrees (Goodlin-Jones, Tang,
logical presentation. Liu, & Anders, 2008; Johnson & Malow,
2008; Krakowiak, Goodlin-Jones, Hertz-
Picciotto, Croen, & Hansen, 2008; Malow,
Oxytocin
McGrew, Harvey, Henderson, & Stone,
OT is a hypothalamic peptide synthesized in 2006). Melatonin (also known chemically as
the paraventricular nucleus and the supraop- N-acetyl-5-methoxytryptamine), a naturally
tic nucleus. Receptors for OT are located occurring hormone produced by the pineal
throughout the brain, including the limbic gland, is considered a key regulator of cir-
system. OT is crucial to the formation of so- cadian and seasonal rhythms and is impor-
cial bonds (Carter, 1998; Insel, 1997; Insel tant for human cognition. Low and abnor-
et al., 1993; Winslow, Noble, Lyons, Sterk, mal patterns of melatonin (Nir et al., 1995;
& Insel, 2003; Winslow, Shapiro, Carter, Tordjman, Anderson, Pichard, Charbuy, &
& Insel, 1993). Research with both animal Touitou, 2005), which ostensibly contribute
models (e.g., Bales, Kim, Lewis-Reese, & Sue to reported sleep disturbances, have been
Carter, 2004; Carter, 1998; Insel, O’Brien, noted in individuals with ASDs. Recently,
& Leckman, 1999; Winslow et al., 2003; evidence for a link between low melatonin
Young, Wang, & Insel, 1998) and humans level and the ASMT gene (which encodes
(Kirsch, et al., 2005; Kosfeld, Heinrichs, the last enzyme of melatonin synthesis) has
Zak, Fischbacher, & Fehr, 2005) provides been reported; this is hypothesized to be a
compelling evidence for the involvement of risk factor for ASDs (Melke et al., 2008).
OT in mediating complex social behavior. Such neurobiological and genetic findings
Furthermore, it appears that OT is an im- provide support for a role of synaptic and
portant moderator of stress (Carter, 1998; clock genes as susceptibility risk factors in
Kirsch et al., 2005; Kosfeld et al., 2005; ASDs (Bourgeron, 2007). Moreover, recent
Neumann, 2002; Neumann, Kromer, To- investigations showing the beneficial effects
schi, & Ebner, 2000). of melatonin in the treatment of ASDs and
Due to its important role in social behav- sleep disturbances has been promising (An-
ior, OT has been proposed as a plausible dersen, Kaczmarska, McGrew, & Malow,
neurobiological substrate in autism (Insel, 2008; Garstang & Wallis, 2006; Giannotti,
1997). Previously it was reported that in- Cortesi, Cerquiglini, & Bernabei, 2006)
dividuals with autism exhibit impaired OT
processing, resulting in higher levels of plas-
Glutamate and GABA
ma OT-X (a precursor to the normal adult
form of OT) and lower levels of OT itself Glutamate and GABA are two essential neu-
(Green et al., 2001; Modahl et al., 1998). rotransmitters in the CNS; they are princi-
Furthermore, higher levels of OT have been pally responsible for excitatory and inhibi-
found in autistic children characterized as tory communication throughout the brain,
aloof (Modahl et al., 1998). Although treat- respectively. Since many brain regions have
ments have only recently been explored, been implicated in the neuropathology of
autism, research on the functioning of these vention offer the best opportunity for the
neurotransmitters would seem to be a prom- optimal development and outcome of chil-
ising area, but they have received compara- dren with ASDs (Birnbrauer & Leach, 1993;
tively limited consideration. The majority Harris, Handleman, Gordon, Kristoff, &
of the findings suggest that the GABAergic Fuentes, 1991; Lovaas, Newsom, & Hick-
system in autism is suppressed and there- man, 1987). The impact of experience on
fore results in enhanced glutamate activity the developing brain is particularly strong
(Fatemi, 2008a; Fatemi et al., 2002; Huss- for the acquisition of certain skills (Knud-
man, 2001). As noted, approximately 30% sen, 2004), such as language and social
of persons with autism have comorbid sei- skills (Wetherby, Watt, Morgan, & Shum-
zures (Volkmar & Nelson, 1990). GABA(B) way, 2007). Outcome predictors include age
receptors play a critical role in maintaining at time of admission, level of IQ, language
the excitatory–inhibitory balance in the functioning, and diagnostic severity (e.g.,
CNS, such that imbalance in these regula- Smith, Groen, & Wynn, 2000). It is believed
tory receptors can result in seizures. Re- that the success of early intervention may be
cently, Fatemi and colleagues (2009) inves- due to brain plasticity (Dawson & Zanolli,
tigated four GABA(B) receptor subunits in 2003).
the cerebellum, Brodmann area 9 (BA 9),
and BA 40, showing reductions in the levels
of at least two of the GABA subunits. In- Behavioral Approaches
terestingly, the presence of seizures did not Applied Behavior Analysis
significantly alter GABA expression. The
findings provide strong evidence for perva- Applied behavior analysis (ABA) is based on
sive GABAergic dysfunction in the brains of scientifically derived theories of learning and
persons with autism. behavior. ABA breaks down complex behav-
iors into individual teachable skills through
a process referred to as task analysis. These
Treatment skills are then taught in a systematic, step-
by-step format as part of an individual-
Even when individuals with ASDs share be- ized, comprehensive behavioral program.
havioral and genetic profiles, it is important This use of intensive, structured behavioral
to keep their unique strengths, challenges, methods was introduced by Lovaas (e.g.,
and needs in mind when choosing among Lovaas, 1987; Lovaas, Koegel, & Schreib-
available treatment options. Individualized man, 1979). In Lovaas’s approach, a trainer
treatments may include consultations with gives an instruction or presents a stimulus,
and services from a number of profession- requires a behaviorally defined response
als and paraprofessionals, including medical from the child, and presents a consequence
doctors, psychiatrists, geneticists, psycholo- that either rewards an appropriate response
gists, teachers, classroom support services, or marks an inappropriate one. The system-
speech and language therapists, occupation- atic presentation of a stimulus, including the
al therapists, and physical therapists. More- child’s response or nonresponse, is common-
over, it has been strongly suggested that care ly known as a trial. Consequently, ABA is
providers and educators receive specialized sometimes referred to as discrete-trial train-
training in ASDs to be most effective. Inter- ing. Although the two terms have become
vention models that utilize more intensive virtually interchangeable, ABA is intended
and interactive training, including hands- to refer to the science of behavior analysis
on activities, modeling, practice, and feed- (Kates-McElrath & Axelrod, 2006).
back, appear most effective (Swiezy, Stuart, Not only do successful ABA programs
& Korzekwa, 2008). Consistency is critical teach skills; they also utilize functional be-
not only in a child’s behavioral and educa- havior analysis to reduce maladaptive be-
tion programming, but also in service deliv- haviors that impede the effectiveness of edu-
ery across medical, home, educational, and cational and intervention programs (Matson
community settings (Swiezy et al., 2008). & Rivet, 2008; Murphy et al., 2005). Mal-
Regardless of treatment choice, it is well adaptive behaviors in autism can range
established that early diagnosis and inter- from stereotypical actions that are odd but
harmless, such as rocking or hand flapping, play (Stahmer, 1995), and social behaviors
to self-injury, such as biting or head bang- (Pierce & Schreibman, 1997).
ing. In addition, some individuals with au-
tism may exhibit impulsive behaviors (e.g.,
Developmental Approaches
running into traffic) or aggressive behav-
iors (e.g., hitting others) (Joosten, Bundy, Developmental treatments for autism focus
& Einfeld, 2009; Matson & Rivet, 2008). on a child’s inherent strengths to increase so-
The ABA approach takes great care to en- cial, emotional, and cognitive skills.
sure that behavioral improvements are the
direct results of the employed technique
Developmental, Individual-Difference,
(e.g., Steege, Mace, Perry, & Longenecker,
Relationship-Based/Floortime Model
2007). Despite procedural concerns regard-
ing Lovaas’s initial research (Gresham & The floortime model assumes that a child’s
Macmillan, 1997; Mundy, 1993; Schopler, actions are purposeful. Within this frame-
Short, & Mesibov, 1989), it is well estab- work, the caregiver is encouraged to build
lished that early intervention based on ABA a relationship by following the child’s lead
can result in significant, comprehensive, and (Wieder & Greenspan, 2003). It is believed
lasting improvements for children with au- that social and communication skills will
tism (e.g., Birnbrauer & Leach, 1993; Eike- follow. Independent, peer-reviewed studies
seth, Smith, Jahr, & Eldevik, 2002; Lovaas, on this method are lacking.
1987; Lovaas et al., 1979; Lovaas & Smith,
1989; McEachin, Smith, & Lovaas, 1993;
Relationship Development Interaction
Smith et al., 2000).
Relationship development interaction (RDI)
attempts to address the social deficits of
Verbal Behavior Intervention
autism by fostering positive interactions.
Verbal behavior intervention is sometimes Proponents believe that the experience of
used along with ABA; it is based on B. F. positive social interactions will encourage
Skinner’s work proposing that language, just a child to value interpersonal relationships,
like any other behavior, is based on oper- and thus will promote the acquisition of lan-
ant principles (Sundberg & Michael, 2001). guage and social skills. Some research indi-
Skinner considered a functional analysis of cates that this may be an effective treatment
language to consist primarily of mands (re- to enhance the social-emotional functioning
quests), tacts (words that are under the con- of children with ASDs (Mahoney & Perales,
trol of the nonverbal environment, including 2003).
nouns, verbs, adjectives, etc.), echoics (vocal
imitation), and intraverbals (conversational
Educational Approaches
language).
A number of public school systems utilize
Treatment and Education of Autistic and
Pivotal Response Training
related Communication-Handicapped Chil-
Although based on the principles of ABA, dren (TEACCH) procedures. In the TEACH
pivotal response training (PRT) targets model, a variety of approaches are used to
behavioral change in a different manner. address an individual’s deficits while en-
Whereas ABA targets individual behaviors couraging independence. A TEACCH class-
and teaches specific skills (e.g., putting a shirt room has well-defined work stations for
on), PRT focuses on increasing children’s separate tasks and relies on visual supports
motivation by focusing on their interests and (written or picture schedules). Several stud-
responding to their initiations. Pivotal skills ies have demonstrated the effectiveness of
such as communication, social exchanges, the TEACCH model in regard to learning,
and self-management are targeted. Research communication, socialization, self-care,
indicates that PRT is successful at increas- and behavior improvements (Panerai, Fer-
ing language ability in children with autism rante, & Caputo, 1997; Schopler, 2000;
(Koegel, O’Dell, & Koegel, 1987; Laski, Schopler, Brehm, Kinsbourne, & Reichler,
Charlop, & Schreibman, 1988), symbolic 1971).
Visual Approaches and language therapy includes the teaching

of nonverbal communication and augmenta-
Video Modeling
tive communication skills.
Video modeling is a well-validated behavior-
al intervention that relies on visual–auditory
Occupational Therapy
technology for the active presentation of ma-
terial on a television or computer screen. Tar- Occupational therapy remediates fine and
geted behaviors are presented to the learner gross motor skills, as well as sensory pro-
in short scenes that are viewed, imitated, and cessing deficits. Many people with autism
practiced. Video modeling has been shown are hypersensitive or hyposensitive to touch,
to be particularly helpful for children with light, or noise. Sensory integration tech-
autism, as a result of reducing the field of niques used to address such concerns may
view, providing the opportunity for repeated include sensory brushing, swinging bounc-
viewing of the targeted behavior, and pre- ing, or deep pressure. Although anecdotal
senting the material in a highly reinforcing reports indicate improvement in regulation
format (Corbett & Abdullah, 2005). Such and focus (Iarocci & McDonald, 2006;
modeling has been used to target a variety Kane, Luiselli, Dearborn, & Young, 2004),
of behaviors, including language, social there is a lack of empirically driven research
skills, perspective taking, play, academics, to support the efficacy of these approaches
and adaptive skills (Charlop-Christy, Le, & (Baranek, 2002; Dawson & Watling, 2000;
Freeman, 2000; Charlop & Milstein, 1989; Kane et al., 2004).
Corbett, 2003; LeBlanc et al., 2003).
Social Skills Training
Picture Exchange Communication System
Difficulties in relating to people and engag-
The Picture Exchange Communication ing in reciprocal conversation are core fea-
System (PECS) is an augmented communi- tures of ASDs. Although reciprocal conver-
cation system that utilizes pictures to help sation skills are typically learned through
children with autism functionally commu- common day-to-day events of a child’s life,
nicate (Bondy & Frost, 1994; Siegel, 1999). it is often necessary to teach these skills
Communicating with pictures is especially directly and specifically to a child with an
helpful for those with motor planning dif- ASD. Basic skills include eye contact, lis-
ficulties who have trouble engaging in sign tening, joint attention, imitation, and turn
language. A study evaluating the efficacy of taking. Successful social interactions also
this system found that children with autism require the sophisticated integration of non-
demonstrated improvements in social com- verbal communication (e.g., facial expres-
munication and a decrease in maladaptive sion, body language, communicative ges-
behaviors (Charlop-Christy, Carpenter, Le, tures), verbal communication (e.g., tone of
LeBlanc, & Kellet, 2002). voice, prosody), perspective taking, emotion
processing, and many other social signals.
Many types of social skill interventions have
Specific Treatments
been developed, such as trained-peer inter-
Depending on a child’s individual needs, it actions, social skills groups, cartoon stories,
may also be important to include other ther- social scripts, video modeling (see above),
apies in a tailored treatment approach. and drama therapy. Specific approaches
include Michelle Garcia Winner’s Social
Thinking Curriculum (www.socialthinking.
Speech Therapy
com) and Carol Gray’s Social Stories (www.
Speech therapy is used not only to habilitate thegraycenter.org).
articulation errors, but also to enhance social Well-designed studies have shown several
and communication skills through the devel- of these strategies to be effective. For exam-
opment of pragmatic language. Pragmatic ple, a 20-week curriculum was designed to
language training assists those who misuse address the social-emotional functioning of
language or misunderstand the meaning or 18 boys ages 8–12 years who were diagnosed
intent of others’ communications. Speech with autism, Asperger syndrome, or PDD-
NOS (Solomon, Goodlin-Jones, & Anders, drug-related dyskinesias (abnormal involun-

2004). Specific targeted skills included basic tary movements); thus other medications,
conversation, facial recognition, emotional such as atypical antipsychotics, are often
understanding, and individual and group considered (Campbell et al., 1997). Atypical
problem solving. While the boys attended antipsychotics, such as risperidone, not only
the 90-minute social skills sessions, their affect dopamine but also reduce 5-HT (Posey
parents participated in semistructured psy- et al., 2008). A number of studies have de-
choeducational training. The study showed termined the effectiveness of risperidone for
statistically significant improvements in emo- behaviors associated with autism. For exam-
tion recognition and problem-solving ability, ple, a double-blind, placebo-controlled study
and a reduction in inappropriate behaviors. of adults with autism found that risperidone
In addition, decreases on depression scores was effective for the reduction of repetitive
were found for older and more cognitively and aggressive behaviors (McDougle et al.,
impaired boys and for mothers (Solomon et 1998). In addition, the Research Units on
al., 2004). (For excellent reviews of other so- Pediatric Psychopharmacology (RUPP) Au-
cial skill interventions, see Rao, Beidel, & tism Network completed an 8-week, dou-
Murray, 2008; Rogers, 2000; and Stichter, ble-blind, placebo-controlled study of ris-
Randolph, Gage, & Schmidt, 2007.) peridone for children and adolescents with
autism. A 57% reduction in rate of irritabil-
ity was noted in the individuals treated with
Pharmaceutical Approaches
risperidone, as compared with a 14% reduc-
As noted throughout this chapter, the be- tion in the placebo group (McCracken et al.,
havior problems of individuals with ASDs 2002). These, among other studies, led to
may hinder their ability to function in the the FDA’s 2006 approval of risperidone for
world. Psychopharmacological treatments the treatment of irritability, aggression, self-
are frequently considered when behavioral injury, and temper tantrums in children and
or educational approaches do not adequate- adolescents with autism (www.fda.gov/bbs/
ly manage problematic behaviors. Although topics/news/2006). Other atypical antipsy-
few medications have been approved for the chotics have been considered to treat autistic
treatment of ASDs by the U.S. Food and symptoms, including olanzapine (Zyprexa)
Drug Administration (FDA) (www.fda.gov/ (Potenza, Holmes, Kanes, & McDougle,
bbs/topics/news/2006), a number of medi- 1999) and ziprasidone (Geodon) (Malone,
cations for ASDs are prescribed “off-label”; Delaney, Hyman, & Cater, 2007).
that is, they are prescribed to individuals or Although SSRIs are usually prescribed
for symptoms outside the scope approved by for symptoms of anxiety, depression, and
the FDA (Moussavand & Findling, 2007). obsessive–compulsive disorder, a number of
It appears that a large percentage of indi- studies (e.g., DeLong, Teague, & McSwain
viduals on the autism spectrum take some Kamran, 1998) have found decreased repeti-
form of medication. Two surveys found that tive behaviors, along with improvement in
approximately half of subjects with PDDs language, and social behaviors. Children
were taking prescription medications (Aman, with autism have also been treated with anti-
Lam, & Van Bourgondien, 2005; Hanson et convulsants (Aman, Van Bourgondien, Wol-
al., 2007). One of these surveys (Aman et ford, & Sarphare, 1995), such as topriamate
al., 2005) found that 16.5% of participants (Topomax) and valproic acid (Depokote),
were prescribed an antipsychotic drug. An- as well as stimulant medications (Ritalin)
tipsychotic medications have been used for to decrease impulsivity and hyperactivity
some time to treat severe behavior problems, (Quintana et al., 1995).
presumably by reducing the activity of dop-
amine in the brain (Posey, Stigler, Erickson,
& McDougle, 2008). The typical antipsy- Controversial Topics
chotic haloperidol (Haldol) has been used
to treat autism-related hyperactivity, aggres- Autism has long been plagued by a pletho-
sion, withdrawal, and stereotypic behavior ra of controversial theories and treatments
(McCracken et al., 2002). However, Haldol spawned from anecdotal reports, parental
has been associated with the development of urgency, and sensationalized media reports.
Most of these have not been subjected to rig- Tomatis and Related Methods
orous clinical research. It is easy to under-
The Tomatis method, which has often been
stand how parents looking for solutions will
compared to auditory integration therapy
eagerly consider alternative ideas and treat-
(Berard, 1993), is another controversial
ments; however, pursuing ineffective inter-
treatment showing limited if any benefit
ventions, even if they are not actively harm-
ful, wastes valuable time and resources that for children with autism (for a review, see
might be applied to more meaningful and Baranek, 2002). Both the Tomatis method
productive endeavors (Baranek, 2002). and auditory integration therapy are forms
of sound therapy that use high- and low-
frequency-fi ltered music designed to modu-
Complementary and Alternative late the acoustical signal. Anecdotal reports
Medicine of Tomatis claim that using modified music
Complementary and alternative medicine stimulates connections between the ear and
(CAM) treatments are often selected by the CNS, resulting in improved communica-
parents because they ostensibly target the tion and behavior in children with autism
causes of autism, as opposed to the symp- (Thompson & Andrews, 2000). However,
toms. Levy and Hyman (2005) have cat- in a recent double-blind, placebo-controlled,
egorized CAM approaches based on the crossover study, no treatment effects were
proposed mechanisms underlying the symp- observed (Corbett, Shickman, & Ferrer,
toms: immune modulation, gastrointestinal 2008).
functioning, neurotransmitter functioning, Other methods lacking empirical support,
or nonbiological mechanisms. The use of to name a few, include the Rapid Prompt-
CAM approaches is widespread, as shown in ing Method and the Son-Rise Program. The
a large chart review study from one leading Rapid Prompting Method incorporates near-
U.S. children’s hospital revealing that such ly continuous interaction and prompting,
approaches had been used for 30% of chil- paired with an alphabet board for responses
dren with autism; in 9% of these cases, the (www.halo-soma.org). The Son-Rise Pro-
methods were considered potentially dan- gram emphasizes building a non-force-
gerous (Levy, Mandell, Merhar, Ittenbach, based, nonjudgmental relationship with a
& Pinto-Martin, 2003). Several CAM treat- child (www.autismtreatmentcenter.org).
ments that have captivated certain sectors
of the autism community; some of these are Biomedical Treatments
described below.
Finally, biomedical treatments for ASDs are
based on the idea that specific in utero or
Secretin postbirth environmental insults may con-
A highly publicized patient series reported tribute to the onset of these disorders. Bio-
the incidental findings of improved social medical theories contend that interactions
and language skills in three children with between genes and environment have the
ASDs following the administration of se- potential to trigger an ASD. Environmental
cretin, a peptide hormone (Horvath et al., insults are thought to include toxic chemicals
1998). Despite the absence of empirical evi- (e.g., heavy metals, medications, antibiotics,
dence regarding the amelioration of symp- pesticides, preservatives), as well as reduc-
toms, parents eagerly sought secretin treat- tions in nutrients presumably due to modern
ment. As a result, dozens of experimental food preparation, cooking, and diet (Tay-
trials were initiated to investigate the effect lor & Rogers, 2005). Although biomedical
of single and repeated doses of intravenous concerns encompass all major systems of the
porcine secretin; many of these were well- body, the most widely publicized biomedi-
designed, double-blind, placebo-controlled cal treatments have been associated with the
crossover trials. The results consistently gastrointestinal and immune systems.
showed secretin’s lack of efficacy for the Gastrointestinal concerns have included
treatment of autistic disorder (e.g., Corbett the so-called “leaky gut syndrome,” which
et al., 2001; Levy, Souders, et al., 2003; purportedly leads to increased permeabil-
Owley et al., 2001; Sandler et al., 1999). ity of the intestines, resulting in an inability
to break down proteins from dairy (casein) effects contributing to the onset of autism
and grains (gluten). Gluten–casein elimina- (e.g., Bernard, Enayati, Redwood, Roger, &
tion diets have been designed to target this Binstock, 2001; Hornig, Chian, & Lipkin,
problem (Cornish, 2002; Knivsberg, Re- 2004). Although the point is still being con-
ichelt, Hoien, & Nodland, 2002). It is fur- tended by some, the Immunization Safety
ther theorized that gastrointestinal problems Review (2004) refuted a causal link between
and poor absorption of nutrients may result autism and vaccines containing thimerosal.
in nutritional imbalances or deficiencies, as The potentially dangerous aftermath of such
well as a buildup of toxins in the system. poorly investigated claims is demonstrated
Proponents have subsequently recommended through the unfortunate reoccurrence of
supplemental enzymes, vitamins, and min- measles. Measles was thought to be eradi-
erals to address nutritional deficiencies. De- cated in the United States; however, 64 new
toxification with vitamin B12 and chelation confirmed cases were reported to the Cen-
therapy have both been used to diminish the ters for Disease Control and Prevention in
alleged buildup of heavy metals in body tis- 2008. It is thought that this increase was at
sue (Martineau, Barthelemy, Cheliakine, & least partially due to the unsupported links
Lelord, 1988). Other measures have includ- between immunizations and ASDs.
ed the use of intravenous immune globulin
in which antibodies extracted from plasma
are administered to treat the immune system Comorbidity and Phenotypes
and are alleged to address core symptoms of
autism. For more information, see the Au- Comorbid symptoms, such as anxiety, de-
tism Research Institute website (www.au- pression, and attention-deficit/hyperactivity
tism.com). disorder (ADHD), contribute to the hetero-
geneous ASD profile. Children and adoles-
It is important to note that most CAM ap- cents with ASDs experience significantly
proaches are not generally accepted by the greater mood disturbance and anxiety than
mainstream medical community, as they are peers do (Gillott, Furniss, & Walter, 2001;
often based on anecdotal reports and limited Kim, Szatmari, Bryson, Steiner, & Wilson,
scientific evidence or theory. Levy and col- 2000). It has also been shown that more se-
leagues have methodically reviewed many vere cases of autism are often distinguished
CAM practices, providing the rationale to by the presence of anxiety (Rescorla, 1988).
refute the use of several, while presenting It has been suggested that social skills and
emerging evidence for some that are prom- physiological arousal may provide protective
ising (Levy & Hyman, 2005, 2008; Levy, and predisposing factors, respectively, in ad-
Mandell, et al., 2003). olescents with ASDs (Bellini, 2006).
Despite the frequent report of co-occurring
ADHD symptoms, the current diagnostic
The Vaccine Controversy
manual (APA, 2000) prevents the practice of
More than a decade of confusion ensued diagnosing ADHD along with a PDD. Nev-
after a leading medical journal, Lancet, pub- ertheless, neuropsychological models are
lished Andrew Wakefield’s 1998 article con- emerging to elucidate the co-occurrence of
tending that ASDs and the measles/mumps/ ASDs and ADHD, and to support the high
rubella vaccine were linked. In February preponderance of comorbid features (e.g.,
2010, Lancet retracted the entire study from Corbett & Constantine, 2006; Corbett,
published record after the General Medi- Constantine, Hendren, Rocke, & Ozonoff,
cal Council of the United Kingdom found 2009; Geurts, Verte, Oosterlaan, Roeyers,
Wakefield’s findings to be false. The asso- & Sergeant, 2004; Goldberg et al., 2005;
ciation between ASDs and vaccines appears Goldstein & Schwebach, 2004; Landa &
to be essentially a temporal link, due to the Goldberg, 2005). An additive or interac-
fact that symptoms often begin between 18 tive effect stemming from dysfunction in
and 24 months of age—a period that often various neural networks may contribute to
coincides with immunizations. It was also the heterogeneous profile (e.g., Castellanos,
suggested that thimerosol, a mercury-based Sonuga-Barke, Milham, & Tannock, 2006;
preservative for many vaccines, had toxic Nigg, Willcutt, Doyle, & Sonuga-Barke,
2005; Sergeant, Geurts, Huijbregts, Scheres, they are for children with ASDs (Matson &
& Oosterlaan, 2003; Sonuga-Barke, 2005). Rivet, 2008).
It has been proposed that children with
both sets of symptoms are more function-
ally impaired and may respond differently Conclusions
to treatment (Arnold et al., 2006; Goldstein
& Schwebach, 2004; Kadesjo & Gillberg, It is important to note that this brief review
2001; Posey, et al., 2006). of some key findings about ASDs is not ex-
haustive and cannot begin to capture the
depth and breadth of this ever-expanding
Adult Care and Treatment field. It is apparent that in order to make
sense of this complex spectrum of neurode-
Most ASD research focuses on the assess- velopmental disorders, many approaches,
ment and treatment of children, whereas ranging from cellular to behavioral, need
comparatively little is known about adults to be employed and synthesized. However,
with ASDs (Eaves & Ho, 2008). Investiga- equally important are multidisciplinary ef-
tions to determine the particular concerns of forts to bring together discrepant findings
both young adults and elderly persons with and to create models that may ultimately lead
ASDs are clearly needed. Limited research to workable theories. For example, identify-
in sexuality reveals that adults with autism ing the similarities and differences in neuro-
demonstrate both appropriate and inappro- anatomy and comparing these with clinical
priate sexual desires, understanding, and presentations will permit expanded insight
behaviors (Hellemans, Colson, Verbraeken, into underlying neurobiology (Bauman &
Vermeiren, & Deboutte, 2007; Stokes, New- Kemper, 2003). Although the field has ac-
ton, & Kaur, 2007). A 5-year longitudinal cumulated significant data, such findings
follow-up study measured the lifestyle out- are infrequently integrated into systematic
comes of 140 males with ASDs; occupation, theories or translated into new hypothesis-
living situation, interpersonal relationships, driven treatments. Currently, the ASD field
and participation in leisure activities were is poised to usher in a new era grounded in
assessed (Cederlund, Hagberg, Billstedt, the scientific method—an era that “moves
Gillberg, & Gillberg, 2008). In general, indi- beyond the descriptive phase of observations
viduals with Asperger syndrome fared better to form hypotheses, collect data systemati-
than those with autism. Twenty-seven per- cally, define the evidence, and establish test-
cent of those with Asperger syndrome dem- able theories” (Zimmerman, 2008, p. vi).
onstrated good outcomes, whereas the re- There is a tendency in the field to leap
mainder reported fair to poor outcomes. Of quickly from data to theory, without the nec-
the individuals with autism, none reported essary systematic replication and validation
good outcomes, and the majority reported steps in between. This is especially critical
very poor outcomes. Not surprisingly, lower in the study of a population with such a het-
IQ was associated with poorer outcomes erogeneous presentation. To this end, there
for both groups (Cederlund et al., 2008). has been a concerted effort in the field to use
Regarding emotional status, relatively high consistent diagnostic tools to improve the se-
rates of depression, anxiety, and suicidal lection, identification, and characterization
ideation have been described in adults with of persons with ASDs. Furthermore, larger
ASDs (Shtayermman, 2007). Currently, a studies using comparable methodologies are
few successful interventions are directed at needed to replicate and extend promising
teaching adults with autism. For example, findings from smaller pilot studies. The ex-
the TEACCH approach has been successful- panded awareness of ASDs has also resulted
ly adapted to work with adults (Van Bour- in exponential growth of a broad array of
gondien & Schopler, 1996). In addition, a approaches and interpretations. Amidst the
10-session, 2- to 3-hour program designed greater insight, however, the ASD field has
to teach self-determination has shown been plagued by a number of isolated and
promise (Fullterton, 1999). Importantly, unusual findings that have resulted in public
challenging behaviors must be considered debate and unfounded theories. This state
when designing programs for adults, just as of affairs has detoured scientific inquiry
and funding. Thus, in the years to come, it Andersen, I. M., Kaczmarska, J., McGrew, S. G., &
will be important to allow rigorous scien- Malow, B. A. (2008). Melatonin for insomnia in
tific findings to guide the field, rather than children with autism spectrum disorders. Journal
public opinion or anecdotal reports in the of Child Neurology, 23(5), 482–485.
Anderson, G. M., Freedman, D. X., Cohen, D. J.,
mass media. In the process, meaningful iso- Volkmar, F. R., Hoder, E. L., McPhedran, P., et
lated findings will have an opportunity to al. (1987). Whole blood serotonin in autistic and
emerge and be integrated into system-based normal subjects. Journal of Child Psychology and
approaches that can be explored in sound Psychiatry, 28(6), 885–900.
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A. N., Hall, K. L., Thompson, S., et al. (2006).
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symbolic ladder in the DIR model through floor J., Lee, L. C., Singer, H. S., Castaneda, J. A.,
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P a r t III
Disorders with
Broader-Spectrum Effects
C h a p t e r 13
Turner Syndrome
M. Paige Powell
Timothy Schulte
Turner syndrome (TS) is one of the most in live births; the other 99% of the fetuses
widely known and examined chromosomal are spontaneously aborted (Hassold, 1986;
abnormalities in females (White, 1994). The Hook & Warburton, 1983; Jones, 1988;
syndrome—which is characterized by ex- Temple & Carney, 1993). TS is found across
tremely short stature; a lack of spontaneous all racial and ethnic groups (Rovet, 1995).
development of secondary sexual character- A number of chromosomal abnormali-
istics, with accompanying infertility; a broad ties can result in TS. The first identified and
chest; webbed neck; and a myriad of skel- most common form of TS is referred to in
etal, renal, and cardiac abnormalities—was the literature as “pure” TS (Jones, 1988;
first identified in 1938 by Henry H. Turner. Temple & Carney, 1993). This form is re-
In 1959, Ford, Jones, Polani, de Almeida, ferred to as 45,X0, indicating that there is an
and Briggs were able to identify the genetic absence of one of the X chromosomes that
abnormality associated with the syndrome: the fetus should have received from a parent,
They linked it with a loss of or an abnormal- usually the paternal chromosome (Jacobs et
ity in one of the two X chromosomes present al., 1990; Jones, 1988). Females with this
in females. This defect of the X chromosome form of TS have only one X chromosome.
can lead to a large number of physical, neu- Approximately 50% of cases of TS have
ropsychological, and emotional sequelae. this genotype. The second most common
form of TS is mosaicism, which occurs in
30–40% of cases. In mosaicism, the cell di-
Etiology vision that replicates the chromosomes fails
to replicate the genetic material completely,
TS occurs in approximately 1 out of every and some cells contain a slightly different
2,000–3,000 live births of female chil- set of chromosomal material. Mosaicism
dren (Jones, 1988; Orten, 1990; Orten & can occur in females with 45,X0 or in fe-
Orten, 1992; Ross, 1990). However, the ac- males with the normal chromosomal pat-
tual conception rate for TS is much higher tern of 46,XX. Other types of abnormalities
(about 2%). It is estimated that only 1% of occur less frequently; these include a partial
pregnancies with female fetuses with TS deletion of one arm of the X chromosome
chromosomal abnormalities actually result (46,X,del[Xp] or 46,X,del[Xq]), isochromo-
261
262 DISORDERS WITH BROADER-SPECTRUM EFFECTS
somes (46,X,i[Xq]), and rings (46,X,r[X]) 1988). There is evidence that people with the
(Jones, 1988; Ross, Roeltgen, Kushner, Wei, “pure” form of TS, the 45,X0 type, are like-
& Zinn, 2000; Ross, Zinn, & McCauley, ly to have more malformations than people
2000; Temple & Carney, 1993). The chro- with the mosaic or other forms of TS (Jones,
mosomal abnormality is thought to occur 1988).
during the division of the sex cell of the par- In the past, for most girls and women with
ent, and there does not appear to be a signifi- TS, diagnosis of TS typically occurred dur-
cant maternal age factor (Jones, 1988). ing late adolescence. The referral for a genet-
ic evaluation was usually precipitated by the
fact that a young woman had failed to begin
Clinical Presentation puberty (Rovet, 1993). Because of the late
Physical Manifestations diagnosis, many children and adults with
TS did not receive the appropriate medical,
There are many physical abnormalities pres- psychological, or educational intervention
ent with TS. These physical problems not (Rovet, 1993). However, the diagnosis of TS
only vary across patients, but vary depending is beginning to occur earlier, during infancy
on which chromosomal abnormality is pres- and early childhood (Mathiesen, Reilly, &
ent. The most obvious and common physical Skuse, 1992), allowing children to receive
characteristics of TS include extremely short appropriate intervention at an earlier age.
stature, often between 4 feet, 6 inches and 4 Prenatal detection of TS may occur during
feet, 10 inches (Jones, 1988); a short, webbed routine chorionic villous sampling or am-
neck; a broad chest with broadly spaced nip- niocentesis. In addition, ultrasound findings
ples; cubitus valgus (i.e., an unusual carrying such as cardiac anomalies, renal anomalies,
angle for the elbows); a short fourth or fifth poly- or ogliohydramnios, or fetal growth
metacarpal or metatarsal; and a lack of de- retardation may trigger chromosomal stud-
velopment of secondary sexual characteris- ies for the fetus (Saenger et al., 2001).
tics, such as enlarged breasts and pubic hair.
The lack of development of secondary sexual
characteristics occurs due to ovarian (gonad- Neuropsychological and
al) dysgenesis. During the fetal stage of de- Psychoeducational Manifestations
velopment and after birth, there is a massive Neuropsychological Manifestations
loss of oocytes or egg cells (ovarian dysgene-
sis), which results in a lack of development of For many years after the discovery of the
the ovaries. This results not only in a failure syndrome, it was widely believed that
to develop secondary sexual characteristics, women with TS also had mental retarda-
but, for the vast majority of women with TS, tion/intellectual disability. This occasionally
in infertility (Jones, 1988). continued to be reported until relatively re-
Girls and women with TS have a wide cently (Orten & Orten, 1992). Research has
variety of other skeletal and facial abnor- shown that this is not the case, and that girls
malities, including scoliosis (curvature of and women with TS have Verbal IQ (VIQ)
the spine), a narrow and high-arched pal- score distributions similar to those of the
ate, ptosis (drooping eyelids), strabismus, a general population (Bender, Puck, Salben-
low posterior hairline, low and rotated ears, blatt, & Robinson, 1984; Garron, 1977;
and inner-ear defects resulting in recurrent Lewandowski, Costenbader, & Richman,
ear infections and hearing problems. Other 1984; McCauley, Ito, & Kay, 1986; McCau-
observable symptoms include hypoplastic ley, Kay, Ito, & Treder, 1987; Money, 1963;
or underdeveloped nails, increase in pig- Money & Alexander, 1966; Rovet, 1990,
mented moles, and lymphedema (swelling of 2004; Rovet & Netley, 1982; Shaffer, 1962;
the hands and feet). Finally, serious medical Waber, 1979). However, the Performance
problems can be found: heart defects, such IQ (PIQ) scores tend to be somewhat lower
as coarctation (narrowing) of the aorta, and than VIQ scores in people with TS, and these
kidney problems (e.g., horseshoe kidney, lower-than-expected PIQ scores may result
double or cleft renal pelvis). Further medical in lower global IQ scores (Rovet, 1995). The
complications can include high blood pres- lower PIQ scores on the Wechsler scales are
sure, obesity, diabetes mellitus, Hashimoto thought to be due to difficulties in tasks that
thyroiditis, cataracts, and arthritis (Jones, require visual–spatial processing.
Turner Syndrome 263
Shaffer (1962) was the first researcher to 1966; Downey et al., 1991; Lewandowski,
suggest the presence of a specific cognitive 1985; Lewandowski et al., 1984, Ross,
profile for TS. His study documented that Roeltgen, & Cutler, 1995), deficits in visual-
women with TS had an average PIQ that constructional skills (Downey et al., 1991;
was approximately 19 points lower than McCauley et al., 1987; Murphy et al., 1994;
their average VIQ. The pattern of VIQ Robinson et al., 1986; Temple & Carney,
scores higher than PIQ scores has been con- 1995), difficulties with visual discrimination
sistently documented in the literature, with and part–whole perception (Silbert, Wolff,
the actual difference or degree of difference & Lilienthal, 1977), and problems with vi-
varying from study to study (ranging be- sual–motor integration (Lewandowski et al.,
tween 8 and 21 points on average) (Bender 1984).
et al., 1984; Buckley, 1971; Downey et al., In addition, deficits have been identified
1991; Garron, 1977; Lewandowski, 1985; in attention, executive functioning, memory,
Lewandowski et al., 1984; McCauley et face processing, and motor skills. In the area
al., 1986, 1987; McGlone, 1985; Money, of attention, difficulties with inhibitory con-
1963; Money & Alexander, 1966; Netley & trol and auditory attention have been found,
Rovet, 1982; Pennington et al., 1985; Rovet, whereas difficulties with sustained atten-
1990; Rovet & Netley, 1982; Shaffer, 1962; tion and focusing have not been identified
Waber, 1979). Despite the consistent finding as problematic for people with TS (Romans,
that PIQ is lower than VIQ in most girls and Roeltgen, Kushner, & Ross, 1997; Ross,
women with TS, a homogeneous cognitive Zinn, & McCauley, 2000). In addition, the
profile has not been documented for females research has found that difficulties with dis-
with TS (Rovet, 1990). However, several traction, planning, and production in a flu-
deficits on specific subtests of intelligence ent manner have been identified as executive
scales have been reported. functioning concerns for individuals with TS
In the first study to examine the specific (Romans et al., 1997; Temple et al., 1996),
deficits in TS (Shaffer, 1962), Verbal Com- but not difficulty with set shifting. For the
prehension on the Wechsler scales was found area of memory, deficits in short-term recall
to be high, with poorer scores on Perfor- and poor visual working memory have been
mance subtests requiring perceptual organi- identified (Buchanan, Pavlovic, & Rovet,
zation (Block Design and Object Assembly) 1998). Deficits in overall working memory
and freedom from distractibility (Arithmetic have also been identified (Berch, 1996; Bu-
and Digit Span). These findings have also chanan et al., 1998).
been confirmed across the literature. Specific Recent studies have focused on face-
Wechsler Performance subtest deficits found processing abilities, which may underlie dif-
in women and girls with TS, compared to ficulties with social interaction. Girls with
control subjects, include the following: Arith- TS were found to have more difficulties with
metic, Digit Span, Object Assembly, Block general face recognition, emotion process-
Design, and Digit Symbol (Dellantonio, Lis, ing, and recognition of familiar faces in
Saviolo, Rigon, & Tenconi, 1984; Downey et both upright and inverted positions (Elgar,
al., 1991; Lewandowski et al., 1984; Money, Campbell, & Skuse, 2002; Lawrence, Kun-
1963, 1964; Shucard, Shucard, Clopper, & tsi, Coleman, Campbell, & Skuse, 2003)
Schachter, 1992; Temple & Carney, 1995). than control subjects had. Finally, motor
Although the literature has been clear and clumsiness and decreased movement speed
consistent regarding the findings of deficien- have also been identified as deficits for girls
cies in nonverbal, visual–spatial areas in TS, and women with TS (Ross, Roeltgen, Feuil-
it has been less clear about the exact nature lan, Kushner, & Cutler, 1998; Ross, Kush-
and cause of the deficits. Across studies, a ner, & Roeltgen, 1996; Ross, Roeltgen, et
wide variety of deficits have been noted. The al., 2000). Research completed by Nijhuis-
most widely reported deficits are visual– van der Sanden, Smits-Englesman, and Eling
spatial processing deficits (Downey et al., (2000) and Nijhuis-van der Sanden, Eling,
1991; Money, 1993; Robinson et al., 1986; Van Asseldonk, and Van Galen (2004) has
Rovet, 1993; Rovet & Netley, 1982; Tem- found that girls with TS have the same ac-
ple & Carney, 1995). Other specific deficits curacy in motor tasks as their typical peers,
that have been reported include problems but that movement speed is much lower, re-
with visual memory (Alexander & Money, gardless of task demands. Difficulties with
planning movements have also been report- frontal cortex regions involving inhibition,
ed (Nijhuis-van der Sanden et al., 2004). attention and working memory. Cutter and
The various cognitive deficits that have been colleagues (2006) found reduced white mat-
identified in TS do appear to continue across ter in the cerebellar hemispheres, parieto-
the lifespan (Downey et al., 1991; Garron, occipital regions, and the splenium of the
1977; Ross, Zinn, & McCauley, 2000). corpus callosum. They also found increased
However, some skills do appear to improve white matter in the temporal and orbitofron-
with age, including motor planning skills tal lobes and genui of the corpus callosum,
(Romans, Stephanatos, Roeltgen, Kushner, as well as lower concentrations of N-acetyl
& Ross, 1998). aspirate in the parietal lobe and high cho-
line levels in the hippocampus. Finally, they
found that the origin of the X chromosome
Neurological Findings
(maternal or paternal) had an impact on
Many studies have attempted to identify the volume of right amygdala–hippocampal
the actual area(s) of dysfunction within the areas, gray matter volume in the caudate
brain associated with the typical cognitive nucleu and thalamus, and bilateral white
deficits seen in TS. Currently there are two matter in the temporal lobes: The presence
theories with some empirical support. Both of the maternal X chromosome led to a
of these theories revolve around the issue of poorer outcome. Hart, Davenport, Hooper,
lateralization of the brain. The human brain and Belger (2006) found that women with
has two hemispheres, left and right, each of TS has less activation of frontoparietal araes
which is responsible for certain cognitive of the brain during visual–spatial working
tasks (i.e., the brain is lateralized). The left memory tasks than did controls. Finally,
hemisphere is thought to be responsible for research by Rezaie and colleagues (2008)
language and symbolic operations. The right found that women with TS had increased
hemisphere is thought to be responsible for leftward brain asymmetry restricted to the
nonverbal information processing (Watson, posterior of the brain and the superior tem-
1981). The first theory regarding dysfunc- poral and parieto-occipital association cor-
tion within the brain and lateralization in tex. Clark, Klonoff, and Hayden (1990) also
TS is that women and girls with TS have found differences in the occipital cortex.
generalized, diffuse right-hemispheric dys-
function (Dellantonio et al., 1984; Kolb &
Psychoeducational Manifestations
Heaton, 1975; Rovet, 1990, 1995; Rovet &
Netley, 1981; Shucard et al., 1992; Silbert Given the various neuropsychological defi-
et al., 1977). This makes intuitive sense, in cits found with TS—specifically, difficul-
view of the findings that women and girls ties with visual–spatial, visual–motor, and
with TS tend to have intact verbal skills (left memory tasks—it is not surprising that edu-
hemisphere) and difficulties with nonverbal, cational difficulties are also associated with
visual–spatial tasks (right hemisphere). TS. The most common learning problem for
The second theory suggests that there is a girls with TS is in the area of mathematics.
lack of, or failure in, development of normal Many authors have reported that TS is as-
lateralization of the brain in people with TS sociated with poorer performance on the
(or global hemispheric dysfunction). Sever- Arithmetic subtests of the Wechsler scales
al researchers have found an apparent lack (Downey et al., 1991; Garron, 1977; Money
of lateralization in the brains of girls and & Alexander, 1966; Shaffer, 1962). In addi-
women with TS (Bender, Linden, & Rob- tion, girls with TS have been found to have
inson, 1994; Bender et al., 1984; McGlone, low achievement in mathematics (Mazzocco,
1985; Netley & Rovet, 1982; Nijhuis-van 1998; Rovet, 1995; Siegel, Clopper, & Sta-
der Sanden et al., 2000; Pennington et al., bler, 1998). Rovet (1995) reported that the
1985; Rovet, 1990). mathematics problems appear to be more
Research with neuroimaging and other related to the conceptual/factual area than
techniques has supported the idea that spe- to the actual computational area. She also
cific brain areas are dysfunctional in girls reported that older girls are more likely to
and women with TS. Tamm, Menon, and have a mathematics disability than younger
Reiss (2003) found dysfunction in the pre- girls, probably due to the fact that math be-
Turner Syndrome 265
comes more conceptual and relies more on sociated with TS. Several studies have exam-
memory skills as children progress through ined the impact of phenotype (i.e., 45,X0 vs.
school. Mazzocco and her colleagues (Maz- mosaicism) on these deficits. As a rule, it has
zocco, 1998, 2001; Mazzocco, Bhatia, & been found that TS subjects with the mosaic
Lesniak-Karpiak, 2006; Murphy & Maz- form of TS tend to have fewer cognitive and
zocco, 2008) have done more specific as- visual–spatial difficulties than girls with the
sessment of the mathematical difficulties of “pure” form of TS have (Bender et al., 1994;
girls with TS. These studies have found that El Abd, Turk, & Hill, 1995; Rovet & Ire-
mathematics deficits are evident as early as land, 1994; Temple & Carney, 1993). More
kindergarten. It appears that girls with TS recent literature has focused on the paren-
have no difficulty understanding and ap- tal origin of the X chromosome loss (Kesler
plying math concepts; they appear to have et al., 2003; Loesch et al., 2005; Skuse et
more difficulty with processing speed and al., 1997), but has not been conclusive as to
completing timed tasks. The visual–spatial whether the origin of the loss has an impact
aspects and verbal and working memory as- on cognitive or behavioral phenotype.
pects of mathematics may also contribute to
the difficulty girls with TS have in math.
Psychosocial Aspects
Although reading has generally been
found to be a well-developed skill for girls Over the past 20 years, an increasing amount
with TS (Mazzocco, 2001; Temple, Carney, of attention has been given to the psycho-
& Mullarkey, 1996), Rovet (1995) reported social aspects of TS. Overall, research has
that some girls may experience difficulty found that girls and women with TS tend
with reading decoding skills, but not com- to have fewer severe mental disorders than
prehension skills. Spelling and reading skills those found in the general population of
appear to remain intact. Rovet (1993) noted females. Women with TS are less likely to
that reading disabilities at times coexist with experience the “positive” symptomatology
the mathematics disabilities in TS, but that of psychopathology, such as acting-out be-
they have not been found to occur alone. haviors, suicidal ideation, and alcohol/drug
A growing body of literature has begun use. However, they do appear to experience
to compare children with TS to children more of the “negative” symptomatology of
who have nonverbal learning disabilities psychopathology, such as a lack of emotion-
(NLD) (Rovet, 1995; Williams, Richman, al reactivity and few or poor relationships
& Yarbrough, 1992). Children with NLD with peers and other intimates (Downey,
are a subgroup of children with learning dis- Ehrhardt, Gruen, Bell, & Morishima, 1989).
abilities who have particular difficulty with Other personality characteristics that have
visual-perceptual skills. These skill deficits been commonly associated with TS have in-
result in difficulties with mathematics, non- cluded high stress tolerance, unassertiveness,
verbal reasoning, and socialization (Strang overcompliance, and a lack of emotional
& Rourke, 1983). There is also a VIQ-PIQ maturity (Baekgaard, Nyborg, & Nielsen,
discrepancy in NLD, with VIQ being higher 1978; Downey et al., 1989; Higurashi et al.,
than PIQ. Manifestations of NLD are most 1986; McCauley et al., 1986; McCauley,
common in children who have identifiable Ross, Kushner, & Culter, 1995; McCauley,
brain disorders such as neurofibromatosis, Sybert, & Ehrhardt, 1986; Nielsen, Nyborg,
head injuries, or loss or absence of brain tis- & Dahl, 1977).
sue, as well as in children who have under-
gone radiation treatment for cancer (Rourke,
Issues in Childhood and Adolescence
1985).
The three major psychosocial areas of
concern for girls with TS are the areas of
Correlations between Phenotype
self-esteem, peer relationships, and social
and Neuropsychological
isolation—areas that appear to be highly in-
and Educational Deficits
terrelated. Across studies, girls with TS have
As in the physical features associated with been found to have low self-esteem (McCa-
TS, there appears to be extensive heteroge- uley et al., 1986, 1995; Perheentupa et al.,
neity in the neuropsychological deficits as- 1974). Among the major sources contribut-
ing to a child’s sense of self-worth are the with social isolation and poor peer relations
child’s interactions with others, especially are reported across the literature (Nielsen et
peers and family members. Major differenc- al., 1977; Rovet, 1993; Skuse, 1987). As girls
es in appearance, such as short stature and are teased for their physical abnormalities,
the other physical anomalies associated with including short stature, they may withdraw
TS, can have a lasting impact on a develop- from peer interactions. Poor peer relations
ing child’s sense of self and self-worth. Short may also be due to hormonal deficits. As
children are often teased and bullied by peers puberty is delayed, children with TS fail to
at school, which may adversely affect their go through the hormonal changes of adoles-
self-esteem (Skuse, 1987), and this appears cence and may be seen as emotionally imma-
to be a major problem for girls with TS (Mc- ture as well as physically immature (Skuse,
Cauley et al., 1986). A child with TS, who 1987). They may prefer to be with children
may be less assertive than her peers (Skuse, younger than themselves (McCauley et al.,
1987), may have greater difficulty in han- 1995; Rovet & Ireland, 1994). Social dif-
dling the teasing in a proactive manner. In ficulties may also be related to the visual–
addition, because children are often treated spatial processing problems associated with
according to the age they appear to be rather TS because children with these difficulties,
than their actual chronological age, a child including girls with TS, often have problems
or adolescent with TS may experience the with understanding the social cues and facial
added burden of being treated like a much expressions of others (affective discrimina-
younger child and not having the behavioral tion) (McCauley et al., 1987; Waber, 1979).
expectations that would correspond to her Other psychosocial difficulties that have
chronological age (Alley, 1983). This again been associated with TS are behavior prob-
will set her apart from her peers and have an lems. Skuse, Cave, O’Herlihy, and South
impact upon self-esteem. Furthermore, it has (1998) found that a large number of the
been found that for girls with TS, the greater adolescent girls in their study exhibited ad-
the number of physical anomalies, the lower justment problems in such areas as somatic
the self-esteem (El Abd et al., 1995). Finally, symptoms, anxiety, and social immaturity.
difficulties with motor coordination and Sonis and colleagues (1983) found that par-
hearing difficulties due to inner-ear abnor- ents of girls with TS reported more behavior
malities may affect self-esteem as well (El problems for their daughters than did parents
Abd et al., 1995). of girls in a non-TS control group. The par-
Academic difficulties can also result in ents of the girls with TS reported that their
lowered self-esteem in children. There is a daughters were experiencing poor peer re-
vast literature base examining the impact of lationships, immaturity, and poor attention
learning disabilities on the development of a skills. In an effort to rule out short stature as
child’s self-esteem and feelings of self-worth the cause for the problems that girls with TS
(Taylor, 1989). The psychosocial problems experience, McCauley and colleagues (1986)
that are evident in children with learning compared girls who had TS with girls who
disabilities, such as poor task motivation, had short stature but not TS. The results of
poor social skills, externalizing behaviors, that study indicated that the girls with TS
depression, and somatic complaints, may had more behavior problems and poorer
continue into adulthood (Jorm, Share, Mat- peer relationships than their constitutionally
thews, & Maclean, 1986). short counterparts. The girls with TS were
As girls with TS grow older, the delay in reported by parents and teachers to be so-
the onset of puberty may further decrease cially immature and to have many problems
their self-esteem during adolescence (Skuse, associated with externalizing behavior, such
1987). There has been some evidence to as impulsivity, overactivity, and poor atten-
suggest that girls with TS have average self- tion span. Rovet (1995) also found more
esteem until puberty, at which time they “hyperactivity” among girls with TS. Rovet
begin to fall behind their peers both physi- and Ireland (1994) found that girls with TS
cally and socially, and their self-esteem de- tended to score lower on measures of so-
creases. As they fall behind, they begin to cial competence and higher on measures of
withdraw and are viewed as socially im- general behavior problems. These behavior
mature (Perheentupa et al., 1974). Problems problems were most noticeable in the areas
Turner Syndrome 267
of social relationships, attention problems, experience mild depressive symptomatology.

immaturity, hyperactivity, and anxiety. In However, there does not appear to be a con-
addition, girls with TS were found to experi- sistent pattern of psychological problems;
ence more problems in school. These prob- nor does there seem to be an increase in the
lems do appear to increase across childhood frequency of psychological problems over
(Skuse, 1987). that seen in the general population (Money
Finally, there have also been reports of a & Mittenthal, 1970; Shaffer, 1962). In ad-
connection between the occurrence of an- dition, Orten and Orten (1992) found that
orexia nervosa in adolescents and adults women with TS reported that they were
with TS and the advent of hormone therapy satisfied with their lives and happy. Women
(Kron, Katz, Gorzynski, & Weiner, 1977; with TS do appear to be less independent of
Muhs & Lieberz, 1993; Taipale, Niittyma- their parents and less likely to marry or live
ki, & Nevalainen, 1982). This appears to be with partners than the general population
related to the onset of sexual development (Nielsen et al., 1977; Nielsen & Stradiot,
and to anxiety caused by the new sexual 1987; Orten & Orten, 1992).
feelings that occur. It is believed that the de- Given the reported perceptual and educa-
velopment of anorexia nervosa in girls with tional problems associated with TS, another
TS who have begun hormonal treatment has area of potential concern is the educational
an etiology similar to that in typically devel- and occupational achievement of adults with
oping girls (Muhs & Lieberz, 1993; Taipale TS. Despite the findings that the perceptual
et al., 1982). It has also been attributed to a and educational difficulties found in child-
distorted body image caused by a combina- hood continue into adulthood (Garron,
tion of the “stocky” body build usually as- 1977; Nielsen & Stradiot, 1987), women
sociated with TS and the perceptual deficits with TS have been found to perform at an
that exist with TS (Darby, Garfinkel, Vale, average or above-average level academically
Kirwan, & Brown, 1981). and to be gainfully employed in a wide va-
riety of occupations (Nielsen et al., 1977;
Nielsen & Stradiot, 1987; Orten & Orten,
Issues in Adulthood
1992).
Like the cognitive aspects of TS, many of the Despite the delay in or lack of development
psychosocial difficulties reported in children of secondary sexual characteristics, it does
with TS continue into adulthood. Women appear that women with TS have a strong
with TS have also been found to experi- female gender identity (Ehrhardt, Green-
ence difficulties with self-esteem (McCauley berg, & Money, 1970; Money & Mitten-
et al., 1986; Pavlidis, McCauley, & Sybert, thal, 1970). However, women with TS may
1995). The impaired development of sec- be less sexually active than average (Pavlidis
ondary sexual characteristics and the sub- et al., 1995). They also report less interest in
sequent infertility often contribute to low sexual relationships (Downey et al., 1989).
self-esteem in adults with TS (El Abd et al., Even with this lack of sexual activity, and
1995; Pavlidis et al., 1995; Skuse, 1987). In maybe because of the lack of interest in
addition, women with TS may continue to sexual relationships, women with TS report
be less emotionally mature and continue to moderate to high levels of sexual satisfaction
experience poor, or a low number of, peer (Pavlidis et al., 1995). However, higher sex-
relationships (Nielsen et al., 1977). ual satisfaction was associated with higher
As reported above, children with TS frequency of sexual intercourse and a higher
may tend to be more hyperactive than their health status. Raboch, Kobilkova, Horejsi,
same-age peers (McCauley et al., 1986; Starka, and Raboch (1987) have hypoth-
Rovet, 1995; Rovet & Ireland, 1994; Sonis esized that the lower levels of interest in sex
et al, 1983); however, adults with TS may may be related to lower levels of sexual hor-
have lower levels of activity than expected mones. They also found that once women
(Downey et al., 1989; Higurashi et al., 1986; with TS were in stable, good relationships,
Money & Mittenthal, 1970; Pavlidis et al., any differences in interest and participation
1995; Rovet, 1995). The reason for this dif- in sexual relationships disappeared. Health
ference is not readily discernible. In addi- status appears to be significantly related to
tion, adult women with TS may be likely to a number of psychosocial issues for adults
with TS. Pavlidis and colleagues (1995) variety of visual-perceptual problems, it is

found that health status was associated with important to obtain a broad range of assess-
higher self-esteem and greater sexual satis- ment in this area. Visual-perceptual instru-
faction. ments can be divided into a number of areas,
including measures of visual-perceptual or
gestalt integration, spatial relations and vi-
Correlations between Phenotype
sual matching, and visual-constructional
and Psychosocial Problems
skills. In addition, it can be helpful to assess
Again, as with physical manifestations and the processing of aural and visual stimuli,
neuropsychological manifestations, there sequencing, and recall. Executive function-
is a wide heterogeneity in psychosocial dif- ing is an area that can be critical to assess for
ficulties. These also appear to be related to girls and women with TS, given the broad
phenotype. Children and adults with the range of effects that deficits in this area can
mosaicism phenotype appear to have fewer contribute to. Memory (both visual and au-
behavioral difficulties than those with other ditory), attention, and concentration should
forms of TS (Pasaro Mendez, Fernandez, be assessed as well.
Goyanes, & Mendez, 1994; Rovet & Ire- Finally, assessment of psychological ad-
land, 1994; Temple & Carney, 1993). justment is very important in evaluating
people with TS. Personality measures can
be divided into three general categories: par-
Assessment ent/teacher reports, child self-reports, and
projective measures. In each of these cat-
Given the wide variety of difficulties that egories, it is essential to assess psychologi-
may be associated with TS, every child with cal symptomatology, self-esteem, and social
this syndrome must be provided with a thor- skills that may require clinical attention.
ough neuropsychological evaluation. It is Assessment of psychological symptomatol-
critical that neuropsychological and educa- ogy should include instruments designed to
tion problems be identified and treated early assess for more general psychopathology, as
in a child’s academic career (Rovet, 1993). In well as instruments designed to assess de-
order to assess for all of the possible sequelae pression, anxiety, social anxiety, and self-
of TS, it is important to develop a comprehen- esteem more specifically. Assessment of in-
sive battery. This battery should include, at a formation processing and coping styles can
minimum, measures of intelligence, achieve- also be helpful for planning intervention for
ment (including instruments designed for people with TS.
intense assessment of mathematics and read-
ing), nonverbal (visual-perceptual) skills, ex-
ecutive function, memory, and personality/ Interventions
behavior.
Assessment for deficits associated with Intervention for children and adults with TS
the cognitive phenotype of TS should start is critical for a positive life outcome. A girl
with the use of a well-standardized compre- or woman with TS is at risk for developing
hensive assessment instrument that explores a wide range of sequelae. The clinical needs
several facets of cognitive functioning, ver- of patients with TS fall across four areas:
bal and nonverbal. Academic achievement is medical, social, academic, and sexual issues
another critical area for assessment in TS. (Mullins, Lynch, Orten, & Youll, 1991).
It is critical for learning disabilities to be
diagnosed so that appropriate interventions
Medical Interventions
can be implemented. Given the likelihood of
academic problems, especially in the area of Because a wide variety of medical problems
mathematics, it is very important to obtain a can occur with TS, it is critical that regu-
thorough educational evaluation. lar medical care be obtained (Mullins et al,
In addition to broad achievement mea- 1991; Orten, 1990; Orten & Orten, 1994;
sures, more specialized instruments may Rovet, 1995). It is also critical that every girl
also be of use in diagnosing learning dis- or woman with TS and her family receive
abilities and designing intervention strate- accurate and sensitive medical information
gies. Because people with TS may exhibit a (Orten, 1990). In 2000 there was a consen-
Turner Syndrome 269
sus workshop at the Fifth International Sym- designed to allow women with TS to become
posium on Turner Syndrome, which resulted pregnant with their own eggs.
in a set of comprehensive recommendations
for the diagnosis and management of TS
Psychosocial Interventions
(Saenger et al., 2001). This set of guidelines
suggested a multidisciplinary approach to As the review above has shown, girls and
treatment and management. Early in life, women with TS can experience a wide va-
assessment of cardiac and renal complica- riety of psychosocial problems. For our pur-
tions associated with TS is recommended. In poses here, these difficulties are divided into
addition, assessment of hypertension is rec- two categories. The first area for attention is
ommended. Due to ear malformations and a the treatment of issues of concern associated
high prevalence of otitis media, assessment with the diagnosis of TS. The second area is
of hearing is recommended, as well as assess- the treatment of specific symptomatology.
ment of potential speech problems. Other
areas to address include the eyes, orthopedic
Issues of Concern Related to the Diagnosis
concerns (e.g., scoliosis), orthodontic con-
cerns (due to small mandibles), weight, lym- One of the first issues that people diagnosed
phedema, and glucose intolerance. with TS have to cope with is the diagnosis
Management of short stature is also rec- of a chronic syndrome with wide-ranging
ommended, given the impact that this can ramifications. Persons who are diagnosed
have on socialization and academic achieve- with a chronic, lifelong illness must adapt
ment. This includes growth hormone thera- to both the physical and psychological se-
py to stimulate growth and thus to increase quelae of the illness, as well as the fact that
adult height. The management of puberty their lives and potentially their views of self
through the use of estrogen replacement have been altered. Russo (1986) and Varni
therapy to stimulate the development of sec- and Wallander (1988) discuss the need for
ondary sexual characteristics and healthy people with chronic illnesses to address the
bones and tissue is also encouraged. With specific stressors that affect their lives and
early and timely use of estrogen and growth to develop positive coping strategies to deal
hormone, most girls with TS can be brought with these stressors. Positive adjustments
to normal height (Rosenfeld et al., 1992). lead to resilience, and poor adjustment leads
This can have a critical impact on the de- to vulnerability to stressors (Varni & Wal-
velopment of self-esteem in these children. lander, 1988). Self-esteem issues are often
If the teasing that begins when a child with involved in this adjustment. Both a person
TS begins to lag behind her peers can be with TS and her family members will have
avoided by helping the child reach her devel- many emotional reactions at the time of di-
opmental/physical milestones on time, self- agnosis, and these reactions are similar to
esteem may be spared (Orten, 1990; Orten those experienced when any major medi-
& Orten, 1994; Perheentupa et al., 1974). cal condition is diagnosed (Orten & Orten,
Interestingly, research exploring the impact 1994). According to Orten and Orten, these
of the use of estrogen on memory in girls reactions can fall into four categories.
with TS has suggested improvements in both The first category of adjustment is the
verbal and nonverbal memory (Ross, Roelt- need to resolve “the personal meaning of
gen, et al., 2000). TS” (Orten & Orten, 1994, p. 241). The
During adulthood, continued treatment age at diagnosis will have an impact on the
for medical conditions is critical, and there initial issues involved in obtaining personal
is an increased emphasis on fertility issues. meaning. For younger children, the main
With recent advances in fertility interven- issues may revolve around medical aspects
tions, such as in vitro fertilization with a of the syndrome and potential medical in-
donor egg, pregnancy is now a possibility terventions (treatments, hospitalizations,
for some women with TS and their partners. and the like). During the teenage years, is-
For women with functional ovaries, the sues may include “being different” from oth-
timing of pregnancy can be critical, given ers and the physical anomalies the patients
the risk of premature ovarian failure. The may have. For late adolescents and adults,
cryptopreservation of ovarian tissue and im- issues surrounding fertility and parenthood
mature oocytes is a current line of research may arise. Coming to terms with these is-
sues may be complicated by the severity of One of the major mediating factors in
the medical problems that a girl or woman coping with stress is perceived social sup-
faces. The impact of the diagnosis can also port (Varni, Rubinfeld, Talbot, & Setogu-
be mediated by the parents’ reactions to the chi, 1989). Because of this, a support group
diagnosis (Orten & Orten, 1994). model for intervention may be very appro-
A second category of adjustment is coping priate. Support groups, with members who
with the reactions of others, especially reac- face similar issues, can provide reassurance,
tions to the patients’ short stature. Teasing information, and advice. Psychoeducational
about short stature often begins during the models often meet the needs and desires of
elementary school years. If growth hormone participants in TS support groups (Mullins
therapy is initiated at the appropriate times, et al., 1991). Attention to family members
this problem may be avoided. However, girls and to their coping with the diagnosis and
with TS may also be teased about other sequelae of TS is also important because
physical abnormalities. For adult women, families can be a major source of support for
short stature and youthful appearance can some girls and women (Mullins et al., 1991;
cause difficulties in the workplace. Teach- Orten & Orten, 1994). A survey by Orten
ing ways to cope and deal with teasing and and Orten (1992) found that a large number
potential discrimination in a positive and of parents were provided with incomplete
helpful manner is a critical part of interven- and pessimistic medical explanations at the
tion for girls and women with TS (Orten & time of diagnosis, and that the parents were
Orten, 1994). very dissatisfied (and at times angry) with
Deciding whether and, if so, when to tell the explanations that they were given. Thus
others about the diagnosis is another issue one of the first areas of intervention with
of particular concern for girls and women families is to assure that they receive accu-
with TS. For children, one form this ques- rate and adequate medical, psychological,
tion may take is whether or not to inform and developmental information regarding
the school about the diagnosis. As with any TS (Orten, 1990).
medical or psychological problem, inform- Good information for women with TS and
ing the school can lead to positive outcomes, families of girls with TS can be found in a
such as greater understanding of and more number of places. One is the Turner Syn-
accommodations to the special needs of the drome Society of the United States (www.
child; however, it can also result in the child’s turnersyndrome.org). This is a nonprofit
being stigmatized and treated differently in organization with the following missions: to
a negative way. The decision to inform or increase public awareness, to increase under-
not to inform the school is one that needs standing of the people who are affected by
to be made jointly by the treatment team, TS, to provide a forum for those affected by
the parents, and the child if she is mature TS to become acquainted with one another,
enough to participate in the decision (Orten and to provide an opportunity for interac-
& Orten, 1994). tion between health care professionals and
Whether or not to tell dating partners or those affected by TS. The society sponsors a
potential intimate relationships about TS is conference each year and offers a number of
a question that is often faced in adulthood. publications on TS. Other web resources in-
Issues surrounding fertility and parenthood clude the MedlinePlus Medical Encyclopedia
again become critical. These issues can have and the Mayo Clinic website. In addition,
an impact on a partner as well as a woman good family communication is important in
with TS. helping girls and women with TS cope with
A final area that girls and women have to issues surrounding it. Finally, individual
deal with when coming to terms with TS are therapy may be important for some girls and
the physical problems and their impact on women at various stages of their lives.
lifestyle and quality of life. Often this in-
volves grieving for lost abilities. It is impor-
Other Specific
tant for girls and women to understand the
Psychosocial Symptomatology
potential medical and cognitive implications
of TS, and to deal with these on a day-to-day As mentioned above, there are several areas
basis. of potential psychosocial symptomatol-
Turner Syndrome 271
ogy for girls and women with TS. Unfor- tervention commonly used for youth with
tunately, little empirical research has been NLD—cognitive behavior modification or
conducted on psychosocial interventions for strategy training (Meichenbaum, 1985)—
people with TS. The first is the area of social was also utilized with the girls with TS.
skills. Most interventions in this area have The intervention included the use of verbal
been cognitive-behavioral in nature. Target mediation skills for planning and execut-
behaviors have included increasing the rate ing a learning task. This allowed the girls
of social interaction, enhancing prosocial with TS to use a well-developed skill area,
skills, and decreasing antisocial or aggressive their verbal skills, to help them learn ways of
behaviors. Interventions have included so- performing a nonverbal task. The results of
cial problem-solving training, anger coping this study showed a significant improvement
training, coaching, and behavioral rehearsal. in spatial task performance in both groups
These interventions can take place in indi- following the cognitive behavior modifica-
vidual therapy or groups (Smith, Barkley, & tion training. This suggests that girls with
Shapiro, 2006). The second major area of TS may be responsive to remediation of their
concern is the symptomatology of hyperac- educational deficits.
tivity and inattention in some girls with TS.
The most common treatment approaches for
these problems are cognitive-behavioral and Summary and Conclusions
psychopharmacological or a combination of
the two (Smith et al., 2006). The National Turner syndrome, a chromosomal abnor-
Cooperation Growth Study supported the mality that affects only females, can result
need for a combination of educational, be- in myriad lifelong physical/medical, psycho-
havioral, and medical treatment (Siegel et al., social, and educational problems. The type
1998). and severity of the problems may vary wide-
ly across patients. However, there are some
Academic Interventions hallmark symptoms associated with the syn-
drome; these include short stature, failure
Early intervention is critical in helping chil- to develop secondary sexual characteristics
dren with learning disabilities. The first issue at puberty, infertility, visual-perceptual dif-
of concern when implementing academic in- ficulties, executive functioning and memory,
terventions are the individual needs of each academic problems with mathematics, and
child. Some children will require placement social skill difficulties. Many of the physical/
in a special education program, while oth- medical problems can be dealt with through
ers may benefit from tutoring alone. It is also supportive therapy, including hormone re-
important to make sure that the expectations placement therapy. Special attention should
for each child are developmentally appropri- be given to the psychosocial sequelae of the
ate and follow a developmental sequence. syndrome, and appropriate therapeutic in-
In addition, interventions work best when terventions should be undertaken. Finally,
parents and the school work as a team with early and appropriate intervention is critical
the child to deal with the special needs of the for continued academic success. With the
child. Finally, it is very helpful to utilize areas proper support, encouragement, and inter-
of strength to remediate or circumvent areas ventions, girls and women with TS can live
of weakness. This is one of the reasons why long, productive, and happy lives.
a thorough educational assessment is impor-
tant. Although there are a wide variety of in-
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C h a p t e r 14
Fragile X Syndrome
and Fragile X–Associated Disorders
Randi J. Hagerman
Fragile X syndrome (FXS) and fragile X– (ASDs); FXPOI in 20% of adult females; and
associated disorders (FXDs) include a broad FXTAS in 10% of older females and 40% of
spectrum of problems, including intellec- older males.
tual disability (ID) and learning disabilities; Significant advances over the last decade
emotional problems; fragile X–associated concerning the neurobiology of FXS have
primary ovarian insufficiency (FXPOI); and led to new treatments for FXS (Hagerman
an aging syndrome associated with tremor, et al., 2009). FMRP, which is missing in
ataxia, and dementia, called the fragile X– FXS, is an RNA transport protein inhibit-
associated tremor/ataxia syndrome (FXTAS). ing the translation of many other mRNAs
These disorders are caused by genetic muta- that occur in the neuron and are important
tions in the fragile X mental retardation 1 for synaptic plasticity and learning (Bassell
(FMR1) gene, which was discovered in 1991 & Warren, 2008). In FXS there is enhanced
(Verkerk et al., 1991). Those with FXS have translation of many proteins throughout the
a full mutation (>200 cytosine–guanine– brain (Qin, Kang, Burlin, Jiang, & Smith,
guanine [CGG] repeats) on the front end of 2005), and one of the consequences is up-
FMR1 leading to silencing or methylation of regulation of the metabotropic glutamate
the gene, such that little or no FMR1 messen- receptor 5 (mGluR5) pathway, leading to
ger RNA (mRNA) is transcribed, and subse- weakening or long-term depression (LTD) of
quently little or no FMR1 protein (FMRP) synaptic connections (Bear, Huber, & War-
is translated. It is the lack or deficiency of ren, 2004). This finding has led to new treat-
FMRP that leads to the physical, behavioral ments for FXS, specifically mGluR5 antag-
and cognitive deficits of FXS. In carriers onists that have been shown to reverse the
with a premutation (55–200 CGG repeats), LTD and weak synaptic connections in the
there is too much mRNA produced, two animal models for FXS (de Vrij et al., 2008;
to eight times the normal level. This extra McBride et al., 2005; Yan, Rammal, Tranfa-
level of mRNA causes a gain of function in glia, & Bauchwitz, 2005). The new trials of
carriers. The resulting phenotypes include mGluR5 antagonists in humans with FXS
neurodevelopmental problems in some boys, have included use of fenobam, which even in
such as attention-deficit/hyperactivity disor- a single dose appeared to be promising in the
der (ADHD) and autism spectrum disorders treatment of adults with FXS (Berry-K ravis
276
Fragile X Syndrome and Fragile X–Associated Disorders 277
et al., 2009). FXS is the most common in- a female. When the gene passes from a male
herited form of ID and the most common with the premutation, he will pass on the
single gene associated with ASDs. It is now premutation to all of his daughters because
leading the way for new targeted treatments the sperm in males with FXS has only the
for neurodevelopmental disorders (Hager- premutation (Reyniers et al., 1993). There-
man et al., 2009). The mGluR5 antagonists fore, whether a male has a full mutation, a
are likely to be helpful for other causes of mosaic pattern (premutation in some cells
ASDs besides FXS. and full mutation in others), or a premuta-
tion, he will only pass the premutation on
to all of his daughters. A female, however,
Prevalence can pass either the premutation or the full
mutation on to her children. The greater
Numerous studies have been done to deter- the CGG repeat number in a carrier female,
mine the prevalence of both the premutation the greater the chance of expansion to a full
and the full mutation in the general popu- mutation in the next generation (Nolin et
lation (Song, Barton, Sleightholme, Yao, & al., 2003). If a female has more than 100
Fry-Smith, 2003). The premutation is more CGG repeats, and she passes the X chromo-
common, and it occurs in approximately 1 some with the mutation on to her child, it
in 130–250 women and 1 in 250–810 males will expand to a full mutation 100% of the
(Dombrowski et al., 2002; Fernandez- time in the next generation. Since females
Carvajal et al., 2009; P. J. Hagerman, 2008). have two X chromosomes, the risk of pass-
The full-mutation allele occurs in approxi- ing the mutation on to the next generation is
mately 1 in 2,500 in the general population 50% with each pregnancy. A carrier mother
(P. J. Hagerman, 2008), but FXS is only can therefore have affected daughters with
recognized in 1 in 3,600 (Crawford et al., FXS, daughters with the premutation, af-
2002). Some individuals with FXS are high- fected sons with FXS, sons with the premu-
functioning and present with only learning tation, and/or normal children without the
problems or emotional problems and not ID, fragile X mutation (McConkie-Rosell et al.,
particularly females with the full mutation 2007).
(Angkustsiri, Wirojanan, Deprey, Gane, & In contrast, a male will pass on the pre-
Hagerman, 2008). Approximately 2–3% of mutation to only his daughters but none of
males with ID of unknown etiology have his sons. His sons will receive the Y chro-
FXS (Slaney et al., 1995). In addition, 2–6% mosome and therefore will be unaffected
of individuals with ASDs have FXS (Hager- by FXS or by the carrier state. Daughters
man, Rivera, & Hagerman, 2008b), so frag- who receive the mutation from their fathers
ile X DNA testing should be carried out in have a high risk of producing children with
all children or adults who present with ID or FXS in the next generation. Therefore, once
ASDs of unknown etiology. the diagnosis of FXS or the premutation is
FXS occurs in all racial and ethnic groups made, it is essential to have genetic counsel-
that have been studied (Sherman, 2002). A ing (McConkie-Rosell et al., 2007). All indi-
relatively high prevalence of both the pre- viduals in the family who are at risk to have
mutation and the full mutation occurs in the premutation or the full mutation should
Finland, Israel, and Tunisia, suggesting a have fragile X DNA testing, which can be
founder effect—that is, the presence of a ordered by any physician and is usually cov-
carrier in the original founding population ered by insurance.
for these areas (Eichler & Nelson, 1996; It is imperative for affected families to
Pesso et al., 2000; Song et al., 2003; Zhong understand the inheritance pattern of FXS.
et al., 1996). Family members should be well informed
of the dynamics of inheritance, so that rela-
tives will understand their risk for involve-
Inheritance ment from either the premutation or the full
mutation. Figure 14.1 shows a family pedi-
The expansion from a premutation to a full gree that demonstrates the change in CGG
mutation only occurs when the FMR1 gene repeats through four generations and the
is passed on to the next generation through types of clinical features in each generation
Male Female
85 24,29 Intellectually unaffected
carriers
Individuals with FXS
and intellectual disability
80,29 24 87,24 Learning disabled
100,30 29 29,30 560 350 85,30 90
780 650,30 84,24 580,24 24
FIGURE 14.1. A pedigree of a family affected by FXS. The numbers represent the CGG repeat num-
bers at FMR1 in each X chromosome. Note that the male with 350 repeats has an unmethylated full
mutation; he does not have intellectual disability (ID), but does have learning disabilities. The female
with 650 repeats has a full mutation and has ID, whereas the female with 580 repeats also has a full
mutation, but has learning disabilities rather than ID.
that can be related to the premutation and also part of the physical phenotype, but it
the full mutation. Involvement in individu- is usually not present until adolescence (La-
als with the full mutation is covered in detail chiewicz & Dawson, 1994). In adolescence
below, followed by a briefer description of or adulthood, the testicular volume may be
premutation involvement. two to three times normal size, although
this is also not always recognized in a physi-
cal examination (Hagerman, 2002b). The
Physical, Behavioral, degree of physical involvement and cogni-
And Cognitive Phenotypes tive involvement in FXS correlates with the
of Full-Mutation Involvement level of FMRP that is present in the blood
(Loesch et al., 2004). Typical physical fea-
Physical Phenotype
tures of FXS are outlined in Table 14.1.
Young children with FXS usually present Many of the physical features in FXS are
with language and motor delays, hypoto- considered part of a connective tissue dyspla-
nia, and hyperactivity. The typical physical sia (Hagerman, 2002b). The high frequency
features of FXS may not be present in early of otitis media difficulties in early childhood
childhood, so it is important not to dismiss is probably related to the connective tissue
a diagnosis of FXS solely because of a lack problems, in that the eustachian tube is eas-
of these physical features (see Figure 14.2). ily collapsible, trapping fluid in the middle
Physical features of FXS include promi- ear. The connective tissue problems on oc-
nent ears, long face, hyperextensible finger casion lead to other medical complications,
joints, double-jointed thumbs, flat feet, soft such as hernias, scoliosis, and mitral valve
skin, and a high-arched palate (Hagerman, prolapse (Hagerman, 2002b).
2002b). Most of these features can be seen Growth abnormalities also may occur in
in the general population, and children with FXS. Young patients often have a large head
FXS do not typically look dysmorphic or circumference, and those with FXS and au-
unusual. On occasion, ears can be dramati- tism have larger heads in early childhood
cally prominent, with cupping in the upper than those with FXS but no autism do (Chiu
part of the pinnae. Females with the full mu- et al., 2007). In puberty, however, the growth
tation are less likely than males to present velocity may be slowed, and short stature is
with typical physical features of FXS. For not uncommon in adulthood (Loesch, Hug-
males, macroorchidism (large testicles) is gins, & Hoang, 1995).
FIGURE 14.2. These siblings all have the full mutation of FXS. Although they do not display typi-
cal physical features of FXS, they do present with characteristic behavioral features of FXS (see text).
Photograph used by permission of the children’s parents.
TABLE 14.1. Typical Physical fensiveness to such an extent that they pull

and Behavioral Features of FXS away from light touch. Tags in clothes or
firm textures of materials can be irritating
Physical features Behavioral features
to them. The extra stimuli associated with
Long ears Poor eye contact transitions—even going from the car into
Prominent ears Tactile defensiveness the house—can lead to behavior outbursts
Long face Hand flapping for children with FXS. Behavioral interven-
Single palmar crease Hand biting tions and therapy, as described below, can
Cardiac murmur or Perseveration
click Hyperactivity
be helpful in alleviating or calming the in-
Hand calluses Diagnosis of attention- tensity of some of these behaviors.
Flat feet deficit/hyperactivity Perseveration is a typical communicative
Hyperextensible finger disorder (ADHD) and behavioral feature in children with FXS.
joints Verbal or physical Children may repeat a certain activity (e.g.,
Double-jointed thumbs outbursts stacking toys, spinning objects, flushing the
High-arched palate Tantrums toilet, or watching the same video) over and
Shyness or social
anxiety over again. Perseveration is also present
in speech—not only in repeating the same
phrase, but in talking about the same subject
continually. Mumbling, echolalia, cluttered
Behavioral Phenotype
speech, and self-talk (i.e., carrying on a con-
Behavioral features of FXS include an ex- versation with oneself, often using different
tremely short attention span, impulsivity, vocal tones) are all commonly seen in indi-
and hyperactivity, as well as hypersensitiv- viduals with FXS (Abbeduto & Hagerman,
ity to visual, auditory, tactile, and olfactory 1997; Hagerman, 2002b).
stimuli (Miller et al., 1999; Roberts et al., Autistic-like features are also common in
2001). Children with FXS often have dif- children with FXS, including hand flapping,
ficulty in crowds and with loud noises be- hand biting, toe walking, poor eye contact,
cause their hypersensitivity and hyperarous- tactile sensitivity, shyness, and social anxi-
al often lead to tantrums or aggression. ety. Full autism—that is, autistic disorder
They may also overreact to some smells with as defined by the Diagnostic and Statistical
a gagging or vomiting response. In addition, Manual of Mental Disorders, fourth edition,
children with FXS may experience tactile de- text revision (DSM-IV-TR) and documented
by standardized autism diagnostic measures borderline or mild-ID range (de Vries et al.,
such as the Autism Diagnostic Observation 1996). Females with normal IQs but with
Schedule (ADOS)—occurs in 30% of boys the full mutation usually demonstrate learn-
with FXS, and DSM-IV-TR defined perva- ing disabilities, including attentional and or-
sive developmental disorder not otherwise ganizational problems and math difficulties.
specified (PDD-NOS) occurs in an additional Approximately 70% of women with the full
30% (Harris et al., 2008). Those with autism mutation who do not have an IQ deficit have
and FXS together have lower IQs than those problems in executive functioning, which
with FXS without autism, but the severity of relate to their difficulty with organization
autism does not correlate with the level of and attention (Cornish, Turk, & Hagerman,
FMRP once the IQ is controlled (Loesch et 2008). Their behavior is often impulsive,
al., 2007). Autism is common in FXS, and and they can be tangential in their speech,
it should be assessed in the evaluation of as well as mood-labile. Young girls and boys
children with FXS because if it is present ap- with the full mutation usually demonstrate
propriate educational interventions should significant shyness and social anxiety, which
be carried out (including applied behavior often interferes with social interactions and
analysis interventions, such as the Denver can predispose them to ASDs (Cordiero et
model or pivotal response training (Rogers al., unpublished raw data). On occasion the
& Vismara, 2008). Children with FXS are at social withdrawal and anxiety may lead to
high risk for autism because the absence or quieter language and even selective mutism
deficiency of FMRP leads to dysregulation of in school, but usually not at home (Hager-
many proteins that are known to be associ- man, Hills, Scharfenaker, & Lewis, 1999).
ated with autism through their action in syn- Studies of neuroanatomical changes in
aptic plasticity, or through dysregulation of FXS have helped to increase our under-
the gamma-aminobutyric acid (GABA) and standing of the neurobehavioral phenotype
glutamate systems in the brain (Belmonte & of FXS (Reiss & Dant, 2003). In general,
Bourgeron, 2006). This dysregulation leads certain parts of the brain are generally larg-
to an imbalance of inhibitory and stimula- er in patients with FXS than in age- and
tory systems, problems with connectivity IQ-matched controls. These areas include
in the brain, weak synaptic connections, the caudate and the thalamus, although the
and growth abnormalities; some of these amygdala is not enlarged, at least in young-
are related to protein tyrosine phosphatase er boys with FXS (Hazlett et al., 2009). The
(PTEN) dysregulation, which occurs in the brains of young children with idiopathic
absence of FMRP (Belmonte & Bourgeron, autism without FXS have a very different
2006; Chonchaiya et al., 2009; Hagerman, neuroanatomical structure from the brains
Rivera, & Hagerman, 2008). of those with FXS either with or without
autism. Boys with autism have a larger
amygdala and a smaller caudate than boys
Cognitive and Neuroanatomical
with FXS (Hazlett et al., 2009). These find-
Phenotypes
ings demonstrate that the genetic etiology
The majority of males with FXS have ID, for autism is more important for determin-
with IQs lower than 70 (Bennetto & Pen- ing brain structure than the behavioral phe-
nington, 2002); females are less affected by notype of autism. The enlarged caudate in
FXS because they have two X chromosomes, FXS may relate to the problems with execu-
and although the full mutation may be pres- tive functioning and ADHD that are com-
ent on one of the X chromosomes, the other is mon in these children.
normal and is producing FMRP. All females
inactivate one of their X chromosomes, and
an activation ratio, which can be calculated Phenotypic Illustrations
from the DNA studies, represents the per-
Case 1
centage of cells with the normal X chromo-
some as the active chromosome. The activa- Case 1, a boy age 4 years, 3 months, was
tion ratio correlates with IQ in females and diagnosed with FXS by FMR1 DNA testing.
with the level of FMRP (Tassone et al., 1999). He has a full mutation that is fully methylat-
Approximately 50–70% of females with the ed. He was born after a normal pregnancy,
full mutation have intellectual deficits in the and his birthweight was 8 pounds, 14 ounces.
He did well in the newborn period, although strates a full mutation that is fully methy-
his suck was poor, he was hypotonic, and lated, and he has no detectable FMRP in
his developmental milestones were mildly peripheral blood. His mother had a normal
delayed. He sat at 10 months and walked at pregnancy, and she was delivered by cesar-
15 months. At present he does not yet speak ean section; his birthweight was 9 pounds,
in phrases, but can use approximately 10–15 5 ounces. He sat at 7 months, crawled at 11
words. He began to hand-flap and bite his months, walked at 21 months, and began
hands in his first year. His father called him speaking in two-word phrases at 3 years. He
“little butterfly” because of his hand flap- had significant reflux in the newborn period
ping. He also chews excessively on things and was a very colicky baby. His parents no-
such as his shirt collar, has poor eye contact, ticed that his behavior was unusual even in
and has problems with perseveration. He is the first year. He would frequently arch his
easily overstimulated and has a high activ- back and focus on ceiling fans; he displayed
ity level, as well as impulsivity and distract- hand flapping and poor eye contact, as well
ibility. In addition, tantrums are a problem as tactile defensiveness. When he was diag-
for him, although he is not physically agnosed with autism, he was qualified to re-
gressive. He has difficulty with transitions ceive appropriate autism preschool services,
and becomes easily overwhelmed on a daily as well as speech–language and occupation-
basis. al therapy. It was not until he was older than
Like many children with FXS, this boy 3 years, well after his autism diagnosis was
has had recurrent otitis media infections. made, that he was found to also have FXS.
Pressure-equalizing (PE) tubes were used to This boy is hyperactive with a very short
help alleviate this problem. His height is at attention span; he has tantrums, but these
the 75th percentile for his age, and both his are not aggressive episodes. He has difficul-
weight and head circumference are at the ty with transitions and anxiety on a daily
95th percentile for his age. He has visually basis. Although some of his autistic behavior
prominent ears as well as ear cupping, but has improved with therapy, he continues to
his face is not long. He has a high-arched seek self-stimulatory input and perseverates
palate, along with hyperextensible joints in spinning and twirling objects. In the past
and double-jointed thumbs. In addition, his on the Vineland Adaptive Behavior Scales,
hands display a single palmar crease. His his Adaptive Behavior Composite score is
cardiac examination is normal, with no click 54, with an age equivalent of 24 months. His
or murmur, and he has flat feet. other scores are as follows: Communication,
His cognitive abilities were assessed sever- 65; Daily Living Skills, 54; Socialization, 65;
al years ago with the Bayley Scales of Infant and Motor Skills, 51. His total score on the
Development and the Vineland Adaptive Be- ADOS is 15, which is well into the autism
havior Scales. On the Bayley, he is perform- range.
ing at a developmental level between 23 and As noted above, he is already receiving
25 months. His mother describes him as dif- special education and various therapies. He
ficult to motivate; she notes that he mainly also spends part of the school day integrated
enjoys watching videos and/or eating. On the into a regular kindergarten, where he is as-
Vineland, his Adaptive Behavior Composite sisted by an aide. Mainstreaming him into
score is 51, which is typical of a child 21–22 the normal classroom is beneficial for him
months of age. His other Vineland scores are because he can learn from and imitate other
as follows: Communication, 52; Daily Liv- children who are performing at a typical
ing Skills, 55; Socialization, 66; and Motor level. He has outgrown some of his autistic
Skills, 49. He has not yet been able to com- tendencies, and his interest in others and so-
plete the Kaufman Assessment Battery for cialization skills have improved over time.
Children (K-ABC) because of significant at- However, he continues to be anxious, easily
tention and concentration problems in addi- overwhelmed, and overstimulated, and he
tion to language deficits. utilizes approach–withdrawal behavior in
most of his social interactions.
His medical history includes a history of
Case 2
sinusitis and recurrent otitis media infec-
Case 2 is a boy age 4 years, 6 months who tions, with more than 20 infections begin-
has FXS and autism. DNA testing demon- ning at 6 months of age. He has not had
hernias or joint dislocations, and his only pattern is a full mutation that is completely
surgery was for PE tubes because of the re- or almost completely unmethylated (Loesch,
current otitis media infections. He original- Huggins, & Hagerman, 2004). In addition,
ly had a history of staring spells occurring individuals with a mosaic pattern (i.e., some
a couple of times a week, and he was unre- cells with the premutation and other cells
sponsive to his name during these spells. An with the full mutation) may also be high-
electroencephalogram was carried out and functioning, particularly if a high percent-
he was found to have spike wave discharges age of cells demonstrate the premutation
in the frontal and parietal areas, although (Tassone et al., 1999). The higher the FMRP
no seizures were documented. Once he was level, the more likely the patient is to main-
started on valproic acid, his staring spells tain an IQ in the borderline or normal range.
stopped, and he became more socially re- Studies have shown that the average IQ in
sponsive. adulthood for a male with the full mutation
His physical examination demonstrates a that is fully methylated is 41; the average IQ
height at the 50th percentile, weight at the for a mosaic male is 60; and the average IQ
75th percentile, and head circumference at for patients with a lack of methylation, or
the 98th percentile for his age. His forehead at least 50% of the mutation unmethylated,
and ears are prominent, but his face is not is 88 (Merenstein et al., 1996). Therefore, it
long. He has a high-arched palate, hyper- appears that the level of FMRP produced by
extensible joints, and flat feet, but does not the gene correlates with an improved prog-
have double-jointed thumbs, a single pal- nosis in adulthood (Tassone et al., 1999).
mar crease, or hand calluses. Cardiac exam
shows a normal rhythm, without murmur or
click. His testicular volume is 3 ml bilater- Premutation Involvement
ally, which is normal for his age.
Individuals with the premutation typically
have IQs in the average range, and they were
Molecular–Clinical Correlations previously thought to be completely unaf-
and Adult Outcome fected by the premutation. However, some
children with the premutation were found
As described earlier, the majority of males to have cognitive deficits or autism, par-
with FXS present with ID, although approx- ticularly boys; these findings led to further
imately 13% have IQs above 70 (Bennetto investigation of the molecular findings in
& Pennington, 2002; Hagerman, Hull, et those with the premutation who had prob-
al., 1994). This number may increase when lems (Tassone, Hagerman, Taylor, Mills, et
younger children are examined. Freund, Pee- al., 2000). Some of these individuals were
bles, Aylward, and Reiss (1995) found that found to have lower levels of FMRP, but the
approximately 50% of preschool boys with most striking and unexpected finding was el-
FXS had intellectual functioning in the typi- evation of the FMR1 mRNA level from two
cal or borderline range. Children with FXS to eight times normal (Tassone, Hagerman,
may present with normal or near-normal ex- Taylor, Gane, et al., 2000). At the same time
pressive vocabulary abilities, and they also of this discovery, several grandfathers with
do well on visual matching tasks, so their the premutation were found to have a similar
initial IQ may look fairly good. However, IQ phenotype of tremor with action and ataxia
usually declines with age as more demands leading to frequent falls (Hagerman et al.,
are made in reasoning. Significant IQ decline 2001). Further studies demonstrated that
typically occurs in the majority of males and this phenotype of tremor and ataxia was
in about 30% of females with the full muta- seen in approximately 40% of male carriers
tion (Bennetto & Pennington, 2002; Wright- who were older than 50 years, and that the
Talamante et al., 1996). A few males are able prevalence increased with age (Jacquemont
to maintain IQs in the normal or borderline et al., 2004). This condition was found to
range in adolescence and adulthood. These be associated with the premutation and a
individuals usually have variant DNA pat- toxicity to the neurons, leading to the for-
terns and are producing a significant level of mation of intranuclear inclusions in neurons
FMRP. For high-functioning males, a typical and astrocytes, in addition to brain atrophy
and white matter disease in the periven- times this can occur together with FXTAS
tricular and subcortical regions and in the (Greco et al., 2008).
middle cerebellar peduncles (Adams et al., An additional unique phenotype seen
2007; Jacquemont et al., 2003). This condi- only in the premutation and not in the full
tion has been named the fragile X–associ- mutation is primary ovarian insufficiency
ated tremor/ataxia syndrome (FXTAS), but or FXPOI. Approximately 20% of women
it also includes executive function deficits, with the premutation will experience cessa-
cognitive decline in all, dementia in some, tion of their menses before age 40, although
and a neuropathy in most. The inclusions a small percentage may become pregnant
appear to be caused by the RNA toxicity of later (Sullivan et al., 2005). This is thought
the premutation, but their formation may be to relate to RNA toxicity in the ovum or
a protective mechanism of the cell to handle in the cells that support the ovum, and it
the protein dysregulation that occurs in cells is more common with higher CGG repeat
with the premutation (Greco et al., 2006). numbers in the premutation range (Sullivan
Various proteins become dysregulated with et al., 2005; Wittenberger et al., 2007). In
the toxicity of the premutation, including addition, women with the premutation have
lamin A/C, alpha B crystallin, heat shock higher rates of depression and anxiety than
proteins, and ubiquitin, and they all are the general population (Roberts et al., 2009).
also sequestered in the inclusions of FXTAS In individuals with FXTAS, inclusions occur
(Arocena et al., 2005). Inclusions also occur throughout the limbic system, so it is likely
in the peripheral nervous system, including that emotional problems in carriers are re-
autonomic ganglia throughout the body, lated to RNA toxicity in the limbic system.
such as pericardial ganglia, periadrenal Within the last decade, several children
ganglia, and myenteric plexus ganglia in the with the premutation have been found to
gastrointestinal system (Gokden, Al-Hinti, have learning deficits; emotional problems
& Harik, 2009). This suggests that RNA such as anxiety; social deficits and ASDs;
toxicity affects the peripheral nervous sys- or even ID (Aziz et al., 2003; Farzin et al.,
tem, leading to various types of autonomic 2006; Tassone, Hagerman, Taylor, Mills, et
dysfunction: impotence (which is common al., 2000). Although this finding led to the
even before the onset of tremor and ataxia), identification of elevated FMR1 mRNA in
orthostatic hypotension, hypertension, and premutation carriers, the focus has been on
even cardiac arrhythmias (Coffey et al., the aging problems in carriers and FXTAS
2008; Jacquemont et al., 2003). Inclusions (P. J. Hagerman & Hagerman, 2004). How-
can also occur in the thyroid gland and in ever, now we know that the premutation can
the Leidig cells of the testicles, which make also cause neurodevelopmental problems,
testosterone (Greco et al., 2007; Louis, particularly in males with the premutation,
Moskowitz, Friez, Amaya, & Vonsattel, because they only have one X chromosome
2006). Testosterone deficiency is common in and are not protected by the second X. Al-
men with FXTAS, and thyroid dysfunction though most individuals with the premuta-
is also common, particularly in women with tion usually have IQs in the average range,
FXTAS (Coffey et al., 2008). ADHD and ASDs are not uncommon in
FXTAS can also occur in about 10% of males (Clifford et al., 2007; Farzin et al.,
women with the premutation who are older 2006).
than 50 years, but dementia is rare because
women are relatively protected by the sec-
Case 3
ond X chromosome (Coffey et al., 2008;
Rodriguez-Revenga et al., 2009). Women Case 3 is a 12-year-old boy who was diag-
with the premutation, however, have a high- nosed as carrying the premutation at 8 years
er rate of autoimmune problems (includ- of age, when DNA testing demonstrated a
ing fibromyalgia and thyroid disease) than CGG repeat number of 79. His mother had
age-matched controls without the premuta- a normal pregnancy; she delivered at full
tion have (Coffey et al., 2008; Rodriguez- term; and the birthweight was 6 pounds, 4
Revenga et al., 2009). In addition, about ounces. He did well in the newborn period
3–4% of women with the premutation may and exhibited normal developmental mile-
also suffer from multiple sclerosis, and some- stones, including sitting at 6 months, walk-
ing at 11 months, riding a tricycle at 3 years Because Case 3’s recent evaluation re-
of age, and riding a bicycle by 7 years of age. vealed not only severe ADHD but aggres-
His coordination has been quite good, and sion and violent ideation, he was started
he has played soccer and other sports, but on aripiprazole (Abilify—2 mg at bedtime,
he has had mild difficulty with handwriting with a gradual increase to 4 mg), an atypical
and drawing. In the language area, he said antipsychotic. This medication has helped
words in the first year and sentences by 2 to stabilize his mood, reduce his anxiety,
years of age. However, he was noted to be further improve his ADHD symptoms, and
hyperactive as a toddler, and this persisted decrease his aggression. He was also started
into his school years; his significant atten- in weekly counseling to help his aggression,
tional problems and impulsivity led to a di- anxiety, and dysthymia. Sertraline was sub-
agnosis of ADHD. He has also suffered from sequently started after the positive effects of
tantrums, which began at 3 years of age but the aripiprazole were noted, and it has fur-
became worse at age 9 and into adolescence. ther improved his mood, anxiety, and obses-
His mother is a premutation carrier with 70 sive ideation.
repeats; her father (the boy’s grandfather) Recent molecular testing for Case 3 dem-
suffers from tremor and ataxia in addition onstrated the presence of a premutation at 66
to mild dementia, and he has been recent- repeats that was completely unmethylated in
ly diagnosed with FXTAS. He lives in an 85% of his cells. However, it also showed an
apartment attached to the main house, and additional light smear in the full-mutation
Case 3’s mother is stressed with the caretak- range with 230 repeats, and this was pres-
ing needs of her father. ent in 15% of his cells and was methylat-
As treatment for his ADHD, Case 3 was ed. Subsequent FMRP levels demonstrated
started on Concerta at 27 mg a day at age that 70% of his lymphocytes stained posi-
8. He is now on 36 mg a day with a good tive for FMRP (Tassone et al., 1999). Case
response and normal growth parameters. 3 is therefore a mosaic male with FXS; his
His behavior has not included hand flapping cognitive abilities are in the average range,
or hand biting, but he had approximately but he has significant emotional and behav-
one tantrum per week in middle childhood, ioral problems, including ADHD, violent
and he has shown more significant problems ideation, mood instability, and dysthymia.
with aggressive behavior both at home and In addition, his FMR1 RNA level is 3.8
at school within the last year. His mother times normal, so he is also at risk for RNA
has remarried during the last year, and he toxicity. In essence, he has a “double hit”—
dislikes his stepfather. A more detailed psy- that is, a mild decrease in FMRP levels that
chological evaluation was recently carried gives him some features of FXS, as well as
out because of his history of both verbal and elevated mRNA levels that may add to his
physical aggression. His emotional assess- psychopathology and perhaps to his ADHD
ment demonstrated severe problems with and his social problems. My colleagues and
anger, anxiety, mood instability, and dys- I have never seen a patient with FXS devel-
thymia. It also revealed obsessive thinking op FXTAS, and it is likely that the lowered
focused on violent ideation. His aggressive level of FMRP can protect individuals from
ideation toward his stepfather was severe, FXTAS.
and intensive counseling was initiated, in
addition to a positive behavioral program in
school. Assessment Issues : Who Requires
Cognitive testing at age 8 years, 10 FMR1 DNA Testing?
months with the K-ABC yielded an overall
Mental Processing Composite score of 100, Children and adults with FXS or premuta-
a Sequential Processing score of 108, and a tion involvement may often present with
Simultaneous Processing score of 95. Cogni- other diagnoses. These may include an ASD,
tive testing at 12 years of age with the third such as PDD-NOS, autism, or Asperger
edition of the Wechsler Intelligence Scale for syndrome; schizotypal personality disor-
Children yielded a Full Scale IQ of 103, a der; or other diagnoses with specific eti-
Verbal IQ of 99, and a Performance IQ of ologies, such as Tourette syndrome, Pierre
107. Robin sequence, Soto syndrome, or even
Prader–Willi syndrome. Tics are seen in ap- exhibits autistic-like features (e.g., hand
proximately 20% of patients with FXS, and flapping, hand biting, or poor eye contact),
abrupt mood swings and ADHD are com- then the diagnosis of FXS or premutation
mon in those with the full mutation and in involvement should be strongly considered,
those affected by the premutation, as they and DNA testing should be carried out.
are in Tourette syndrome. Children with Similarly, not all children with learning dis-
Tourette syndrome do not usually demon- abilities need to be tested for FXS. However,
strate the cognitive deficits that are present if a learning disability involves math deficits
in FXS, however. The large head circumfer- (particularly in a female), and it is combined
ence in childhood frequently causes FXS to with shyness, social anxiety, or physical
be confused with Soto syndrome or cerebral features related to FXS and/or with a fam-
gigantism. Approximately 5% of patients ily history of ID or consistent with an FXD,
with FXS can have a cleft palate, which can then this child should be tested for fragile
be confused with other clefting syndromes, X mutations. In addition, patients who have
including Pierre Robin sequence. As previ- selective mutism or schizotypal personality
ously discussed, autism and other ASDs also disorder and other features consistent with
overlap with FXS. Obsessive–compulsive FXS or FXDs should be tested.
behavior is often seen in FXS, and occasion- An FXS or FXD diagnosis is important
ally the obsessive behavior may focus on eat- from two perspectives. First, it allows genet-
ing, which can lead to obesity and a pheno- ic counseling to be given to multiple family
type similar to Prader–Willi syndrome. This members who may be carriers of fragile X
is called the Prader–Willi phenotype (PWP) or affected by FXS. In addition, a diagnosis
in FXS, and it is associated with obesity, of FXS or FXD helps in the development of
hyperphagia, delayed puberty, and often a treatment programs, including the various
small phallus. This PWP is not associated interventions described below.
with a 15q deletion that is causal to Prader–
Willi syndrome. However, recently a down-
regulation of cytoplasmic FMR1-interacting Treatment
protein (CYFIP1), a sister protein that binds
to FMRP and whose gene is located at the There is no cure for FXS or FXDs, but vari-
15q region, was documented in individuals ous interventions and treatments are helpful
with the PWP compared to controls (Now- for affected children and adults. For FXS
icki et al., 2007). The CYFIP1 level in indi- the treatment team should include multiple
viduals with the PWP was much lower than professionals, including a special education
that of controls, and the level was also much teacher, a speech–language pathologist, an
lower than that seen in individuals with FXS occupational therapist, a physician, and a
without the PWP (Nowicki et al., 2007). psychologist (Braden, 2000; Hagerman,
Why CYFIP1 is down-regulated in the PWP 2002a; Hagerman et al., 2009; Scharfenaker,
is not known, but those with the PWP also O’Connor, Stackhouse, & Noble, 2002).
have a higher ASD rate than is seen in FXS
without the PWP (Nowicki et al., 2007).
Medical Follow-Up
It is important to consider fragile X test-
and Psychopharmacology
ing in all individuals who have ID or ASDs,
when the etiology for these problems is un- The medical treatment of FXS includes vig-
known. In addition, if there is a family his- orous intervention for recurrent otitis media
tory of ID, the chance that this could be due infections, which can further exacerbate the
to FXS increases dramatically. As noted ear- language delays in FXS (Hagerman, Altshul-
lier, FXS causes 30% of X-linked ID, and in Stark, & McBogg, 1987). In addition, ap-
general FXS is the most common inherited proximately 20% of patients have seizures;
form of ID or ASD known. these can further interfere with normal
Not all children with hyperactivity should development and academic progress, and
be tested for FXS. However, if a hyperac- they require treatment (Hagerman, 2002a;
tive child has cognitive deficits or typical Hagerman et al., 2009). Other medical prob-
physical features associated with FXS, has lems associated with loose connective tissue
a family history consistent with FXDs, or include rare hernias, rare joint dislocations,
mitral valve prolapse, sinus infections, and leads to LTD of synaptic plasticity, so that
gastroesophageal reflux. Medical interven- synaptic connections are weakened. FMRP
tions for these problems have been discussed is the inhibitor of this pathway; therefore,
elsewhere (Hagerman, 2002a). in the absence of FMRP there is enhanced
Medical interventions can be most helpful LTD, which is thought to lead to the ID in
for the behavior problems that are usually FXS (Bear et al., 2004). Therefore, the use
present in FXS. For the preschool child, tan- of mGluR5 antagonists should block this ef-
trums and hyperarousal are common diffi- fect, and this has been proven in the mouse
culties, in addition to a short attention span. and Drosophila models of FXS (de Vrij et
Stimulant medications (see below) may ben- al., 2008; Dolen & Bear, 2008; McBride et
efit some preschool children, but may exac- al., 2005). Now treatment with mGluR5 an-
erbate behavioral problems in others (Berry- tagonists has begun to be studied in patients
K ravis & Potanos, 2004; Hagerman et al., with FXS, and preliminary positive respons-
2009; Hagerman, Murphy, & Wittenberger, es have been seen in a single-dose trial of
1988). Additional medications, including clo- fenobam (Berry-K ravis et al., 2009). Lithium
nidine (Catapres), guanfacine (Tenex), and also down-regulates the mGluR5 system,
aripiprazole (Abilify), can also help ADHD and an open trial of lithium in individuals
symptoms (Hagerman et al., 2009). Abilify with FXS demonstrated positive behavioral
is an atypical antipsychotic that appears to effects, with some signs of improved cogni-
be helpful in low doses for the majority of tion as well (Berry-K ravis et al., 2008).
children and adults with FXS, not only for Another new targeted treatment in FXS
improving attention but also for stabilizing is minocycline, which lowers the level of
mood and improving anxiety and aggres- matrix metalloproteinase (MMP9), one of
sion (Hagerman et al., 2009). Currently a a family of proteins important for synaptic
controlled trial is taking place in Indiana to plasticity. MMP9 levels are high in the ab-
test the efficacy of Abilify in the treatment sence of FMRP, and treatment of the knock-
of FXS. out mouse model of FXS with 1 month of
For the treatment of moodiness, aggres- minocycline at birth improved synaptic con-
sion, anxiety and obsessive–compulsive nections and also improved behavior and
behavior, the selective serotonin reuptake cognition (Bilousova et al., 2009). Therefore,
inhibitors (SSRIs) have been remarkably help- human trials are being initiated in children
ful in FXS (Berry-K ravis & Potanos, 2004; with FXS, although in children younger than
Hagerman, Fulton, et al., 1994, 2009). The 8 years minocycline can lead to the graying
SSRIs include fluoxetine (Prozac), sertra- of teeth. Long-term minocycline treatment
line (Zoloft), paroxetine (Paxil), citalopram can lead to graying or darkening of other tis-
(Celexa), escitalpram (Lexapro), and fluvox- sues, including skin, at any age. In addition,
amine (Luvox). They are relatively safe and pseudotumor cerebri or increased intracra-
easy to monitor because they do not require nial pressure, as well as drug-induced lupus,
regular blood work or electrocardiograms. can occur as a rare side effect of minocycline
The side effects include diarrhea, agitation, treatment. Further studies, including a con-
hyperactivity, sleep disturbances, abdomi- trolled trial, are needed before minocycline
nal pain, and the rare occurrence of mania. can be broadly recommended for treatment
They are commonly used in adolescence and of children with FXS. This new age of tar-
adulthood, and limited experience is avail- geted treatments in FXS should lead to ex-
able regarding their use in childhood. Con- citing benefits from treatment in cognition
trolled studies are needed to document their and behavior. It should also encourage more
efficacy, specifically in FXS. widespread screening efforts, including new-
The most exciting aspect of treatment in born screening.
FXS is the development of targeted treat- Treatment of premutation involvement in-
ments that can reverse the neurobiologi- cludes treatment of ADHD with stimulants,
cal abnormalities documented over the last and treatment of the emotional problems (in-
few years. As noted at the beginning of this cluding anxiety and depression) with SSRIs
chapter, the absence or deficiency of FMRP (Bourgeois et al., 2009; Hagerman, Hall, et
leads to up-regulation downstream in the al., 2008). Treatment of FXPOI may include
mGluR5 pathway. This pathway normally the use of hormone replacement therapy
(Wittenberger et al., 2007). Treatment of the ing verbal expression, including the use of
tremor, the ataxia, and the pain problems rhythm, movement, dancing, and singing.
associated with neuropathy in patients with The combination of speech–language ther-
FXTAS is more complicated; a recent review apy with occupational therapy can be help-
has been published on this topic (Hagerman ful, particularly for less verbal children with
et al., 2008a). FXS (Scharfenaker et al., 2002). Therapies
can be even more effective when they are
implemented at home as well as in school.
Speech–Language
The use of augmentative and alternative
and Occupational Therapy
communication can be successful for chil-
All children who are significantly affected dren with FXS who are nonverbal. Many
by FXS can benefit from speech–language different methods of communication can
therapy and occupational therapy (Schar- be used to augment a child’s speech pro-
fenaker et al., 2002; Schopmeyer & Lowe, duction or provide an alternative to speech
1992). Speech and language deficits in FXS (Beukelman & Mirenda, 1992; Greiss-Hess
include auditory processing problems, clut- et al., 2009), and an evaluation can deter-
tering, mumbling, poor pragmatics, motor mine which of these may be useful. For in-
dyspraxia, and difficulties with abstract rea- stance, some children may use signs and ges-
soning. Speech–language therapy can focus tures to communicate with others. Pointing
on each of these deficits. Even in a child to pictures, or using the Picture Exchange
without ID, deficits in higher linguistic skills Communication System, can also be a use-
and pragmatics may exist. Strengths in the ful form of communication and choice mak-
language area include memory and imitation ing. Parents and teachers can create picture
skills, a fine sense of humor, and empathy in books or cards to help a child communicate
social interactions if there is no ASD. The his or her needs (e.g., the child can point to
memory strengths and the imitation skills a picture of a glass of water when he or she
can be well utilized in a therapy intervention is thirsty). For choice making, the child can
program (Scharfenaker et al., 2002). choose between pictures of two things or
Sensory integration occupational therapy activities (e.g., pictures of going outside or
can also be helpful for children with FXS. of playing in the house). More complicated
Physical calming techniques, such as brush- picture boards can also be successful in gen-
ing of the arms and legs, joint compression, erating expressive language. For instance,
and deep back rubs, can be helpful in de- the child can select pictures that represent
creasing hyperarousal behavior or aggres- the words “I,” “want,” and “hug,” to gen-
sion. In addition to sensory integration erate the sentence “I want [a] hug.” Finally,
therapy, a focus on fine and gross motor co- speech output devices may be used to help a
ordination and on motor planning is helpful child communicate his or her needs through
in therapy. Hypotonia also improves with synthesized or digitized speech (Hagerman,
time and with intervention. 1999).
Additional techniques can be used to
improve oral strength and verbalizations.
Computer-Based Interventions
PROMPT therapy has been studied in young
children with ASDs but without FXS (Rog- Computer technology is a useful adjunct to
ers et al., 2006), and anecdotal information the educational experience for children with
suggests that it is also beneficial for children FXS. They usually enjoy working on com-
with FXS. For jaw and mouth strength, sev- puters, and they show talent in this area.
eral approaches are suggested. For instance, Computers can be utilized to enhance at-
introducing a variety of textured foods can tention and build vocabulary skills, in addi-
help decrease oral sensitivity. Bagels, fruit tion to improving written language output.
leather, and chewy candy are excellent at Adaptive peripherals, such as an expanded
improving oral function. Simple games, such keyboard or IntelliKeys, can be useful in
as playing tug of war with a wet washcloth helping children with FXS to use a computer
during bathtime, can also promote increased (IntelliTools, Inc., 1996).
jaw strength (Scharfenaker et al., 2002). The use of both visual and auditory feed-
Other methods can be used for stimulat- back computer technology is most beneficial
for children with FXS. Computers can help will imitate the behaviors and language of
sustain attention in some children with FXS the lower-functioning children. Therefore,
who are otherwise easily distracted in stan- an inclusion setting is recommended for a
dard learning environments. There is such a child with FXS whenever possible, so that
wide variety of software available in differ- the other children in the class can model ap-
ent topics of learning that it is important to propriate behavior for the child with FXS.
evaluate a child’s cognitive level and visual– An emerging area of intervention in those
spatial, memory, motor, and language skills, with FXS is in the first year of life, as new-
in order to match a beneficial program to born screening becomes more widespread.
the child (Braden, 2002; Greiss-Hess et al., Rogers and Vismara (2008) have reviewed
2009; Scharfenaker et al., 2002). Some help- early intervention efforts for young children
ful programs include IntelliTalk from Intel- with autism, and such interventions, includ-
liTools, which is a talking word processor ing the Early Start Denver model, can be
that can speak letters, words, sentences, and utilized in toddlers with FXS (Vismara &
a combination of all three (IntelliTools, Inc., Rogers, 2008). As targeted treatments are
1996); and Co-Writer from Don Johnston, shown to be safe in young children, they
Inc., which is a combination of a diction- should also be combined with intensive early
ary and software that uses artificial intelli- interventions to correct the central nervous
gence to predict what a person wants to say system deficits in FXS and guide more nor-
(Greiss-Hess et al., 2009). Programs such as mal development.
Co-Writer were initially established to aid
people with physical limitations, but chil-
dren with learning and cognitive disabilities Conclusions
have also benefited tremendously from these
programs. The broad spectrum of involvement in FXS
requires a variety of interventions specific to
each individual. Although there are similar
Behavioral and Educational
physical, cognitive, and behavioral char-
Interventions
acteristics among children with FXS and
The use of behavioral intervention tech- FXDs, there is no set curriculum that will
niques, including structure and positive be effective for every child. For instance,
behavioral reinforcement, is beneficial for some children who are premutation carriers
children with FXS. Several references out- may not require medical or educational in-
line behavioral interventions for children tervention, whereas others may benefit from
with FXS (Braden, 2000; Chonchaiya et medication to help with anxiety or ADHD,
al., 2009; Hills-Epstein, Riley, & Sobesky, or from tutoring to help with school difficul-
2002). A controlled trial of a sleep interven- ties. Children who are affected by FXS usu-
tion in children with FXS was also beneficial ally benefit from special education support,
(Weiskop, Richdale, & Matthews, 2005). speech–language and occupational therapy,
Children with FXS can be often educated and medication; however, there is no set for-
in an inclusion setting in the regular class- mula as to the extent of therapy or the spe-
room (Spiridigliozzi et al., 1994). If cogni- cific medications that will be most helpful
tive deficits or behavioral problems are sig- for each individual child. For this reason, it is
nificant, then an aide or paraprofessional essential for every child with FXS to be seen
can be utilized in the classroom to modify by a physician and a team of professionals
assignments or to give extra explanation who are familiar with FXS and can create an
to the child with FXS (and perhaps others appropriate program for the child. A list of
who need it). An inclusion setting helps to Fragile X clinical and research centers from
improve social skills, since the child imi- throughout the United States and Canada is
tates the typical and appropriate behavior now expanding internationally and can be
of the other children. Education in a seg- found on the website for the National Frag-
regated program exclusively with children ile X Foundation (www.fragilex.org). Once
who have special needs can be problematic, a family knows of the FXS or FXD diagno-
particularly if all of the other children are sis, it is helpful for the family to contact the
lower-functioning, since the child with FXS National Fragile X Foundation, which has
a network of parent support groups and re- Bennetto, L., & Pennington, B. F. (2002). Neurop-
source centers around the country and inter- sychology. In R. J. Hagerman & P. J. Hagerman
nationally. The toll-free phone number of the (Eds.), Fragile X syndrome: Diagnosis, treat-
National Fragile X Foundation is 800-688- ment, and research (3rd ed., pp. 206–248). Balti-
more: Johns Hopkins University Press.
8765. The National Fragile X Foundation
Berry-K ravis, E., & Potanos, K. (2004). Psychop-
can also provide educational information in harmacology in fragile X syndrome—present and
papers, books, videos, and conferences for future. Mental Retardation and Developmental
both parents and professionals. Disabilities Research Reviews, 10(1), 42–48.
Berry-K ravis, E., Sumis, A., Hervey, C., Nelson,
M., Porges, S. W., Weng, N., et al. (2008). Open-
Acknowledgments label treatment trial of lithium to target the un-
derlying defect in fragile X syndrome. Journal of
This work was partially supported by grants from Developmental and Behavioral Pediatrics, 29(4),
the National Institute of Child Health and Human 293–302.
Development (Nos. HD036071 and HD 02274); Berry-K ravis, E., Hessl, D., Coffey, S., Hervey, C.,
Grant Nos. NIA AG032115, NCRR RR024146,
Schneider, A., Yuhas, J., et al. (2009). A pilot
and NIDCR DE019583 from the National Insti-
open-label single-dose trial of fenobam in adults
tute on Aging; and Grant No. 90DD0596 from the
Health and Human Services Administration of De- with fragile X syndrome. Journal of Medical Ge-
velopmental Disabilities. netics, 46(4), 266–271.
Beukelman, D. R., & Mirenda, P. (1992). Augmen-
tative and alternative communication manage-
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C h a p t e r 15
The Mucopolysaccharidoses
Michael B. Brown
The mucopolysaccharidoses (MPS disor- Scheie syndrome (MPS IS), 1 in 840,000 to 1

ders) are a group of progressive, hereditary in 1,300,000 live births; Hurler–Scheie syn-
diseases that result from abnormalities of drome (MPS HIS), 1 in 280,000 live births;
glycosaminoglycan (acid mucopolysaccha- Hunter syndrome (MPS II), 1 in 100,000 to
ride) metabolism (Spranger, 2007). There 150,000 live births; Sanfilippo syndrome
are six types of MPS disorders, several of (MPS III), 1 in 24,000 to 1 in 200,000 live
which have a number of subtypes (see Table births; Morquio syndrome (MPS IV), 1 in
15.1). The estimated prevalence of these dis- 75,000 to 1 in 1,000,000 live births; and
orders is as follows: Hurler syndrome (MPS Maroteaux–Lamy syndrome (MPS VI), 1 in
IH), 1 in 76,000 to 1 in 144,000 live births; 100,000 to 1 in 1,300,000 live births (Chen,
2006). Very few cases of Sly syndrome (MPS
VI) have been reported worldwide (Neufeld
TABLE 15.1. Classification of the MPS
& Muenzer, 2001).
Disorders
MPS IH Hurler syndrome Etiology, Features, and Course

MPS IS Scheie syndrome
Pathophysiology
MPS IHS Hurler–S cheie syndrome
MPS II Hunter syndrome The MPS disorders are the largest group of
MPS IIIA Sanfilippo syndrome, Type A
lysosomal storage disorders (Herring, 2008).
Lysosomes are intracellular structures con-
MPS IIIB Sanfilippo syndrome, Type B
taining enzymes that can break down or
MPS IIIC Sanfilippo syndrome, Type C metabolize complex molecules. The complex
MPS HID Sanfilippo syndrome, Type D molecules are brought into the lysosomes for
MPS IVA Morquio syndrome, Type A metabolism in the course of normal physi-
MPS IVB Morquio syndrome, Type B ological processes. In the MPS disorders,
MPS IVC Morquio syndrome, Type C there is a failure of specific genes to produce
MPS VI Maroteaux–Lamy syndrome
a sufficient level of active enzymes necessary
to break down the mucopolysaccharides.
MPS VII Sly syndrome
As a result, large quantities of the incom-
293
TABLE 15.2. Enzyme Deficiencies in MPS Disorders

Type of disorder Enzyme deficiency
MPS IH Hurler syndrome Alpha-L-iduronidase
MPS IS Scheie syndrome Alpha-L-iduronidase
MPS IHS Hurler–S cheie syndrome Alpha-L-iduronidase
MPS II Hunter syndrome Iduronate sulfatases
MPS IIIA Sanfilippo syndrome, Type A Heparan-N-sulfatase
MPS IIIB Sanfilippo syndrome, Type B Alpha-N-acetylglucosaminidase
MPS IIIC Sanfilippo syndrome, Type C Acetyl CoA-alpha-glucosaminide-acetyltransferase
MPS HID Sanfilippo syndrome, Type D N-Acetylglucosamine-6-sulfatase
MPS IVA Morquio syndrome, Type A Galactose-6-sulfatase
MPS IVB Morquio syndrome, Type B Beta-galactosidase
MPS VI Maroteaux–Lamy syndrome N-Acetylgalactosamine-4-sulfatase
MPS VII Sly syndrome Beta-glucuronidase
pletely metabolized material accumulate in been an inactivation of the normal X chro-

the lysosomes. The abnormal accumulation mosome (Spranger, 2007).
produces the symptoms and complications
of these disorders. There are several en-
Major Features
zymes required for the degradation of muco-
polysaccharides, and the MPS disorders are The abnormal accumulation of incompletely
classified according to the specific enzyme metabolized mucopolysaccharides produces
deficiencies that cause them (Bach, 2004; a number of characteristic clinical features,
Herring, 2008; see Table 15.2). the most striking of which are skeletal ef-
fects. The complete range of skeletal features
occurs in Hurler syndrome; these features
Genetics
occur to varying degrees in each of the other
Each of the MPS disorders, with the excep- MPS disorders. Excessive lysosomal stor-
tion of Hunter syndrome, is an autosomal age also affects other organ systems, most
recessive disorder (Chen, 2006). In an au- notably the cardiovascular, respiratory, and
tosomal recessive disorder, each parent nervous systems. Neurological involvement
must be a carrier of the abnormal gene for results in progressive dementia in many of
a child to develop the disorder. Both males the MPS disorders.
and females are affected by the autosomal
recessive MPS disorders. The variation in
MPS I (Hurler Syndrome, Scheie Syndrome,
the severity of clinical manifestations of the
and Hurler–Scheie Syndrome)
disorders in different individuals is a result
of allelic mutations and the level of residual Children with Hurler syndrome have char-
enzyme activity (Spranger, 2007). acteristic skeletal effects known as dysos-
Hunter syndrome is a recessive, sex-linked tosis multiplex (Alman & Goldberg, 2005;
disorder (Chen, 2006). The affected gene Neufeld & Muenzer, 2001). Specific fea-
site is located on the X chromosome, and tures include (1) widened collarbone and
as a result females carry the recessive gene ribs; (2) progressive curvature of the lower
for the disorder. The disorder consequently spine (lumbar kyphoscoliosis); (3) signifi-
occurs almost exclusively in males, as males cant shortening of stature; (4) shortened
receive only one X chromosome; therefore, neck; (5) stubby, claw-shaped hands; (6)
there is no second X chromosome to provide contractions of the joints; (7) enlarged head;
a dominant (normal) version of the gene to (8) flattening of the bridge of the nose, wide
override the effect of the recessive (impaired) nostrils, thick lips, and large and protruding
gene. Females can be affected if there has tongue with open mouth; and (9) thick hair
The Mucopolysaccharidoses 295
and excessive body hair. Hurler syndrome spine (kyphoscoliosis); (7) waddling gait
is the most severe of the three syndromes; and inward-turned knees; (8) finger and
Scheie and Hurler–Scheie syndromes both joint stiffness, and early arthritis in hips and
have less severe skeletal expressions. Rap- knees; (9) depressed nasal bridge and pro-
idly progressing cognitive impairment is the truding lower jaw; (10) broad mouth, with
rule in Hurler syndrome, whereas cognitive the appearance of a permanent grin; and (11)
functioning is generally spared in Scheie and dental abnormalities, including thin and pit-
Hurler–Scheie syndromes. ted enamel, widely spaced conical teeth, and
excessive tooth wear (Alman & Goldberg,
2005; Cervantes & Lifshitz, 1990; Nelson
MPS II (Hunter Syndrome)
& Kinirons, 1988). Persons with this disor-
The features of Hunter syndrome include der have normal or near-normal intelligence
(1) a depressed nasal bridge and distortion (Cervantes & Lifschitz, 1990).
of facial bones; (2) enlarged head; (3) a dis-
tinctive posture of hunched shoulders, with
MPS VI (Maroteaux–Lamy Syndrome)
the joints of the limbs held in partial flexion;
(4) joint stiffness and a claw-like hand de- Children with Maroteaux–Lamy syndrome
formity; (5) very short stature or dwarfism; have dysostosis multiplex, the same char-
and (6) a thickening and overgrowth of hair acteristic skeletal effects as in Hurler syn-
on the body (Young, Harper, Newcombe, & drome. Children with this syndrome may
Archer, 1982b). exhibit variations in the severity of the skel-
etal manifestations. Intellectual functioning
remains in the normal range (Bach, 2004).
MPS III (Sanfilippo Syndrome)
Both severe and milder versions of the disor-
The presentation of Sanfilippo syndrome der have been identified.
is dominated by severe neurodegenera-
tive disturbance (Cleary & Wraith, 1993).
MPS VII (Sly Syndrome)
Progressive intellectual disability occurs
rapidly, accompanied by serious behavior Sly syndrome is characterized by skeletal
disturbances that include hyperactive be- manifestations similar to those of Hurler
havior, physical aggression, noncompliance, syndrome but often with slower progression
and self-stimulatory behaviors (Nidiffer & (Spranger, 2007). Unusual facial appear-
Kelly, 1983). There is usually only mild so- ance, hepatosplenomegaly, and short stature
matic involvement of the sort typical of the are common. Both mild and severe forms of
other MPS disorders until late in the course the disorder have been reported, along with
of the disorder (Spranger, 2007). Stature is a form of the disorder that is present at birth
near normal, and the facial features com- (Neufeld & Muenzer, 2001).
mon to the other MPS disorders are usually
not present. Joint stiffness is mild and rarely
Developmental Course
causes mobility problems.
The features of the MPS disorders gener-
ally become apparent in early childhood,
MPS IV (Morquio Syndrome)
though some of these disorders may first be
The primary features of Morquio syndrome diagnosed as late as adolescence. Each of the
are skeletal deformities, with secondary ef- disorders has a typical developmental course
fects on the nervous and cardiovascular that includes the age of onset of symptoms
systems. The characteristic features include and the progression of impairment.
(1) shortened trunk, neck, legs, and arms;
(2) short stature or dwarfism, depending
MPS I (Hurler, Scheie,
on the severity of the disorder; (3) unstable
and Hurler–Scheie Syndromes)
knee joints; (4) enlarged elbows and wrists;
(5) flattened vertebrae, with underdevel- Children with Hurler syndrome appear nor-
opment of a portion of the cervical verte- mal at birth and grow rapidly during their
brae; (6) expanded thoracic rib cage, with first year (Nelson & Crocker, 1999). A de-
marked inward curvature of the lumbar celeration of growth occurs at some point
between 6 and 18 months of age (Neufeld & Harper, 1982). Physical development is
& Muenzer, 2001). Learning peaks in the typically normal at first, with the abnormal
second or third year of life, and afterward facial configuration and growth defects be-
developmental regression occurs, with a loss coming evident by early childhood (Avery
of previously learned skills. Progressive in- & First, 1994). Intellectual performance is
tellectual disability results, and language also typically relatively normal. Survival is
facility is gradually lost. The ability to walk possible into the fourth decade and beyond,
is gradually lost, and most children with and persons with the disorder may continue
MPS IH remain incontinent (Bax & Coville, their education, marry, and have children.
1995). Many children have difficulty feed- Death is usually caused by cardiac or pul-
ing themselves because of poor coordination monary complications (Young & Harper,
and swallowing difficulties. The children 1982).
also become less interested in the environ- The severe or early-onset form of Hunter
ment. Maximum functional age is usually syndrome has an average age of onset of 2.5
between 2 and 4 years. Death frequently oc- years, with an average age at death of 11.8
curs by age 10 (Neufeld & Muenzer, 2001), years (Young & Harper, 1983). This form of
typically as a result of cardiovascular disor- the disorder is marked by progressive neuro-
ders, respiratory problems, or complications logical involvement, which results in a pla-
of neurological damage (Nelson & Crocker, teau of learning and developmental skills at
1999). some point between ages 2 and 6. The pla-
The symptoms of Hurler–Scheie syn- teau is followed by a regression in cognitive
drome usually begin between 3 and 8 years skills and behavior. Intellectual disability has
of age (Spranger, 2007). Children develop an insidious onset and becomes profound.
mild facial deformities, shortened stature, Seizure disorder is common, especially past
and stiffened joints. Hepatosplenomegaly age 10. The children become emaciated, and
(enlargement of the liver and spleen) and there is significant wasting of body mass
hernia are frequent complications (Neufeld (neurodevelopmental cachexia). Ninety per-
& Muenzer, 2001). Visual losses may occur cent of those affected are bedridden by age
due to corneal clouding or glaucoma. Intel- 10. Death usually results from pulmonary
lectual development is typically normal or complications of the cachexic state (Young
only mildly impaired. Hydrocephaly is com- & Harper, 1983).
mon. Deafness and heart valve disorders are
typical. Persons with this syndrome usually
MPS III (Sanfilippo Syndrome)
survive into adulthood.
Scheie syndrome is at the milder end of the Children with Sanfilippo syndrome (MPS
clinical spectrum of these disorders (Sprang- III) are typically first diagnosed at about
er, 2007). This disorder is characterized by age 5 (Cleary & Wraith, 1993; Neufeld &
joint stiffness, deformity of the hands, and Muenzer, 2001; Nidiffer & Kelly, 1983).
corneal clouding. Stature is usually normal, The features of the disorder begin to appear
as is intellectual functioning. The diagnosis between 2 and 6 years of age. The rate of
is usually made in the teens, and life expec- achievement of developmental milestones is
tancy is generally not affected. normal up to this time, although delay or
loss of language and memory may be the
most notable early symptoms. The present-
MPS II (Hunter Syndrome)
ing symptoms include hyperactivity, devel-
Two forms of Hunter syndrome, mild and opmental delay, hirsutism, and poor sleep.
severe, have been identified based on onset, Some children develop episodes of intracta-
complications, and course of the disorder ble diarrhea. There may also be increasingly
(Young, Harper, Newcombe, & Archer, severe temper tantrums and aggressive be-
1982a, 1982b). Within each form, however, havior. Some children have panic-like symp-
considerable individual variation can exist toms in unfamiliar places. Cognitive decline
(Bach, 2004). The mild or late-onset form continues with progressive dementia. The
has an average age of onset of 4.3 years and skeletal features common to the MPS dis-
an average age at death of 21.7 years (Young orders are usually less severe in Sanfilippo
syndrome and tend to become obvious only IVB (the intermediate form of the disorder)
in the later stages of the disorder. have the classic characteristics in a less se-
After age 10, the behavioral symptoms vere form. They have a final height greater
often become less severe. Typical problems than 50 inches and usually have normal-
include falls caused by lack of coordina- appearing dentition. The diagnosis of this
tion, and difficulty with feeding as a result form is usually made during the childhood
of impaired swallowing. Joint stiffness and years.
spasticity interfere with mobility and may
necessitate the use of a wheelchair. Seizures
MPS VI (Maroteaux–Lamy Syndrome)
are not uncommon. Most individuals with
Sanfilippo syndrome survive into their teens, The severe form of Maroteaux–Lamy syn-
although some persons live into their second drome includes pronounced skeletal defor-
or third decade. mities with intact intellectual functioning
There are four forms of Sanfilippo syn- (Neufeld & Muenzer, 2001; Spranger, 2007).
drome, designated as IIIA, IIIB, IIIC, and The head is usually large, with a short neck,
IIID, each associated with a different enzyme broad flat nose, and wide nostrils. The skin
abnormality (see Table 15.2). The clinical and hair are thick and course. Liver enlarge-
presentation of each type appears similar, ment is common, and the abdomen may pro-
although there are reports of persons whose trude. The spine may be curved, and joint
behavior was not problematic until their late mobility may be limited. Stature is signifi-
teens (Kim, Berger, Bunner, & Carey, 1996) cantly shortened and is noticeable between
and of others who were still mobile into their 2 and 3 years of age. There is wide variation
20s (Cleary & Wraith, 1993). in the presentation of the disorder, including
a mild version of the disorder that results in
less severe skeletal involvement.
MPS IV (Morquio Syndrome)
Individuals with Morquio syndrome (MPS
MPS VII (Sly Syndrome)
IV) appear normal at birth, and the char-
acteristics of the disorder develop during in- Individuals with Sly syndrome may vary
fancy or childhood. There have traditionally in the expression of symptoms (Neufeld &
been two widely recognized forms of this Muenzer, 2001). The more severe, early-
disorder, designated as MPS IVA and MPS onset type of this disorder begins by age 3.
IVB, which differ in the severity of symp- Skeletal abnormalities are moderately severe
toms and the age at detection (Neufeld & and result in shortened stature. Intellectual
Muenzer, 2001). A more recent typology disability is frequently moderate, but not
(Alman & Goldberg, 2005) includes a third progressive. The later-onset form of the dis-
variant of Morquio syndrome, MPS IVC. order occurs after age 4. Skeletal involve-
This mild variant of the disorder results in ment may be mild or severe. Intelligence is
much less severe clinical manifestations. usually normal. A severe neonatal form of
Stature is nearly normal, with only mild the disorder can be present and has caused
skeletal abnormalities. This form is usually infant death.
first diagnosed in adolescence.
Persons with MPS IVA (the severe form
of the disorder) appear normal at birth, but Medical, Psychological,
shortened stature appears by about 1 year and Social Complications
of age. Final height is usually less than 50
inches. Younger children have difficulty with Any MPS disorder is a developmental disor-
continence, although most children over 10 der with significant impact on an individual’s
are continent (Bax & Coville, 1995). The di- physical, psychological, and social develop-
agnosis of the severe form of the disorder is ment. Many of the complications, especially
usually made between 1 and 3 years of age. the physical and cognitive complications,
Individuals with the severe variant of the dis- are results of the accumulation of mucopoly-
order usually live until their third or fourth saccharides in the tissues. The social impact
decade (Bach, 2004). Children with MPS is secondary to the child’s level of physical
disability, difficulties in communication and Neuropsychological Complications

understanding as a result of cognitive limita-
Little is known about the specific neuro
tions, and the presence of difficult behaviors
psychological aspects of the MPS disorders
characteristic of several MPS disorders.
because formal neuropsychological study
of children with these disorders has rarely
Medical Complications been undertaken (Shapiro & Klein, 1994).
Complications of MPS disorders occur in Children with the MPS disorders are not
many organ systems (Alman & Goldberg, routinely referred for neuropsychological as-
2005; Avery & First, 1994; Neufeld & sessment; reasons have included the lack of
Muenzer, 2001). The enlargement of the treatment available for the disorders, as well
liver and spleen (hepatosplenomegaly) reas the advanced stage of the disorders by the
sults in a protuberant abdomen, and hernia time diagnoses are usually made. The exces-
occurs frequently. Chronic, intractable diar- sive storage of mucopolysaccharides in the
rhea is frequently found in Hunter and San- tissues does affect both the gray and white
filippo syndromes. Carpal tunnel syndrome matter of the brain.
(entrapment of nerves in the wrist) can re- The primary neuropsychological compli-
sult in further impairment in the use of the cation of the MPS disorders is progressive
hands and arms. dementia. Dementia differs from intellectual
Cardiovascular problems, especially val- disability in that intellectual disability is a
vular disorders, are usually evident in older slowing in the attainment of developmental
children and adolescents with MPS disor- milestones, whereas dementia is a reduction
ders. Respiratory disorders are common, in- in the previously attained level of function-
cluding increased rates of respiratory infec- ing. In those MPS disorders that result in
tions, airway obstruction, and pulmonary dementia, there is an initial slowing of de-
hypertension. Sleep apnea may result from velopment, followed by a plateau in level of
obstructions in the respiratory system. Deaf- functioning. Skills that have been developed
ness, due to both progressive thickening of are subsequently lost. Language delays occur
the skull (conduction loss) and sensory im- in the severe form of Hunter syndrome and
pairment, is likely in the severest forms of in Sanfilippo syndrome (Shapiro, Lockman,
the disorders (Herring, 2008). Glaucoma Balthazar, & Krivit, 1995). All patients with
and retinitis pigmentosa can occur, which, Hurler syndrome in one study who had been
along with corneal clouding, often affects treated with bone marrow transplantation
vision. (BMT) had residual learning problems, al-
Dentition is frequently affected in the though none had severe mental retarda-
MPS disorders, especially in Morquio and tion (Guffon, Souillet, Maire, Straczek, &
Maroteaux–Lamy syndromes (Nelson & Ki- Guibaud, 1998).
nirons, 1988; Smith, Hallett, Hall, Wardrop, Hydrocephaly (an accumulation of ce-
& Firth, 1995). Delayed tooth eruption and rebrospinal fluid surrounding the brain) is
weaknesses in enamel can occur. Abnor- common, especially in Hurler and Hunter
malities of tooth morphology, such as wide syndromes. Children with Sanfilippo syn-
spacing and a sharp, conical shape, are com- drome and the severe form of Hunter syn-
mon. Excessive wear on the tooth surface drome often have seizures (Cleary & Wraith,
may result. 1993; Young et al., 1982a). Neurological
The abnormal formation of the cervical symptoms may also be caused by spinal cord
vertebrae, especially in Morquio syndrome, compression due to the buildup of extradur-
may lead to misalignment of these vertebrae al soft tissue (Alman & Goldberg, 2005).
(atlantoaxial subluxation). This can cause
spinal cord compression, leading to paralysis
Behavioral Complications
and death (Ashraf, Crockard, Ransford, &
Stevens, 1991; Neufeld & Muenzer, 2001). Children with MPS disorders have a high
Spinal misalignment and narrowing of the prevalence of certain behavior problems
airway also create potentially serious prob- (Bax & Colville, 1995). Parents of children
lems with establishing an airway and pro- with Hurler syndrome describe their chil-
viding anesthesia if surgery is necessary. dren as anxious or fearful. Many are con-
sidered to be restless, with little aggressive Parents are unlikely to have regular out-
behavior. Sleep problems are seen in some side help in managing the day-to-day care
children, but these are reflections of their of a child with such a disorder. They often
medical problems rather than of a behavior feel uncomfortable leaving their child with
problem. Overactivity is common in chil- other caregivers, sometimes because of the
dren with Hunter syndrome up to age 10. fear that the child may die while the parents
There is a high rate of aggressive/destruc- are gone. In addition, parents often face in-
tive behavior in children under 5. Excessive creased pressures caused by repeated medical
fearfulness occurs in most and is especially procedures, associated behavior problems,
likely in younger children. Problems with and the financial demands of having a child
sleep, such as difficulty settling and going to with a major chronic disorder. Relatively
sleep, occur frequently. Behavior problems few families receive any type of assistance
(overactivity, aggression, and defiance) tend from a mental health care provider.
to arise early in the course of Hunter syn- Parents are very concerned and frequently
drome in children with the severe form of worried about their child’s prognosis. Many
the disorder. In the milder form of Hunter are frustrated by the lack of information
syndrome, behavioral problems are more available to parents and professionals at the
likely to occur in adolescence, presumably local level. There is often a lack of adequate
because of the adjustment problems posed community support and assistance. Parents
by the adolescents’ unusual appearance and frequently feel helpless (Nidiffer & Kelly,
their knowledge of their prognosis (Young 1983) and isolated (Bax & Coville, 1995).
et al., 1982a). Parents feel a great deal of distress when
Sanfilippo syndrome causes the most dra- their child becomes so impaired that they
matic behavioral symptoms of all the MPS are unable to communicate with him or her
disorders (Bax & Coville, 1995; Nidiffer & (Bax & Coville, 1995). They are also con-
Kelly, 1983). Restlessness is a common fea- cerned about the effect of the child with MPS
ture in children with MPS III, and children on siblings (Nidiffer & Kelly, 1983). Sibling
commonly wander around home and school; relationships may be affected by jealousy be-
they also mouth clothing and other objects. cause of the extra parental attention to the
Parents often describe their children as un- needs of the child with MPS, or the burden
predictable, with frequent aggressive and of providing extra care for an ill sibling. Sib-
destructive behaviors, including hitting oth- lings may also be concerned that their own
ers. These behaviors seem unprovoked and acceptance by their peers will be affected by
do not appear to be accompanied by anger. the presence of a sibling with such signifi-
Difficult behavior at night is also common, cant problems.
including staying up during the nighttime
hours, wandering, and restlessness. Many
families have had to use secure sleeping ar- Identification, Treatment,
rangements or resort to having a child sleep and Intervention
in a parent’s room so as to provide supervi-
sion over night. Because the MPS disorders occur so rarely,
Children with Morquio syndrome have a parents, school personnel, and local health
relatively low level of behavioral problems, care providers are likely to have little first-
compared to those with the other MPS dis- hand experience with these disorders. Early
orders. Sleep problems are present, especial- identification is important to allow for early
ly in the 5- to 9-year-old group. Many chil- treatment and intervention. A number of
dren between ages 10 and 14 are described medical, educational, and allied health care
by their parents as fearful (Bax & Colville, specialists are required for optimal care, es-
1995). pecially for those children with more severe
forms of the disorders (see Table 15.3). Close
communication and collaboration among
Psychosocial Complications
parents, educators, and health care provid-
Family stress often occurs because of the ers are vital to create an atmosphere of trust
multiple demands of the MPS disorders (Bax and support, which is necessary in dealing
& Coville, 1995; Nidiffer & Kelly, 1983). with these disorders.
TABLE 15.3. Treatment Providers Involved in Comprehensive Care

for MPS Disorders
Physicians Educational specialists Health care providers
Anesthesiologist Early intervention specialist Pediatric dentist
Cardiologist Special education teacher Occupational therapist
Child psychiatrist Instructional assistant Physical therapist
Neurologist School psychologist Psychologist
Neurosurgeon School nurse Rehabilitation counselor
Ophthalmologist School social worker Speech–language clinician
Orthopedic surgeon
Pulmonologist
Diagnosis behaviors present in Sanfilippo syndrome

may be misdiagnosed as attention-deficit/
Children with MPS disorders usually pres-
hyperactivity disorder. This underscores the
ent for diagnosis as a result of developmental
importance of a medical workup on all chil-
delay or the development of characteristic
dren with developmental difficulties as part
skeletal features. Early diagnosis is impor-
of an evaluation of behavioral problems.
tant because intervention (especially the
Prenatal diagnosis is possible and is rou-
newer therapies) is more effective in children
tinely conducted when there is a known
who have not yet suffered neurological inju-
risk that the fetus will be affected by one
ry due to accumulation of mucopolysaccha-
of the disorders (Bach, 2004; Neufeld &
rides (Herring, 2008). Mucopolysaccharides
Muenzer, 2001). Fetal fibroblasts circulat-
are excreted through the urine, and analysis
ing in the amniotic fluid can be obtained
of mucopolysaccharide levels in the urine
through amniocentesis from the 13th to the
can be measured for an initial diagnosis.
16th week of gestation. These cells can then
The outcome of urinary screening is some-
be cultured and assayed for activity of the
times inaccurate, and its utility varies with
relevant enzyme. Chorionic villus sampling
the different types of MPS disorders. More
obtains small pieces of the placenta through
definitive diagnosis requires an enzyme assay
needle biopsy from the 10th or 11th week of
of cultured fibroblasts or leukocytes (white
gestation (Bach, 2004). These cells are then
blood cells). In this procedure, cell samples
analyzed for enzyme activity or mutation
are taken and grown in a culture medium.
analysis.
The cells are then subjected to tests for the
presence of the enzyme in question.
The differential diagnosis for MPS dis- Medical Issues and Interventions
orders includes other diseases that produce
Children with MPS disorders have many
dysostosis multiplex and physical appear-
characteristic medical problems that are the
ance typical of the MPSs (Matalan, 1996; see
targets of medical interventions. There has
Table 15.4). The hyperactivity and tantrum
generally been no definitive treatment for
the MPS disorders, and supportive treat-
ments are beneficial for improving children’s
TABLE 15.4. Genetic Diseases quality of life (Rudolph, Rudolph, Hostetter,
Considered in the Differential Diagnosis
Lister, & Siegel, 2002). A number of recent
of the MPS Disorders
efforts to develop definitive treatments have
GM1 gangliosidosis Mucolipidosis III shown promise for some of the MPS disor-
Mannosidosis Mucolipidosis IV ders, however.
Fucosidosis Multiple sulfatase
Aspartylglucosaminuria deficiency Supportive Treatment
Mucolipidosis I Kneist syndrome
Spondyloepiphyseal
Supportive treatments focus on alleviating
Mucolipidosis II the manifestations and complications of the
(I-cell disease) dysplasias
MPS disorders (Neufeld & Muenzer, 2001).
Children commonly need supportive inter- Definitive Treatment

ventions for cardiovascular complications
A number of efforts have been made to de-
and respiratory difficulties. Upper-airway
velop definitive biological treatments to cor-
obstruction and sleep apnea may require
rect the basic defects that cause the MPS
surgical interventions, and respiratory infec-
disorders or to provide adequate levels of
tions and middle-ear infections need prompt
and aggressive treatment. Because of the dif- enzymes in the body. These treatments have
ficulties of maintaining an airway, persons shown promise for some of the MPS disor-
with MPS disorders who need general anes- ders. The optimal results of these definitive
thesia must be cared for in a setting that has treatments will come from early intervention
experience in providing anesthesia services prior to the tissue and organ damage caused
for this group (Neufeld & Muenzer, 2001). by accumulation of mucopolysaccharides
Interventions for hearing loss are fre- (Muenzer & Fisher, 2004).
quently necessary, and children with MPS Two types of transplantation procedures
disorders should receive regular evaluation have been used for treating MPS disorders.
for sensory and conductive hearing loss BMT is a form of treatment that replaces
(Alpern, 1992). Hearing aids can be helpful abnormal cells and supplements the genetic
for many children with these disorders who production of the enzyme. Hematopoietic
have hearing loss. Auditory training, such as stem cell transplantation replaces abnor-
instruction in making use of residual hear- mal cells using infusions of umbilical cord
ing and lip reading, may be useful for some blood. Both BMT and hematopoietic trans-
children. Alternative communication skills plantation have had similar effects for MPS
may be necessary for higher-functioning IH (Hurler syndrome). Improvements have
children and adults who have tracheotomies been noted in improved neurological, he-
because of airway obstruction, or who have patic, and cardiac functioning, along with
total hearing loss. improvements in the airway, joint move-
Regular dental care is important to pre- ment, and hearing (Muenzer & Fisher,
vent or address potential dental problems, 2004). BMT has not had a noticeable ef-
which are especially common for children fect on the progression of skeletal disease,
with Morquio syndrome (Nelson & Ki- however, and there is no evidence yet of
nirons, 1988). Surgical treatment of impact- the effect on skeletal disease of cord blood
ed teeth may be necessary. The possibility of transplantation. BMT has been effective on
endocarditis is increased by the presence of the non-neuropsychological symptoms of
cardiovalvular disease, which is commonly Hunter syndrome (Guffon, Bertrand, For-
present in the MPS disorders. Prophylactic est, Foulhoux, & Froissart, 2009). BMT has
treatment is indicated to prevent the occur- improved motor function for one child with
rence of infective endocarditis secondary to Maroteaux–Lamy syndrome on long-term
dental procedures. follow-up (Wang, Hwu, & Lin, 2008).
Skeletal and mobility difficulties are com- Shapiro and colleagues (1995) found that
mon problems for children with MPS disor- BMT prior to age 2 resulted in stabilization
ders (Neufeld & Muenzer, 2001). Both sur- of intellectual functioning for children with
gical and nonsurgical interventions are used Hurler syndrome who had IQs above 70
in the management of the orthopedic prob- prior to the procedure. BMT did not alter the
lems associated with these disorders (Her- progressive course in any children with San-
ring, 2008). Surgery may be necessary to filippo syndrome. No children with Hunter
correct spinal deformity and to stabilize cer- syndrome received BMT prior to the age of
vical instability in those situations where the 2, and all but one of the children failed to
instability may lead to neurological impair- show an alteration in the course of the dis-
ment. Surgical treatment is also indicated to ease. This may demonstrate that the sever-
reduce median nerve compression in carpal ity of the disease and the age at onset are
tunnel syndrome. Nonsurgical treatments important factors in successful outcomes of
include physical therapy to minimize joint BMT. BMT, like any organ transplantation,
contractures and the use of splints or braces. remains an expensive procedure with signifi-
Some children will need to use a wheelchair cant mortality and morbidity rates (Batshaw
for mobility. & Tuchman, 2007).
Enzyme replacement therapy has been well to behavioral intervention strategies

used successfully to reduce some of the man- (Nidiffer & Kelly, 1983). Behavioral inter-
ifestations of MPS I and MPS VI. Treatment ventions have been successful in decreasing
over 26 weeks with a human recombinant the sleep problems of children with Sanfil-
form of alpha-L-iduronidase has produced ippo syndrome (Coville, Watters, Yule, &
reduction in urinary glycosaminoglycan ex- Bax, 1996). It is important to remember
cretion, improvement in liver volume, and that discomfort, changes in routine, and
enhanced physical endurance in children the level of environmental stimulation may
with MPS IS (Scheie) and MPS HS (Hurler– lead to or exacerbate difficult behavior. A
Scheie) disorders (Miebach, 2005). Because thorough assessment of behavioral problems
the enzyme does not cross the brain–blood should include an assessment of the physi-
barrier, it is likely not to affect the neuro- cal environment, behavioral antecedents,
logical manifestations of the disorder. Treat- and consequences of the problems, as well
ments over 24–48 weeks with N-acetylga- as an evaluation of the child’s characteristics
lactosamine-4-sulfatase reduced lysosomal (Jacob-Timm & Daniels, 1998).
storage and improved physical endurance Few studies have examined psychophar-
and joint function in children with Maro- macological interventions for the behavioral
teaux–Lamy syndrome (MPS VI; Harmatz difficulties of children with MPS disorders.
et al., 2004). Enzyme replacement therapy Such interventions have produced variable
has ameliorated the non-neurological mani- responses (Cleary & Wraith, 1993). Meth-
festations of Hunter Syndrome (Rudolph et ylphenidate has not been useful in reducing
al., 2002). Enzyme replacement therapy may the hyperactivity of children with Sanfilippo
also be advantageous for some children with syndrome (Jacob-Timm & Daniels, 1998).
MPS IH (Hurler syndrome) because it offers Thioridazine and haloperidol do reduce
fewer risks than BMT and improves somatic the hyperactivity, although these drugs also
symptoms (Muenzer & Fisher, 2004). have potential side effects that create ad-
ditional problems (Wraith, 1995). Wraith
(1995) also found that benzodiazepines and
Psychosocial Issues
chloral hydrate are effective sleep medica-
Like all children, children with MPS disor- tions for children with Sanfilippo syndrome.
ders have a wide range of personality traits Carbamazepine has been successfully used
and habits. Their feelings and behaviors are to reduce overactivity, aggressive outbursts,
affected by many factors, including their and labile mood in an adolescent with San-
family, the extent of their physical problems, filippo syndrome (Kim et al., 1996).
and their level of cognitive functioning.
Family and friends generally have positive
Family Issues
feelings and relationships with their fam-
ily member with an MPS disorder, and the Parents of children with MPS report that they
affected child is treated by others in many have joys and pleasures in raising their chil-
ways as any child would be treated. Many dren similar to those experienced by parents
have few or no issues with negative behav- of nondisabled children. The diagnosis of a
iors, and when such behaviors are present, severe disorder, however, has a powerful ef-
they are similar to those of children experi- fect on parents, who must deal not only with
encing problems with similar cognitive and their own feelings but with a complex array
physical effects. of medical and educational providers (Chen
Some children with MPS disorders, espe- & Miles, 2007). For parents whose children
cially children with MPS III subtypes, may have MPS disorders, the latter dealings are
exhibit significant behavioral issues. Unfor- often complicated by most health care and
tunately, psychological services are rarely educational providers’ lack of familiarity
provided in the ongoing management of chil- with the disorders. The path from first con-
dren with these disorders (Bax & Colville, cerns to a definitive diagnosis is often long.
1995). Clinical experience with MPS dis- Parents may be overwhelmed by the many
orders suggests that the difficult behaviors stressors that result from having a child with
(such as the aggressive outbursts of children a progressive genetic disorder (Perszyk &
with Sanfilippo syndrome) may not respond Perszyk, 2004). This is compounded by the
fact that life expectancy is reduced for most with severe disabilities can be found in Chen
children with MPS disorders. and Miles (2007).
Providing information and helping parents Empathy and emotional support are very
locate support groups (see Table 15.5) can helpful responses from treatment providers.
be of great benefit to parents overwhelmed Training parents in behavior management
by the challenges of a child with an MPS dis- techniques, or providing referrals for parent
order. Parents can receive enormous support counseling and/or psychopharmacological
from talking with other parents who can interventions, may help parents cope with
understand their situation and provide not their child’s behavior problems. Parents may
only empathy, but good information on re- also need assistance in accessing the neces-
sources and strategies that are not otherwise sary medical care for the complications of
widely accessible. The National MPS Soci- an MPS disorder. Since the need for medi-
ety, for example, provides many invaluable cal care is likely to be complex and ongoing,
programs, information and support for par- then parents may need assistance with insur-
ents. These include an annual parent con- ance, government benefits, or access to com-
ference, regional social events, small grants munity groups that could provide material
for the purchase of special equipment, and assistance for the family. Parents of children
a number of parent volunteers who can talk with MPS III disorder face especially diffi-
with parents whose children are newly diag- cult challenges because of the combination
nosed. Perszyk and Perszyk (2004) provide of sleep and behavior problems (Rudolph et
a useful description of the needs of families al., 2002). Environmental modification is
with children with genetic disorders over the necessary, and the provision of regular re-
course of these disorders. A very useful ap- spite care can help families take some time
proach to working with families of children for themselves.
Family members of a child with an MPS
disorder may experience grief at a number
TABLE 15.5. Information and Support of times, beginning with the diagnosis of
Resources for Parents and Professionals the disorder and, for a child whose disorder
is fatal, extending to the child’s death (and
Alliance of Genetic Support Groups
4301 Connecticut Avenue NW, Suite 404
beyond). Deterioration in the child’s condi-
Washington, DC 20008-2369 tion is likely to cause a renewal of the feel-
202-966-5557 ings of loss, grief, and helplessness that oc-
www.geneticalliance.org curred when the initial diagnosis was made.
Information on a wide range of support groups Providing anticipatory guidance in advance
in local communities. of a child’s death will increase the family
members’ ability to deal with bereavement
Canadian Society for Mucopolysaccharide (Davies et al., 2004). In a case where the dis-
and Related Disease
P.O. Box 30034
order is likely to cause death during child-
RPO Parkgate hood, the family members may benefit from
North Vancouver, British Columbia, Canada support and counseling to help them deal
V7H 2Y8 with issues of grief and loss. Referrals to
800-667-1846 resources that can assist with grief support
www.mpssociety.ca and in-home care in the later stages of the
An information and advocacy organization for disorder (such as a hospice or a community
persons with MPSs and their families. bereavement support group) will be useful
for some families.
National MPS Society
P.O. Box 14686
Durham, NC 27709-4686 Genetic Counseling
877-MPS-1001
www.mpssociety.org Genetic counseling services can be useful for
A support and advocacy organization for MPS families with a history of an MPS disorder.
disorders. Information, names of specialists The geneticist or genetic counselor will take
who treat these disorders, and ways to contact a detailed history of the family to help de-
other families of children with these disorders termine the risk of the specific disorder in
are available.
future children (Schonberg & Tifft, 2007).
The geneticist can also discuss the risks and and medical/health care will need to be
benefits of prenatal diagnostic tests after addressed. No research has addressed in-
pregnancy occurs. The genetic counselor terventions for the specific educational and
can assist the parents in considering their psychosocial problems posed by the MPS
reproductive options (such as artificial in- disorders. Adaptation of methods and tech-
semination with donor sperm or eggs) if nologies currently used for children with
the parents are found to be genetic carriers. multiple disabilities is a sound approach.
Parents may also feel guilt because of the in-
herited nature of these disorders, which may
Psychoeducational Assessment
affect their marital relationships or attitudes
toward having more children in the future Any child with an MPS disorder should
(Perszyk & Perszyk, 2004). Further counsel- receive careful evaluation of psychosocial
ing may be necessary to assist with difficul- adjustment, cognitive functioning, and be-
ties related to these feelings of guilt. havior. Psychological testing serves several
Persons who are carriers of a genetic useful functions (Shapiro & Klein, 1994).
disease can be identified before they have Tests can document deterioration of func-
children who may develop the disorder. tioning over time, allowing the clinician to
Widespread population screening for MPS determine the progression of the disease.
disorders does not occur at this time (Gahl, Improvement or stability of functioning as
1999). Screening of the mother’s family is determined by psychological testing can also
warranted for known cases of Hunter syn- provide outcome data for evaluating treat-
drome, which is an X-linked disorder. Atten- ment. This may be especially useful for when
tion to future pregnancies is prudent for the working with children who are going to be
other MPS disorders, which are autosomal or have been treated with BMT.
recessive disorders; testing will permit the Psychoeducational assessment may also be
identification of risk for future children who useful in determining the appropriate cur-
may be born with an MPS disorder. A sig- riculum and school placement for children
nificant problem for parents of children with with MPS disorders. Documentation of de-
Sanfilippo syndrome is that this diagnosis is terioration may help teachers adjust their ex-
usually made relatively late, making effective pectations and strategies for those children
genetic counseling more difficult. It is not who have progressive dementia. The docu-
uncommon for parents to have additional mentation of normal intellectual function-
children with Sanfilippo syndrome prior to ing may also help teachers and parents have
having a diagnosis made for their first child appropriately high academic and vocational
(Nidiffer & Kelly, 1983). expectations for children with MPS disor-
ders that result in alterations of physical ap-
pearance without intellectual impairment.
Educational Issues and Interventions
Shapiro and Klein (1994) have described
Most children with MPS disorders are likely several issues relevant to the assessment of
to need assistance in school through special individuals with the MPS disorders, par-
education services. Students can qualify for ticularly the more severe variants of these
special education services under the “multi- disorders. Sensory deficits, including hear-
ple disabilities” or “other health-impaired” ing loss and vision impairment (due to cor-
categories. Parents of children with disabili- neal clouding and cataracts), complicate
ties have worked tirelessly through national the assessment of cognitive abilities. The
support groups (e.g., in the case of MPS dis- behavioral problems that are characteristic
orders, the National MPS Society) to help of Sanfilippo syndrome, including restless-
local, state, and federal decision makers un- ness, hyperactivity, limited attention span,
derstand the difficulties that they have en- disruptive behavior, and tantrums, pose se-
dured in obtaining appropriate services for rious obstacles to testing. Attention deficits,
their children. distractibility, and hyperactivity are noted
The fact that these disorders are degen- in children with Hurler syndrome in early
erative or progressive is an important factor childhood. Hearing loss, vision impairment,
in planning for school services. Difficulties and movement difficulties also affect the
with behavior management, socialization, selection of psychoeducational tests. Strate-
gies for selecting and administering tests for support and assistance as regression in be-
children with these problems and disabilities havior and cognitive skills occurs. Many of
are available elsewhere (McLean, Wolery, & the strategies that are useful for all children
Bailey, 2003; Sattler, 2006, 2008; Shapiro with severe or multiple disabilities (Best,
& Klein, 1994; Teeter & Semrud-Clikeman, Heller, & Bigge, 2005; Downing, 1996) will
2007; Vess & Douglas, 1996). be useful for children with MPS disorders.
Planning and goal development may be
difficult for educational personnel who do
Early Intervention
not have experience with children whose dis-
Early intervention programs (formerly re- orders are progressive, since the traditional
ferred to as infant stimulation programs) are focus is on improvement in skills and less-
available in virtually all communities (Gu- ened support as improvement occurs. Plans
ralnick & Conlon, 2007). These programs should be based on short-term goals. Teach-
include a variety of supports, interventions, ers frequently need additional support to ac-
and coordination services for children with cept a child’s limited skills and deteriorating
developmental problems and their families. course. The use of specific and observable
Infants and very young children with Hurler goals for maintaining cognitive and social
syndrome (Nelson & Crocker, 1999), and skills will be helpful for developing educa-
children with the other MPS disorders, may tional strategies.
obtain substantial benefit from an early in- The ability of children with progressive
tervention/stimulation program. It is im- disorders to maintain mobility and related
portant to obtain maximum intellectual physical skills is directly related to receiv-
gain prior to the inevitable deterioration of ing a free and appropriate education. Many
cognitive skills characteristic of several vari- children with MPS disorders benefit greatly
ants of these disorders. The resulting gains from early and regular adaptive physical
in cognitive, language, self-help, and motor activity to maintain and improve mobility,
skills will be especially important before the coordination, and other physical skills. The
early plateaus in learning are reached. En- provision of adaptive physical education will
rollment in a preschool early intervention also be beneficial in maintaining and/or im-
program as soon as a diagnosis is made is proving social and cognitive skills.
warranted. Coordination of educational and The rapid loss of communication skills
support services during the transition from experienced by many children with MPS
an infant/toddler program to the school set- disorders creates significant challenges to
ting is an essential area for professional at- their participation in educational activities.
tention. Speech therapy services tailored to main-
taining communication skills for the longest
possible time will contribute to an enhanced
Educational Planning and Programming
education experience for children with these
The degenerative nature of these disorders is disorders. Because hearing loss is a com-
one of the most important yet difficult fac- mon consequence of the progression of MPS
tors to take into account for children’s in- disorders (Alpern, 1992), special attention
dividualized education programs (IEPs). Be- is required to identify and monitor hearing
cause of the rather rapid regression in skills loss and to maintain communication in the
and behavior experienced in the severe forms classroom. Assistive technology services can
of the MPS disorders, frequent monitoring make a significant contribution to an effec-
is required so that changes in an IEP can tive educational program. One framework
quickly be made to support a child whose for assessment, intervention, and program
skills are deteriorating. Educational strate- planning for children with hearing loss
gies should encourage appropriate partici- can be found elsewhere (Vess & Douglas,
pation, new learning, or the preservation of 1996).
established skills. Alterations in the learning Powell-Smith, Stoner, Bilter, and Sansosti
environment and in methods of instruction (2008) provide a practical perspective on
are frequently necessary to adapt to a child’s building a supportive educational environ-
cognitive, mobility, or behavior problems. ment for students with severe disabilities.
The IEP should include rapidly increasing Educational personnel should emphasize the
development and maintenance of functional through instructional activities, such as co-

life skills and should utilize activity-based operative learning and encouraging support
learning whenever possible. The principle for all children in the classroom.
of normalization helps to prevent undue re- Socialization is an important factor in
striction in the educational program or op- the decision about classroom placement
portunities for students who have severe dis- for students with MPS disorders. Parents
abilities, such as those found in many forms may have some concerns about inclusion or
of MPS disorders. Additional information mainstreaming, but in general it is a posi-
on educational strategies and issues can be tive step to keep students in classrooms with
found in Brown and Trivette (1998) and in nondisabled children. Since MPS disorders
the National MPS Society’s (2008) Educa- are progressive, however, the grade level at
tion Strategies and Resources booklet. which a child with an MPS disorder should
be placed may not be clear and may become
less so as time passes. From the perspective
Behavioral Issues
of socialization and participation, it is gen-
Some children with MPS disorders (espe- erally best for students with MPS disorders
cially children with MPS III) may exhibit to remain in a mainstreamed classroom with
difficult behaviors in the school setting (es- children to whom they are most similar in
pecially problems with overactivity, restless- terms of cognitive behavior and level of so-
ness, and fearfulness). It is not uncommon cialization. This may trigger some resistance
for educational personnel either to fail to set from school personnel, and often requires
limits because of a child’s physical impair- some level of compromise with grade place-
ment, or to treat a problem behavior as a dis- ment as a child grows physically larger. Sug-
cipline issue rather than a complication of gestions for assessing the success of an in-
the child’s medical condition. Teachers and clusive educational setting for a child with
administrators frequently need additional MPS disorders can be found in the National
assistance in managing the behavior prob- MPS Society’s (2008) Education Strategies
lems that may occur in children with these and Resources booklet.
syndromes. Adolescents with Morquio, Maroteaux–
Positive behavior support principles should Lamy, Scheie, and Hurler–Scheie syndromes
be used whenever possible to improve behav- and with the mild form of Hunter syndrome
ior, with an emphasis on use of reinforce- have some of the same psychosocial needs as
ments (Cataldo et al., 2007; Powell-Smith et do other adolescents. During this time, sex-
al., 2008). The focus of these interventions uality and physical appearance become es-
is on improving both functioning and qual- pecially important. Additional support and
ity of life for a student with MPS. Positive education are necessary during this time,
behavior support strategies involve changes and educational personnel should work
in the educational environment, as well as closely with parents to help address the com-
strategies that assist the student to function plications that an MPS disorder may create
effectively within this environment. These for adolescents. Support programs for young
alterations to the learning environment and adults are often available through national
instructional methods are often helpful in organizations such as the National MPS So-
decreasing problem behavior. Appropriate ciety.
psychopharmacological intervention may be
necessary as an adjunct to behavioral and
Academic and Career Expectations
educational interventions.
Although there are many similarities in the
manifestations of MPS disorders, children
Socialization
with these disorders exhibit a wide range of
School attendance and socialization are to impairment. Teachers and parents should
be encouraged and fostered through class- not assume from the outward skeletal mani-
room integration and specific social skills in- festations of the disorders that intellectual
terventions. Students’ independence should development is significantly delayed. For
be supported in all areas. Teachers can do example, children with Scheie syndrome,
much to improve the acceptance of a child Hurler–Scheie syndrome, Morquio syn-
drome, Maroteaux-Lamy syndrome, and the mation sessions about loss for students in
less severe variant of Hunter syndrome are the classroom. Frequently the local hospice
likely to have normal or only mildly delayed has programs or outreach services that can
intellectual development. Appropriately high be useful at this time.
expectations of academic achievement will
foster realistic self-appraisal and enhanced
Health Services in the School
academic achievement.
Vocational maturity in adolescents with Children with MPS disorders may have a
chronic health concerns is largely contin- wide range of medical problems that affect
gent on the attitudes and efforts of parents, their school program. The most frequently
teachers, and counselors (Brolin, 1980). Ac- encountered include problems with mobil-
ademic and vocational programming should ity, respiratory difficulties, and cardiovas-
foster independence and autonomy. Voca- cular issues for which care is necessary in
tional goals should be set realistically high. the school setting. Some students may have
Planning for transition from school to post- sleep apnea, which may present as daytime
secondary education or the world of work sleepiness. Sometimes students may have
should focus on helping students pursue vo- medical conditions that call for specialized
cations in a manner similar to that of their medical interventions for which training is
peers (Davis, Anderson, Linkowski, Berger, necessary. Medication may be prescribed for
& Feinstein, 1991). associated medical or behavioral issues, and
teachers will need to monitor the student or
perhaps administer medication. Educational
Developing Support Systems
and medical personnel must work together
Teachers and peers should be educated about with parents to develop a health care plan
the condition, abilities, and special needs to ensure that a student with an MPS disor-
of a child with an MPS disorder. Teachers der receive proper care while in the school
may be unsure of their ability to teach chil- setting; Heller (2004) discusses many useful
dren with these disorders. Their competence suggestions for integrating health and edu-
should be supported, as they will find that cational programs.
many of the skills they use in teaching non-
impaired children are the skills that will en-
able them to work well with children who Summary
have these syndromes.
The use of peers in the regular education The MPS disorders are progressive genetic
classroom has been helpful to students with disorders that result from genetic mutations
MPS disorders, their teachers, and their affecting the metabolism of glycosamino-
classmates. Classmates have participated in glycans (acid mucopolysaccharides). Incom-
activities to promote inclusion of students pletely metabolized mucopolysaccharides
with MPS disorders into the classroom mi- are deposited in the lysosomes of the con-
lieu. Using team-based learning, for example, nective tissues, bone, and major organs.
allows a student with MPS to participate in The disorders are characterized by varying
learning activities at his or her appropriate degrees of physical, sensory, cognitive, and
level. Downing and Eichinger (1996) discuss behavioral impairments secondary to accu-
how to select, train, and utilize peers in in- mulation of metabolites in the body. Chil-
clusive classrooms with students who have dren with some of the MPS disorders have
serious disabilities. been found to have higher rates of behavior
Teachers and peers will need support in problems, including overactivity, aggressive-
dealing with their feelings of loss in a case ness, restlessness, and fearfulness.
where the child’s condition worsens and Supportive medical and psychosocial
the child either leaves school or dies. The treatments have been most commonly pro-
course of MPS disorders is typically chronic, vided because for many children there is
so there is time to plan and prepare for this no successful direct treatment for the MPS
eventuality. School mental health profes- disorders. Supportive treatments focus on
sionals can be involved in working with the alleviating the manifestations and com-
parents and the teacher in designing infor- plications of the disorders. More recently,
however, BMT, cord blood transplantation, ligrino, & N. J. Roizen, (Eds.), Children with dis-
and enzyme replacement therapy have had abilities (pp. 285–297). Baltimore: Brookes.
varying degrees of success for some of the Bax, M. C., & Colville, G. A. (1995). Behaviour in
disorders. Children with MPS disorders are mucopolysaccharide disorders. Archives of Dis-
ease in Childhood, 73, 77–81.
likely to need assistance in school through Best, S. J., Heller, K. W., & Bigge, J. L. (2005).
special education services, where difficulties Teaching individuals with physical or multiple
with behavior management, socialization, disabilities. Upper Saddle River, NJ: Pearson
and medical/health care will need to be ad- Education.
dressed. Brolin, D. E. (1980). Vocational preparation of per-
Although MPS disorders are difficult dis- sons with handicaps. Columbus, OH: Merrill.
orders, it is important to remember that de- Brown, M. B., & Trivette, P. S. (1998). Mucopoly-
spite the stressors, parents of children with saccharide disorders. In L. Phelps (Ed.), Health
MPS report that their joys and pleasures in related disorders in children and adolescents
raising their children are similar to those (pp. 442–452). Washington, DC: American Psy-
chological Association.
experienced by parents of nondisabled chil- Cataldo, M. F., Kahng, S., DeLeon, I. G., Martens,
dren. Nevertheless, family stress levels are B. K., Friman, P. C., & Cataldo, M. (2007). Be-
often high due to the multiple demands of havioral principles, assessment, and therapy. In
these chronic disorders. A multidisciplinary M. L. Batshaw, L. Pelligrino, & N. J. Roizen
approach to assessment and intervention is (Eds.), Children with disabilities (pp. 539–556).
necessary, and local care providers are un- Baltimore: Brookes.
likely to have experience with these disorders. Cervantes, C. D., & Lifshitz, F. (1990). Skeletal
Information and evaluation from regional dysplasias with primary abnormalities in carbo-
or national specialists may be required. In- hydrate, lipid, and amino acid metabolism. In S.
volvement of parents and professionals asso- Castells & L. Finberg (Eds.), Metabolic bone dis-
ease in children. New York: Dekker.
ciated with national support groups (such as Chen, H. (2006). Atlas of genetic diagnosis and
the National MPS Society) provides critical counseling. Totowa, NJ: Humana Press.
information and support for caregivers and Chen, D., & Miles, C. (2007). Working with fami-
families. Close communication and collabo- lies. In F. P. Orelove, D. Sobsey, & R. K. Silber-
ration among parents, educators, and health man (Eds.), Educating children with multiple dis-
care providers are essential to assist children abilities: A collaborative approach (pp. 31–65).
with these disorders and their families. Baltimore: Brookes.
Cleary, M. A., & Wraith, J. E. (1993). Management
of mucopolysaccharidosis type III. Archives of
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C h a p t e r 16
Noonan Syndrome
Phyllis Anne Teeter Ellison
Biogenetic disorders of childhood are of NS is accompanied by multiple congenital

interest to pediatric neuropsychologists be- anomalies with variable expressivity across
cause they frequently interfere with children’s individuals, and may be hard to detect in
neuropsychological, cognitive, psychoso- mildly affected individuals (Johannes, Gar-
cial, and academic development. Medical cia, De Vaan, & Weening, 1995; van der
complications accompany many biogenetic Burgt, 2007). It is characterized by craniofa-
disorders, and these place added psychologi- cial anomalies including ptosis, hypertelor-
cal and financial stress on family members. ism, and epicanthus; downslanting palpebral
These interrelated variables have been sys- fissures; low-set, posteriorly angulated ears;
tematically investigated for some syndromes a deeply grooved philtrum with high, wide
(e.g., Tourette syndrome), but other genetic peaks of the vermilion border of the upper
disorders are less well understood. Clini- lip; a high, arched palate; and micrognathia.
cians have long been interested in how ge- In addition to these features, the syndrome is
netic disorders affect development, inter- often accompanied by congenital heart dis-
fere with neuropsychological and cognitive ease (pulmonary valve stenosis), skeletal ab-
functioning, and affect overall psychologi- normalities (short stature, webbed neck, and
cal adjustment across environments—home, thorax abnormalities), genital malforma-
school, and community. In order to provide tions, and cognitive impairments (Johannes
ecologically valid assessment and interven- et al., 1995, p. 571; Limal et al., 2006; van
tion planning, pediatric neuropsychologists der Burgt, 2007). Risk for juvenile myelo-
should consider the impact of biogenetic monocytic leukemia (JMML) has also been
disorders on these various dimensions, and reported in individuals with NS (Jongmans
should provide meaningful interventions to et al., 2005).
address these needs. Noonan syndrome (NS) In 1883, Kobylinski reported a case of a
is discussed in this chapter, with a focus on 20-year-old male who presented with un-
clinical presentation, common characteris- usual features (for a review of this and other
tics and associated medical and neuropsy- early studies, see Noonan, 1994). The pa-
chological complications, assessment issues, tient’s characteristics included small stature,
and intervention planning. low-set ears, webbed neck, micrognathia
311
(i.e., unusual smallness of the jaw), and other 1994, p. 548) due to a lack of research on
symptoms overlapping with those of several NS. Although not sex-linked, NS is consid-
present-day syndromes, including NS (Noo- ered to be an autosomal dominant inherited
nan, 1994, 2005). In 1930, Ullrich pub- condition that typically involves congeni-
lished case studies of children with physical tal heart disease (50–80%), with other as-
anomalies resembling those of Kobylinski’s sociated physical characteristics including
patient (e.g., webbed neck and short stature) below-average height, facial abnormalities,
and sexual infantilism (i.e., small testes). In and chest deformity (Limal et al., 2006;
1938, Turner described female children who Noonan, 1994, 2005; Noonan, Raaijmak-
had similar physical characteristics (e.g., ers, & Hall, 2003).
webbed neck, short stature, and sexual in-
fantilism) and whose underlying disorder
was later identified as a sex chromosome ab- Prevalence R ates
normality. Ullrich–Turner syndrome (UTS)
or Turner syndrome, as this disorder came Estimates of prevalence rates for NS vary
to be called, thus was defined as a complete from 1 per 1,000 births to 1 per 2,500 (Nora,
or partial absence of, or other anomaly in, Nora, & Sinka, 1974; van der Burgt, 2007).
the X chromosome in some or all body cells Some studies suggest higher rates, ranging
(Wiederman, Kunze, & Dibbem, 1992). from 1 per 1,000 for severe symptoms (Men-
Ullrich expanded his interests in rat re- dez & Opitz, 1985) to 1 per 100 for milder
search conducted by Bonnevie, who pro- expressions (Noonan, 1994). Although not
duced mice with webbed necks and swollen sex-linked, NS affects males and females at
limbs through genetic mutations (Noonan, a 2:1 ratio (Tartaglia, Corrdeddu, Chang,
1994). Europeans adopted the term Ullrich– & Shaw, 2004). There appear to be no ra-
Bonnevie syndrome to describe children who cial differences in the occurrence of NS, and
are now considered to have NS. Noonan and the syndrome has been found in countries
Ehmke (1963) published reports of nine pa- all over the world. NS is the most common
tients (six males and three females) who were genetic disorder in children with congenital
believed to exhibit a distinct syndrome. These heart disease (it is found in 1.4% of children
children had small stature and various facial with cardiac defects), and its rate of occur-
abnormalities, including hypertelorism (i.e., rence is even higher for children undergoing
abnormally large distance between eyes), surgery for pulmonary stenosis (17%; Noo-
ptosis (i.e., drooping of the eyelid), and low- nan, 1994, 2005).
set ears. Some of the males had undescended
testes. Other abnormalities included chest
deformities, and all the patients had vascular Genetic Factors, Familial
pulmonary stenosis (Noonan, 1994). Opitz Transmission, and Pathogenesis
and Weaver (1985) confirmed that this indeed
was a separate syndrome, and suggested the Although symptoms of NS have a superficial
name Noonan syndrome. Although the term resemblance to the symptoms of Turner syn-
Turner phenotype remained in use for a num- drome (which involves an absent or defective
ber of years, NS became more prevalent in chromosome), research has not verified sex-
the literature in about 1968; it was also soon linked inheritance, in that NS occurs in both
dissociated from sex-linked abnormalities, as males and females (van der Burgt, 2007). A
it was found in both males and females (Al- number of patients with NS also have von
lanson, 2007; Noonan, 1994). “Soon it was Recklinghausen neurofibromatosis (NFvR),
realized that some female patients with nor- so speculations that chromosome 17 (which
mal chromosomes previously diagnosed as is abnormal in patients with NFvR) was in-
having the UTS were in fact females with the volved in NS were also investigated, without
‘male Turner syndrome,’ i.e., the same syn- positive findings (Sharland, Taylor, Patton,
drome described by Noonan” (Mendez & & Jeffrey, 1992). While the exact genetic
Opitz, 1985, p. 494). anomaly for NS has not been found (Noo-
“Many pediatricians have only a limited nan, 1994, 2005), there have been some ad-
knowledge of this condition” (Noonan, vances in identifying four major genes that
Noonan Syndrome 313
are associated with NS: PTPN11, KRAS, Developmental Considerations

SOS1, and RAF1 (Allanson, 2005, 2007).
Prenatal Period and Early Infancy
Sequence analysis of the PTPN11 gene shows
“missense” mutations in up to 50–60% of Individuals with NS generally have an unre-
patients with NS (Jongmans, Otten, Noor- markable prenatal history. About one-third
dam, & van der Burgt, 2004; Tartaglia et of NS pregnancies do have complications
al., 2001, 2002); 10–13% show “missense” caused by polyhydramnios (excess of am-
mutations in SOS1 exons 1–23 (Schubbert niotic fluid). Cystic hygromas (fetal edema)
et al., 2006); KRAS mutations are found in have also been found with ultrasound tech-
fewer than 5% of patients (Schubbert et al., nology (van der Burgt, 2007), and excessive
2006); and “missense” mutations in RAF1 weight loss in the first week of life has been
exons 1–17 are seen in 3–17% of patients reported as well (Noonan, 1994). It has been
(Pandit et al., 2007). suggested that fetuses with polyhydramnios,
Mother-to-child inheritance seems likely, pleural infusions, and edema should be test-
as many males have cryptorchidism (i.e., ed for NS (van der Burgt, 2007).
undescended testes), and some are infer- Feeding problems are relatively common;
tile (Noonan, 1994, 2005). Approximately 39% of babies with NS have moderate diffi-
30–75% of cases result from parent-to-child culties, and 24% show severe problems that
transmission (Allanson, 2007). Parents with require tube feeding (Sharland, Burch, McK-
many symptoms are more likely to transmit enna, & Patton, 1992). Projectile vomiting
the disorder (risk is 50%), whereas those may also be present (Gilbert, 1996). Failure
with mild symptoms have lower risks (<1%; to thrive has been reported in infants with
Allanson, 2007). Although NS appears to NS (Allanson, 2007), and lethargy, poor
have strong genetic transmission (i.e., a child feeding, and vomiting may lead to hospital-
inherits a copy of the affected gene from a ization, according to Noonan (1994). The
parent), there is also evidence that some feeding difficulties do resolve themselves in
mutations appear spontaneously (Allanson, later infancy, although repeated concerns
2007; Mayo Clinic, 2009). about failure to thrive may be part of the
The variable expressivity of NS makes early developmental picture.
detection of mild cases difficult, so indi-
viduals may carry the gene but may not be
Childhood and Early Adolescence
aware of it. The phenotypic changes over
the lifespan from birth to adulthood may be Both physical and cognitive/intellectual de-
misleading, because a parent may not look lays have been found in a relatively large
like a child, but pictures of the parent as an number of children diagnosed with NS.
infant will show similarities. Consequently, Short stature is found in the majority of chil-
a careful review of family pictures at various dren (80%), and a 2-year gap between bone
ages on both maternal and paternal sides of age and chronological age is common (Gil-
the family may reveal whether a particular bert, 1996). Hypotonia may also be present
case is sporadic or familial in nature (Noo- (Noonan, 1994, 2005), and motor delays are
nan, 1994, 2005). The risk that subsequent common (van der Burgt, 2007). Delayed pu-
offspring will have NS is reduced if it is a berty has been reported; undescended testes
sporadic case; however, if it runs in families, are frequently observed; and small testicular
there is a 50% risk that an offspring will also size and infertility often occur in later stages
have the disorder (Noonan, 1994, 2005). (Gilbert, 1996; Mendez & Opitz, 1985; van
Others suggest that in the developing der Burgt, 2007).
brain, growth factors directly influence a Thomas and Stanhope (1993) suggest that
number of proteins that generate neuronal patients who are below the 3rd percentile for
development. Genetic mutations are thought height before puberty should be considered
to inhibit basal neurogenesis in favor of as- as candidates for growth hormone (GH)
trogenesis or atrocytic growth (see Gauthi- treatment. Initial benefits in height have been
er et al., 2007). This variation in neuronal found in children treated with GH (Ahmed
growth may contribute to the cognitive fea- et al., 1991; Limal et al., 2006; Osio, Dahl-
tures of NS. gren, Wikland, & Westphal, 2005). Despite
promising findings, Limal and colleagues attacks, problems with self-awareness, and
(2006) report that individuals with muta- difficulties identifying and expressing emo-
tions in the PTPN11 gene are less responsive tions (Verhoeven, Wingbermühle, Egger,
to GH treatment. van der Burgt, & Tuiner, 2008).
Adulthood
Neurological Compromise
Although signs and symptoms of NS may
lessen with age (van der Burgt, 2007), the Various neurological problems in patients
mean height of adults with NS may be up with NS have been described. Sharland,
to two standard deviations below the norm Burch, and colleagues (1992) reported that
(Noonan, 1994, 2005). While 30% of adults recurrent seizures are a problem for 13% of
with NS reach normal height, below-average these patients. Infrequent peripheral neurop-
height growth rates in adults have been doc- athy has also been reported. For example,
umented: Up to 50% of females and 40% of Noonan (1994) found mild myelomeningo-
males have height growth rates below the 3rd cele (protrusion of the cord and meninges
percentile (Noonan et al., 2003). Ultimate from a defect in the vertebral column) in a
adult height is affected by parental size, and patient with recurring tethered cord. “Other
wide variations have been found, but most neurologic complications have included
females reach 5 feet and males reach 5 feet, spina bifida occulta, subarachnoid hemor-
5 inches. rhage from aneurysm, and syringomyelia,”
as well as optic glioma and medulloblastoma
(Noonan, 1994, p. 552). Malignant schwan-
Psychosocial Compromise noma was reported by Kaplan, Opitz, and
Gosset (1968), while Noonan (1994) also
The psychosocial features of NS are not well found a number of benign schwannomas.
documented. Lee, Portnoy, Hill, Gillberg, As noted earlier, Noonan (1994, 2005)
and Patton (2005) have not found specific and van der Burgt (2007) indicate that hy-
behavioral or psychopathology in children pertonia is common, and it can be associat-
with NS, but social interactions may be comed with poor coordination. The interaction
promised as a result of other complications. of hypertonia with visual problems may ac-
First, children with NS often have poor mus- count for the coordination difficulties.
cle tone, which tends to affect their athletic
ability (Gilbert, 1996), and early milestones
are often delayed (Allanson, 2007). Chil- Medical Risks
dren with NS are thus frequently poor at
Congenital Heart Disease
sports, and this fact may reduce their natu-
ral opportunities for play and socialization. A number of congenital heart diseases are
Because they also tend to mature late, they associated with NS and are identifiable at
often prefer to play with younger children birth (Gilbert, 1996; van der Burgt, 2007).
(Gilbert, 1996). The social consequences Pulmonary stenosis, in which the valve in
of chronic medical complications (cardiac, the pulmonary artery is misshapen (nar-
orthopedic, etc.) need further study in pa- rowed) or not adequately formed, is the most
tients with NS. However, Lee and colleagues common cardiac problem (50–65%); atrial
(2005) indicate that for the most part, chil- septal defect, in which the wall dividing the
dren with NS show self-esteem comparable right and left upper heart chambers is im-
to that of age-matched peers. properly formed, is not uncommon (10%);
Although it is important to note that there ventricular septal hypertrophy, where there
is no evidence of consistent psychiatric or is an increase in the wall separating the
behavioral disorders in patients with NS, right and left lower heart chambers, is also
adults with NS appear to have some psy- found (10%); and ventricular septal defects,
chosocial problems (Allanson, 2007). They where there is a hole between the right and
have been found to have relatively high rates left lower chambers, are found in approxi-
of depression (20%; Noonan, 2005). Other mately 5% of patients with NS (Allanson,
emotional problems include anxiety, panic 2007; Noonan, 1994, 2005; Shaw, Kalidas,
Noonan Syndrome 315
Crosby, Jeffery, & Patton, 2007). Noonan Opitz, 1985; van der Burgt, 2007). Lymphat-
(1994) indicates that virtually every type of ic dysplasia (abnormal or obstructed drain-
cardiac defect has been found in individu- age of the lymphatic system) has produced
als with NS. Hypertrophic cardiomyopa- various complications, including edema and
thy, including both the obstructive and the protein-losing enteropathy. Lymphatic con-
nonobstructive types, occurs in 20–30% of ditions can also create complications after
patients (Shaw et al., 2007). Cardiomyopa- surgery.
thy frequently involves both the right and
the left ventricles, is noticeable at birth or
Leukemia
develops in later infancy or childhood, and
involves muscle disarray and thick walls in Persons with NS appear to have an increased
the coronary arteries. risk for childhood leukemia, particularly
Other cardiac problems include dysplastic those with a germline mutation in PTPN11
pulmonary valve and mitral valve prolapse. (Allanson, 2007). Jongmans and colleagues
Various congenital defects may require sur- (2005) also indicate a risk for juvenile myel-
gery or medications, while others may not omonocyctic leukemia JMML in individuals
need further treatment (Gilbert, 1996; Shaw with mutations in PTPN11.
et al., 2007). Electrocardiograms are used
to identify abnormal defects (e.g., left-axis
Genitourinary Problems
deviation or dominant S wave over the pre-
cordium) and sometimes can be helpful or The fact that the majority of males with NS
confirmatory in the diagnosis of NS (Noo- have undescended testes (cryptorchidism),
nan, 1994). Noonan (1994) suggests that often bilaterally, may result in deficient sper-
all patients with NS should undergo cardiac matogenesis and infertility (van der Burgt,
evaluations as soon after birth as possible, as 2007). Male puberty may be delayed for as
well as frequent, periodic checkups, because much as 2 years, which appears related to
not all cardiac problems present at birth. bone age (Noonan, 1994, 2005); moreover,
secondary sexual characteristics may not
be adequately developed (Allanson, 2007).
Thrombocytopenia
Females are not typically infertile, and they
Some patients with NS have shown de- may have either normal or delayed puberty
creased numbers of blood platelets (Mendez (van der Burgt, 2007). Maternal transmis-
& Opitz, 1985). In addition, various bleed- sion of NS is three times greater than pa-
ing abnormalities have been reported, internal transmission, which appears likely
cluding factor IX deficiency and von Wille- to be due to male infertility resulting from
brand disease (Mendez & Opitz, 1985). cryptorchidism. Noonan (1994) also reports
Flick, Sing, Kizer, and Lazarchick (1991) that patients with NS may have renal abnor-
estimate that as many as 20% of patients malities (10%), but that most of these have
with NS have clinically significant blood little serious medical impact on the affected
coagulation abnormalities. In a case study, individuals.
Flick and colleagues (1991) found that a
23-year-old patient with chronic idiopathic
Orthopedic Problems
thrombocytopenic purpura also had cyclo-
oxygenase deficiency, which was thought to A number of different orthopedic problems
be the primary mechanism for the patient’s have been found in individuals with NS, with
platelet defect. Tofil, Winkler, Watts, and as many as 90% of patients showing chest
Noonan (2005) caution that life-threatening deformity such as prominent-pectus caria-
bleeding may occur in patients with NS un- tum or hollowed-pectus excavatum (van der
dergoing surgery. Burgt, 2007). Other orthopedic problems
have been reported, including scoliosis (10–
15%), talipes equinovarus (a deformity of the
Lymphatic System Difficulties
foot in which the heel is turned inward and is
Although it is not pathognomonic for NS, plantar-flexed—t ypical clubfoot; 10–15%),
lymphatic involvement has been found in pa- radioulnar synostosis, cervical spine fusion,
tients with NS (Allanson, 2007; Mendez & or contractures of the joints (Lee et al., 2001;
Noonan, 1994, 2005). Lee and colleagues good school performance (Sharland, Burch,
(2001) suggest that scoliosis with thoracic et al., 1992). Others report ranges of cogni-
lordosis may develop early in life and can be tive impairment between 15% and 35% of
severe. Early detection and treatment are im- patients with NS (van der Burgt, 2007).
portant. The hypotonia that is common may A Full Scale IQ (e.g., on the third edition of
improve with age. Other anomalies include the Wechsler Intelligence Scale for Children)
abnormal angle of the elbow, curved fifth may mask specific abilities when there are
finger, blunt and squared fingertips, shield- significant Verbal–Performance discrepan-
like chest, and widely spaced nipples (Noo- cies. In a small-scale study of children with
nan, 1994, 2005). NS, profile analysis showed that individuals
varied in their pattern of verbal and nonver-
bal strengths. In one case, a patient did show
Neuropsychological Impairments a specific deficit in verbal reasoning skills;
however, in four cases, praxic or nonverbal
Most of the research on NS to date has been abilities were compromised (Money & Kalus,
directed at documenting the physical char- 1979). Specifically, the latter cases showed
acteristics of NS; limited information is difficulty with the visual-constructional as-
available about the central nervous system pects of the Wechsler scales. These authors
or neuropsychological features (intellectual, hypothesized that the visual-constructional
speech, or hearing problems) of the disorder disabilities found in patients with NS “as
(Hopkins-Acos & Bunker, 1979). A few iso- well as [patients with] Turner’s syndrome,
lated studies or single-subject designs have despite the disparity of the two syndromes
investigated specific neuropsychological cytogenetically, puts constraints on what
deficits, but these investigations should be importance may be attributed to the missing
considered preliminary. Research suggests chromosome of 45,X Turner’s syndrome in
that hypotonia is common, and poor coordi- formulating theories regarding the X and Y
nation is also reported (Fakouri & Fakouri, chromosome as determinants of sex differ-
1998; Lee et al., 2001; Noonan, 1994, 2005; ence in hemispheric dominance and verbal–
van der Burgt, 2007). praxic disparity in ‘normal girls’ and boys”
(Money & Kalus, 1979, p. 850). Further
study is needed to confirm this hypothesis
Attention and Concentration
and to delineate more clearly any differences
Although there are no large-scale studies between verbal and nonverbal abilities in pa-
documenting attention and concentration tients with NS.
difficulties in patients with NS, attention
deficits have been reported in some cases
Sensory, Motor, and Visual
(van der Burgt, 2007).
Perceptual Skills
There is ample evidence to suggest that
Intellectual and Academic
motor, visual-perceptual, and sensory defi-
Development
cits are associated with NS (Hopkins-Acos
The intellectual functioning of individu- & Bunker, 1979; Noonan, 1994, 2005; van
als with NS can range from mild cogni- der Burgt, 2007). Motor difficulties that
tive deficiency (Lee et al., 2005; Noonan, may be secondary to hypertonia and poor
1994, 2005; van der Burgt, 2007) to supe- muscle tone appear early in life (e.g., poor
rior abilities (Finnegan & Hughes, 1988; sucking in infancy) and often continue into
Money & Kalus, 1979). Mendez and Opitz early childhood (Gilbert, 1996). Children
(1985) reviewed 63 papers reporting the in- with NS are often described as clumsy, are
tellectual functioning of individuals with frequently poor in sports, and have a ten-
NS and found that 24% of these individu- dency to “knock into objects” (Gilbert,
als had cognitive impairments. In a study of 1996, p. 216). Visual-perceptual difficul-
100 students with NS, 5% attended schools ties have also been reported, and squinting
for physically disabled students, 11% were and myopia (nearsightedness) may be prob-
in programs for slow learners, and 84% at- lems as well (Gilbert, 1996; van der Burgt,
tended regular education classrooms and had 2007).
Noonan Syndrome 317
Language Skills rants further investigation. Consideration

of the effects of early cardiac problems and
Delays in language acquisition are quite
restriction of sensory–motor experiences is
common (25–75%) in children with NS,
also of interest. The extent to which children
and a majority of children show articulation respond to early intervention is of primary
problems (Allanson, 2007; van der Burgt, concern. In addition, van der Burgt (2007)
2007). Speech and hearing deficits have also suggests that the possibility of hearing prob-
been reported in a case study of a child with lems should be investigated early. Later stud-
NS (Hopkins-Acos & Bunker, 1979). In this ies show that hearing loss resulting from
young child, “slightly depressed pure-tone otitis media may be common in patients
thresholds” were reported with a “slight with NS (15–40%) (van der Burgt, 2007).
downward shift for both ears on the typano- Sensory–neural damage may also result in
grams,” which were consistent with a “mild loss of hearing in the low-frequency (10%)
conductive loss” (Hopkins-Acos & Bunker, and high-frequency (25%) ranges.
1979, p. 497). Further speech–language
evaluation showed that the child was func-
tioning significantly below expected age lev- Organization, Sequencing, Learning,
els on measures of language comprehension, Memory, and Executive Functions
with more pronounced difficulties in verbal An extensive review of MEDLINE and
expressive skills. A functional assessment of PsycINFO indicated that research to date
his communication intentions and behav- has not explored problems with organiza-
iors, via systematic, structured observations tion, sequencing, learning, memory, or exec-
of the child in his home interacting with his utive functions in individuals with NS. Gil-
mother, his brother, and the clinician, also bert (1996) does indicate that children with
yielded signs of significant delays. NS may have specific difficulties in learning
Hopkins-Acos and Bunker (1979) sug- to speak and may be slow to mature. The
gested a relationship among the child’s extent to which individuals with NS have
congenital heart problems, reduced sen- compromised intellectual abilities may also
sory–motor exploration experiences, and predict difficulties in these areas as well, but
speech–language delays. The child did show research and clinical case reports are needed
improvement with an early intervention pro- to verify this hypothesis.
gram designed to treat speech–language de-
lays. When he was later placed in a normal In conclusion, as Hopkins-Acos and Bun-
kindergarten classroom, he made improve- ker (1979) commented, most research to date
ments in language comprehension, includ- has focused on the physical characteristics
ing three-part commands, same–different, associated with NS, with less emphasis on
and other verbal concepts; reading through neuropsychological abilities. Thus it is dif-
visual recognition of letters; writing his ficult to predict which individuals will dis-
name; social interactions; and independent play select deficits, apart from generalized
and group activities. He continued to show difficulties associated with low intellectual
below-average abilities in the perceptual– functioning.
motor area and had difficulty catching and
throwing a ball, balancing on one foot, and
working with pencils or crayons. Delays were Assessment and Diagnostic Issues
most significant in visual-perceptual, motor,
and phonological development (Hopkins- Clinical Findings That Aid
Acos & Bunker, 1979). Remediation efforts in Diagnosis
focused on increasing functional skills to The diagnosis of NS is often made from clin-
facilitate communication by combining non- ical findings (Noonan, 1994, 2005; van der
verbal signs with appropriate verbalizations Burgt, 2007). Typically the facial features
that encouraged the “reciprocal nature of are helpful for making a diagnosis, although
social-linguistic behavior” (Hopkins-Acos these are difficult to discern in newborns.
& Bunker, 1979, p. 503). Noonan (1994) and van der Burgt (2007)
The extent to which other children with indicate that the following features are typi-
NS evidence speech–language delays war- cally present: (1) sloping forehead; (2) thick
ears, which may be posteriorly positioned; are briefly reviewed in order to highlight the
(3) hypertelorism, with down-slanting of the major features and characteristics that dis-
palpebral fissures (folds protecting eyes), a tinguish NS.
deep-set philtrum (groove of the upper lip),
and sometimes retrognathia (jaw positioned
Turner Syndrome
in the back of the frontal plane); (4) marked
edema of the neck, with excess nuchal skin Turner syndrome (see Powell & Schulte,
(skin on the back of the neck); (5) relatively Chapter 13, this volume, for a full discus-
enlarged head from infancy through age 2 sion) is characterized by the following: short
years; (6) flat cheekbones with prominent, stature, webbed neck, redundant skinfolds
round eyes; (7) depressed nasal bridge; (8) or edema of the neck, lymphedema of the
stocky body, with chest deformities that be- feet and hands, ptosis of the eyelids, microg-
come more prominent with age; and (9) short nathia, renal anomalies, cardiac defects (e.g.,
neck. These features do change in childhood, coarctation of the aorta), poor development
and the face becomes more coarse, triangu- of secondary sexual characteristics, and
lar, and sharper in adolescence and adult- primary amenorrhea. A child with Turner
hood. A low hairline in back may obscure syndrome may not be diagnosed at birth.
web-like features on the neck. Adults tend Despite physical features (e.g., webbed neck,
to have obvious nasolabial folds, with a high ptosis, short stature) and medical problems
hairline in front, and transparent, wrinkled (e.g., cardiac defects) similar to those of NS,
skin (Noonan, 1994, 2005; van der Burgt, Turner syndrome can be reliably differenti-
2007). ated through genetic tests.
Although a scoring system for clinicians
was devised by Duncan, Fowler, and Farkas
von Recklinghausen Neurofibromatosis
(1981), the diagnosis of NS is still relatively
subjective (Noonan, 1994, 2005). However, NFvR (also known as NF1) is characterized
it is important to determine the maternal by multiple café au lait spots and skin tu-
use of alcohol or other teratogens (e.g., an- mors, with skeletal (i.e., clubfoot, dislocation
ticonvulsants) and to identify other chromo- of the hips) and neurological signs (Wieder-
somal abnormalities, to rule out competing man et al., 1992; see Payne & North, Chap-
diagnoses. Others suggest that laboratory ter 17, this volume, for a full discussion).
studies, including chromosome analysis and NFvR is thought to be an autosomal domi-
DNA analysis (PTPN11, KRAS), may be nant disorder with variable expressivity, and
appropriate (van der Burgt, 2007). Exten- chromosome 17 has been implicated. Chil-
sive cardiological examination, including dren may show classic signs of NFvR with
echocardiography, is also recommended. NS, and are generally diagnosed as having
Several cases of individuals with NS have “neurofibromatosis–Noonan syndrome”
shown fetal edema (Bowie & Black, 1986; (NFNS; Wiederman et al., 1992). In some
van der Burgt, 2007) and cystic hygroma cases, the NS signs may be subtle but none-
(i.e., a watery tumor on the neck; Don- theless clinically evident (Opitz & Weaver,
nefeld, Nazir, Sindoni, & Libviggi, 1991) 1985). Opitz and Weaver (1985) suggest
in utero. Graham (1996) suggests that diag- that NFNS is nosologically discrete, not
nosis for mildly affected individuals can be an unusual form of either syndrome; that
made after a careful cardiac evaluation and it is as common as NFvR; and that it has
consideration of the adult expression of the an unknown pathogenesis, although males
disorder. have different manifestations of the syn-
drome (fusiform swelling of nerve strands)
compared to females (classic cutaneous neu-
Key Issues in Regard
rofibromas and a propensity to develop ret-
to Differential Diagnosis
roperitoneal/visceral neurofibromas. Allan-
A number of other syndromes should be son, Hall, and Van Allen (1985) have also
excluded when one is making a diagnosis reported patients with NFNS, and likewise
of NS, including Turner syndrome, NFvR, suggest that this is a single disorder distinct
and Aarskog syndrome. These syndromes from the separate syndromes.
Noonan Syndrome 319
Aarskog Syndrome Initial research investigating GH treat-

ment to increase height has shown promise
Although Aarskog syndrome is considered
(Limal et al., 2006; van der Burgt, 2007).
an X-linked recessively inherited syndrome,
There have been reports of improved growth
there is some evidence that it can be partially
velocity in prepubertal and pubertal chil-
manifested in females (i.e., short stature with
facial and hand features), so there may be dren with NS. Gilbert (1996) suggests that
an autosomal recessive inheritance linkage in some cases, surgery may be warranted to
as well (Wiederman et al., 1992). Features treat undescended testes. Surgical interven-
of Aarskog syndrome that resemble those tion prior to school age may increase fertility
of NS include short stature and unusual fa- and may decrease other malignant complica-
cial features (hypertelorism, downslant of tions.
the palpebral fissures, ptosis). Aarskog syn-
drome and NS can be differentiated, howev- Psychosocial, Educational,
er, as NS “does not include the penoscrotal and Emotional Interventions
anomaly, but includes pulmonary stenosis,
pterygium, [and] mental retardation” (Wie- Although specific treatment plans have not
derman et al., 1992, p. 194). been investigated, techniques for address-
ing cognitive, speech–language, visual-
perceptual, and academic difficulties may
Treatment and prove helpful. Access to educational services
Intervention Planning may be appropriate under the special educa-
tion category of “other health-impaired.” It
Medical Treatment is apparent that some children with NS may
Cardiac surgery may or may not be warrant- require psychological support for other is-
ed, depending on the severity and symptoms sues associated with coping with a chronic
of the heart disease (Noonan, 1994, 2005; medical disease. Further long-term follow-
van der Burgt, 2007). Although balloon up is needed to determine whether children
valvuloplasty has been used to treat pulmo- with NS have a predictable developmental
nary stenosis, difficulties have been noted course (particularly when cognitive difficul-
when the valve is dysplastic (i.e., abnormal ties are present), or whether the syndrome
in size or shape; Marantz et al., 1988). In is so heterogeneous that its progression re-
these instances, if balloon valvuloplasty is mains highly individual. Vocational training
not successful, then surgery is an alternative. or preparation for the work force may be
Noonan (1994) also notes that in some cases particularly challenging for individuals with
the valve may need to be resected to relieve associated cognitive difficulties or more seri-
obstructions. Other surgical procedures ous medical problems.
may be needed to treat the various cardiac Parents may benefit from counseling and
problems associated with NS. In rare cases, realistic planning for a child’s future. Fam-
children with NS and cardiomyopathy have ily education and support are also recom-
undergone heart transplants, but the general mended, as families may not be well in-
course and prognosis for cardiomyopathy formed about the disorder. Further research
are not well known. is needed to more clearly establish effective
Bleeding problems and easy bruising may practices for children and adolescents with
also need attention; in such cases, platelet NS and their families.
counts should be tracked, and aspirin prod-
ucts should be avoided (Noonan, 1994).
Some report that these problems may resolve Conclusions
by adulthood (see van der Burgt, 2007). As
noted earlier, cases of ALL have been report- A multidisciplinary approach is recommend-
ed in children with NS, although it is not ed for an individual with NS, so that medical
known whether NS places a child at higher follow-up, psychoeducational interventions,
risk for other malignancies. Obviously, med- vocational training, and parental support
ical screening and follow-up treatment are can be coordinated. These interventions
important in these cases. should be monitored regularly so that the
child will have the best possible adult out- Duncan, W. J., Fowler, R. S., & Farkas, L. G.,
come. For children with NS, a neuropsychol- (1981). A comprehensive scoring system for eval-
ogist needs to move beyond being a diagnos- uating Noonan syndrome. American Journal of
tician into playing the role of advocate and Medical Genetics, 10, 37–50.
Fakouri, C., & Fakouri, E. (1998). Noonan syn-
counselor. Section 504 of the Rehabilitation drome. In L. Phelps (Ed.), A guidebook for un-
Act of 1973 (a civil rights law banning dis- derstanding and educating health-related disor-
crimination on the basis of disabilities) and ders in children and adolescents (pp. 474–479).
the Individuals with Disabilities Education Washington, DC: American Psychological Asso-
Improvement Act of 2004 empower chil- ciation.
dren, adolescents, and adults with medical Finnegan, J. A., & Hughes, H. E. (1988). Very su-
and genetic disorders to gain the vocational perior intelligence in a child with Noonan syn-
and educational training needed for life suc- drome. American Journal of Medical Genetics,
cess. The extent to which we can foster this 31, 385–389.
kind of ecologically valid intervention may Flick, J. T., Sing, A. K., Kizer, J., & Lazarchick,
J. (1991). Platelet dysfunction in Noonan’s syn-
optimize the potential for individuals with drome: A case with a platelet cyclooxygenase-like
NS to become self-reliant, self-sufficient, deficiency and chronic idiopathic thrombocy-
and/or completely independent. topenic purpura. American Journal of Clinical
Pathology, 95, 739–742.
Gauthier, A., Furstoss, O., Araki, T., Chan, R.,
Acknowledgment Neel, B., Kaplan, D., et al. (2007). Control of
CNS cell-fate decisions by SHP-2 and its dysregu-
I would like to extend my thanks to Jane Walczak, lation in Noonan syndrome. Neuron, 54(2), 245-
the librarian at Children’s Hospital in Milwaukee, 262.
Wisconsin, for her assistance in accessing many of
Ghaziuddin, M., Bolyard, B., & Alessi, A. (1994).
the references for my research on NS.
Autistic disorder in Noonan syndrome. Journal
of Intellectual Disability Research, 38, 67–72.
Gilbert, P. (1996). The A–Z reference book of syn-
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C h a p t e r 17
Neurofibromatosis Type 1
Jonathan M. Payne
Kathryn N. North
Neurofibromatosis type 1 (NF1) is an au- cognitive and learning difficulties, and the
tosomal dominant genetic disorder with theoretical basis for future clinical trials.
a prevalence of approximately 1 in 3,500
(Huson & Hughes, 1994). The hallmark
features of NF1 are cell proliferation and the Historical Perspective
development of nerve sheath tumors known
as neurofibromas. Although the diagnosis Numerous antique illustrations of patients
of NF1 is based on the presence of distinc- with multiple dermal tumors, and a likely
tive cutaneous manifestations, such as café diagnosis of NF1, appeared throughout the
au lait spots, axillary freckling, cutane- 17th and 18th centuries (e.g., Monstrorum
ous neurofibromas, and Lisch nodules (iris Historia, 1642, reported by Madigan &
hamartomas), the most common complica- Masello, 1989; see also Zanca & Zanca,
tion of NF1 in childhood is cognitive dys- 1980). One of the earliest descriptions, dis-
function. Although the cognitive phenotype covered amongst the documents of the Bo-
of NF1 is quite variable, approximately 80% lognese physician and naturalist Ulisse Al-
of children with NF1 experience moderate drovandi (1522–1605), concerns the patient
to severe impairment in one or more areas “Homuncio”—a man presenting with short
of cognitive functioning (Hyman, Shores, & stature and large, flabby masses of flesh less
North, 2005). The cognitive domains com- than 2 inches thick, hanging from the left
monly affected include attention, executive side of his head and trunk. “Buffon’s girl”
function, language, and visual perception of 1749 shows a little girl represented with
(Hyman et al., 2005). It is not surprising to several cutaneous anomalies, including dark
find that cognitive deficits often undermine leaf-shaped areas of hyperpigmentation on
performance in the academic environment, the limbs and trunk, a large raised lesion
and some form of learning disability (LD) is with the appearance of “pigskin” encircling
estimated to be present in up to 70% of chil- the trunk, and “life jacket”–shaped lesions
dren (Brewer, Moore, & Hiscock, 1997). In with a diffuse plexiform neurofibroma (re-
this chapter, we discuss the clinical and ge- ported by Ruggieri & Polizzi, 2003). One
netic features of NF1, the neuropsychology of the most complete early accounts of the
of the disorder, the pathogenesis underlying disorder dates from a case described by
322
Neurofibromatosis Type 1 323
von Tilesius in 1793. Referred to as “Wart are schwannomas of the eighth cranial (au-
Man,” the patient was described as having ditory) nerve, meningiomas, and peripheral
“countless growths on his skin [fibrous tu- nerve schwannomas (Yohay, 2006).
mors], a few spots of irregular color on his
legs [café au lait spots], a stocky large head
[macrocephaly], and a somewhat high shoul- Clinical Aspects and Complications
der on one side [scoliosis].” It wasn’t until
Prevalence
1882, however, that Friedrich von Reck-
linghausen provided the first systematic NF1 is one of the most common single-gene
description of the clinical and pathological disorders to affect the human nervous sys-
features of NF1, which later became known tem with a frequency of approximately 1 in
as Recklinghausen disease. He published 3,500 (Huson & Hughes, 1994; Riccardi,
two case reports in a monograph entitled 1992; Upadhyaya & Cooper, 1998). Popu-
On Multiple Neurofibromas of the Skin and lation-based prevalence rates range from 1
Their Relationship to Multiple Neuromas. in 960 in 374,440 patients in Israel (Garty,
von Recklinghausen correctly identified the Laor, & Danon, 1994) to 1 in 6,711 in
pathology of the cutaneous and subcutane- 2,375,304 patients in Italy (Clementi, Bar-
ous tumors—“These skin and nerve tissues bujani, Turolla, & Teconi, 1990). NF1 has
represent minglings of both neural elements been identified in all ethnic groups; it occurs
and connective tissue”—and created the with equal frequency in males and females;
term neurofibroma. and an estimated 2–3 million individuals are
At the turn of the 20th century, Thomson affected worldwide (Seizinger, 1993).
(1900) identified the genetic nature of the
disorder, demonstrating that the disease was
Diagnostic Criteria
familial in 30 of 77 cases. At about this time,
numerous case reports of NF1 appeared in Although von Recklinghausen described
the medical literature, often overestimat- NF1 as a clinical entity in 1882, it wasn’t
ing disease complications and focusing on until 1987 that accepted diagnostic criteria
more severe cases. Preiser and Davenport were established, as noted above. According
proposed autosomal dominant inheritance to these criteria (NIH Concensus Develop-
in 1918; however, it was not until the 1950s ment Conference, 1988), NF1 is present in a
that the first large, reasonably accurate sur- patient who has two or more of the follow-
veys of the disease appeared (Borberg, 1951; ing signs: (1) six or more café au lait macules
Crowe, Schull, & Neel, 1956). (5 mm or larger in prepubertal individuals,
Detailed research into the various clini- 15 mm or larger in postpubertal individu-
cal manifestations and complications of als); (2) two or more neurofibromas of any
NF1 has increased markedly since the early type, or one or more plexiform neurofibro-
1980s, beginning with the landmark work mas; (3) freckling in the axilla or inguinal
of Riccardi (e.g., 1981). In 1987, definitive regions; (4) an optic pathway tumor (optic
diagnostic criteria for NF1 and NF2 were glioma); (5) two or more Lisch nodules (be-
proposed (National Institutes of Health nign iris hamartomas); (6) a distinctive os-
[NIH] Consensus Development Conference, seous lesion such as sphenoid wing dysplasia
1988), enabling accurate and uniform clini- or thinning of the cortex of the long bones,
cal diagnoses of the two disorders. The NF1 with or without pseudoarthrosis; or (7) a
gene was cloned in 1990, and its gene prod- first-degree relative with NF1 according to
uct, neurofibromin, was identified (Wallace the preceding criteria. These diagnostic cri-
et al., 1990). A few years later, the NF2 teria are suitable for both adult and pediat-
gene was cloned, with merlin (also known as ric populations, and nearly all patients with
schwannomin) identified as its gene product NF1 meet the criteria by 20 years of age
(Rouleau et al., 1993). Although NF2 is also (DeBella, Szudek, & Friedman, 2000). The
an autosomal dominant disorder, NF1 and number of clinical features included in the
NF2 are caused by different genes, and their NIH diagnostic criteria increases with age,
clinical manifestations are quite distinct. however, making a clinical diagnosis can be
Both are characterized by neural tumors; difficult within the first year of life. Indeed,
however, in NF2 the predominant tumors approximately 46% of children sporadically
affected by NF1 will fail to meet NIH di- (MRI)—to provide a more reliable diagnosis
agnostic criteria within the first year of life, for young children, results show that they do
as they typically display just one cardinal not significantly increase the sensitivity of
clinical feature, usually multiple café au lait the NIH diagnostic criteria (DeBella, Posk-
spots (DeBella, Szudek, & Friedman, 2000). itt, Szudek, & Friedman, 2000).
Most children with an affected parent, how-
ever, can be identified within the first year
Clinical Manifestations
of life because the diagnosis requires just
and Their Frequencies
one sign in addition to a positive family
history. Whereas some diagnostic features The clinical complications of NF1 and their
(e.g., Lisch nodules, cutaneous and subcu- frequencies have been reviewed in several
taneous neurofibromas) are less common in centers around the world (Friedman &
young children and do not reach maximum Birch, 1997; Huson, Harper, & Compston,
frequencies until adulthood, others increase 1988; Riccardi, 1992; Young, Hyman, &
rapidly during childhood. As such, the re- North, 2002; Table 17.1).
liability of the NIH diagnostic criteria im-
proves every year as a child grows older, and
Café au Lait Macules
by 8 years of age, 97% of all patients with
NF1 meet the criteria. Although some have The most common feature of NF1 is the pres-
suggested including NF1-specific features— ence of café au lait macules—ovoid, dark-
such as T2-weighted hyperintensities (T2H) pigmented areas of skin that can range from
seen on head magnetic resonance imaging several millimeters in size to covering a sub-
TABLE 17.1. Prevalence of Clinical Manifestations of NF1 in Four Major Studies

Young et al. Friedman & Riccardi Huson et al.
(2002) Birch (1997) (1992) (1988)
Feature (n = 495) (n = 1,728) (n = 953) (n = 135)
Café au lait macules (6+) 95% 90% 100% 84%
Skinfold freckling 80% 85% — 67%
Discrete neurofibromas 50% 54% — —
One plexiform neurofibroma 27% 24% 40% 32%
2+ plexiform neurofibromas 5% 5% — —
Internal neurofibromas 6% — — —
Lisch nodules 94% 59% 84% 96%
Asymptomatic optic gliomas 4% — — —
Symptomatic optic gliomas 6% 4% — 2%
Seizures 5% 6% 6% 7%
Hydrocephalus 3% 4% — —
Congenital heart disease 4% 2% — —
Hypertension 4% 4% — —
Endocrine abnormalities 6% — — —
Short stature 18% — — 34%
Precocious puberty 5% 4% — —
Scoliosis 23% 26% 25% 10%
Pseudoarthrosis 3% 2% 1% 4%
Sphenoid wing displasia 7% 11% — —
Other bone abnormalities 11% — — —
Macrocephaly 38% — — 45%
Noonan phenotype 9% 4% — —
Total neoplasms 5% 5 — —
CNS neoplasms 3% 2% — —
stantial portion of the body (Ward & Gut- (Korf, 2002; Ward & Gutmann, 2005). Un-
mann, 2005). The early appearance of these like cutaneous neurofibromas, some plexi-
macules is often the first feature of NF1; if form neurofibromas are congenital in origin,
they are not present at birth, they tend to and it is these tumors that are more likely to
become visible within the first 2 years of life. cause significant cosmetic disfigurement and
The presence of one or more café au lait ma- subsequent psychosocial distress (North,
cules is common in the general population, 1998; Rosser & Packer, 2002c). Plexiform
but the presence of six or more macules indi- neurofibromas may be present superficially,
cates a strong likelihood of NF1. or may infiltrate muscle, bone, and viscera,
which can cause significant pain (Rosser &
Packer, 2002c; Ward & Gutmann, 2005). Su-
Skinfold Freckling
perficial neurofibromas are easier to identify
A common feature of NF1 is intertriginous and tend to be visible within the first 2 years
freckling. Up to 80% of children with NF1 of life (Rosser & Packer, 2002c). As many
display freckling within regions that are not plexiform neurofibromas may be silent and
typically exposed to sunlight (De Schepper, not identified until later in life, it is difficult
Boucneau, Lambert, Messiaen, & Naeyaert, to determine accurate prevalence rates; how-
2004). Freckling is typically observed in ax- ever, estimates suggest that approximately
illary and inguinal regions, but can also be one-quarter to one-third of individuals with
present around the base of the neck, and un- NF1 develop plexiform neurofibromas (Korf,
derneath the breasts in women (Korf, 2002). 1999). Plexiform neurofibromas carry an
This characteristic pattern typically emerges increased potential for transformation into
between 3 and 5 years of age. malignant peripheral nerve sheath tumors
(Arun & Gutmann, 2004). The latter are
particularly aggressive and generally have a
Neurofibromas
poor response to treatment. The lifetime risk
As noted earlier, neurofibromas are benign of malignant peripheral nerve sheath tumors
tumors of the nerve sheath. Although dif- in NF1 is approximately 8–13% (Evans et
fering classification systems exist for the al., 2002).
various forms of neurofibromas (see Rosser
& Packer, 2002b, for discussion), the main
Lisch Nodules
types of neurofibromas are cutaneous and
plexiform. Cutaneous neurofibromas tend Lisch nodules are harmless iris hamar-
to be discrete nodular growths that involve tomas that do not compromise vision. Seen
the dermal (and, in some cases, subcutane- through a slit lamp, they are rare in children
ous) tissue. These nodular growths typically under 6 years of age, commonly appear in
range from 1 to 2 centimeters in size and children between the ages of 6 and 10 years,
may protrude above the skin (Korf, 2002; and are present in over 98% of adults with
Rosser & Packer, 2002b). Cutaneous neuro- NF1 (Lubs, Bauer, Formas, & Djokic, 1991).
fibromas generally begin to appear at about Lisch nodules are pathognomonic of NF1
puberty and continue to increase in number and are an extremely useful diagnostic tool;
throughout adulthood, with peak plexiform they are also frequently used for screening
growth periods during times of hormone parents of affected children.
change, such as adolescence and pregnan-
cy. These small neurofibromas are present
Optic Pathway Gliomas
in almost all adults with NF1. Cutaneous
neurofibromas tend to be slow-growing and Optic pathway gliomas (OPGs) are the most
are not malignant; although they do not common central nervous system tumors
usually cause any pain or discomfort, they in patients with NF1, with the majority of
may be associated with significant cosmetic cases involving the anterior visual pathway
burden for some individuals (Young et al., (see Listernick, Louis, Packer, & Gutmann,
2002). 1997, for a review). They are usually detect-
On the other hand, plexiform neurofibro- ed prior to age 6 years, with the mean age of
mas tend to grow along the length of larger diagnosis approximately 4 years (Gutmann,
nerves and arise from multiple nerve fascicles 2002; Ward & Gutmann, 2005). OPGs tend
to be slow-growing and in some cases can Genetics and Family Patterns

resolve spontaneously (Rosser & Packer,
2002a). Although present in 15–20% of NF1 results from a mutation in the NF1
patients on cranial imaging, only 30–50% gene on the long arm of chromosome 17.
of OPGs become symptomatic, with com- Mutations can occur virtually anywhere
mon sequelae including reduced visual acu- within the NF1 gene and can consist of
ity, visual field defects, afferent pupillary deletions, insertions, nonsense mutations,
defects, optic nerve atrophy, proptosis, and missense mutations, and intronic mutations
strabismus (Rosser & Packer, 2002a; Sin- (Yohay, 2006). NF1 is inherited in an auto-
ghal, Birch, Kerr, Lashford, & Evans, 2002; somal dominant fashion, with 50% risk of
Thiagalingam, Flaherty, Billson, & North, transmission to offspring. Despite almost
2004). Precocious puberty may also occur in complete penetrance by adulthood, the phe-
children with OPGs, usually as a result of notypic expression of NF1 varies dramati-
hypothalamic infiltration (Listernick, Char- cally among affected individuals and even
row, Greenwald, & Mets, 1994). The first within families (Viskochil, 2002). There
line of treatment for symptomatic OPGs is are poor correlations between the specific
chemotherapy; it is preferable to defer any mutation and disease phenotype, except in
necessary radiotherapy until after the age of patients with entire gene deletion (~5% of
5 years, due to the cognitive sequelae asso- patients). These individuals display a more
ciated with radiotherapy (Rosser & Packer, severe phenotype, including earlier onset,
2002a; Young et al., 2002). Although it is large load of neurofibromas, severe and gen-
common clinical practice for patients to un- eralized cognitive impairment, dysmorphic
dergo annual ophthalmological examina- facial features, and increased risk of malig-
tions throughout their first 10 years of life, nancy. This genetic variability suggests that
routine MRI surveillance is usually not rec- additional genetic and environmental factors
ommended for patients with NF1 (Ward & play a role in determining the phenotypic ex-
Gutmann, 2005). pression of the gene; these pose a challenge
to the prediction of the future course of the
disorder for an affected individual (Ward &
Orthopedic Abnormalities
Gutmann, 2005). The NF1 gene has a high
NF1 is also associated with skeletal system mutation rate, with > 50% of cases the result
abnormalities, including scoliosis, sphenoid of sporadic mutations. Given the frequency
wing dysplasia, and pseudoarthrosis, at of NF1, this represents one of the highest
prevalence rates of up to 20%. Most NF1- single-locus mutation rates known in hu-
related scoliosis is mild and does not require mans.
intervention. Less common, however, is a The NF1 gene was first identified and
severe, rapidly progressive dysplastic sco- successfully cloned in 1990, and encodes a
liosis that requires surgical correction (~5% 220- to 250-kDa protein called neurofibro-
of patients). When associated with paraver- min (Wallace et al., 1990). Neurofibromin is
tebral neurofibromas, dysplastic scoliosis primarily expressed in neurons, astrocytes,
can produce abrupt angle curvature, spinal oligodendrocytes, and Schwann cells, and
cord compression, and consequent acute or shares high sequence homology with guano
chronic neurological complications. sine triphosphatase (GTPase) activator pro-
Sphenoid wing dysplasia is generally uni- teins (Gutmann, 2002; Ward & Gutmann,
lateral and may or may not be associated 2005). An important feature of these pro-
with a local neurofibroma. Although it is teins is their involvement in the regulation of
usually of little clinical significance, in some cell proliferation and differentiation, leading
instances it can progress and affect the in- to the hypothesis that NF1 is a “tumor sup-
tegrity of the bony orbit. In addition, corti- pressor gene.” In this regard, neurofibromin
cal thinning and bowing of the long bones, normally limits cell growth, and its absence
particularly the tibia, can lead to repeated or reduced expression results in increased
fractures with incomplete healing; this can cell growth. Like other GTPase activator
result in the appearance of a false joint, proteins, neurofibromin interacts with ras,
known as pseudoarthrosis (Stevenson et al., a key intracellular signaling protein that is
1999). important for regulating cell growth and
survival. Ras is a GTP-binding protein that ing, personal history, and parental reports,
is active in the GTP-bound state and inactive rather than on standardized measures of in-
in the guanosine diphosphate (GDP)–bound telligence. It is now accepted that mental re-
state. Neurofibromin inhibits the activity of tardation (IQ < 70) is not a typical manifes-
ras GTPase proteins by catalyzing the hy- tation of NF1, and estimates vary between
drolysis of active GTP-bound ras to inactive 4% and 8% (Hyman et al., 2005; North et
GDP-bound ras. Loss of neurofibromin real., 1997). Although this is approximately
sults in elevated levels of active GTP-bound two to three times the rate seen in the gen-
ras, stimulating cell proliferation and tum- eral population, it is relatively low compared
origenesis (Williams et al., 2009). to the rates for other genetic disorders af-
fecting the central nervous system (Hyman
et al., 2005; Ozonoff, 1999).
Cognitive Profile One of the most robust findings of stud-
ies examining the cognitive profile in NF1 is
One of the most common complications of a distinct downward shift in the bell curve,
NF1 in childhood is cognitive dysfunction. compared with both the general population
As noted earlier, approximately 80% of chil- and unaffected siblings. The mean Full Scale
dren with NF1 experience significant impair- IQ tends to cluster around the high 80s to
ment in one or more areas of cognitive func- low 90s (Hyman et al., 2005; Levine, Ma-
tioning (Hyman et al., 2005). Since the early terek, Abel, O’Donnell, & Cutting, 2006).
1990s, the common aim of many cognitive In the past, there has been a suggestion of
studies has been to determine the “cognitive a bimodal distribution of IQ scores in NF1,
profile” of children with NF1—that is, to ar- with a peak around 85 and another at 100
rive at a general consensus about the type (North, Joy, Yuille, Cocks, & Hutchins,
and severity of cognitive impairments specif- 1995; Ozonoff, 1999); however, this has
ically related to the disorder. Although the proven difficult to replicate across studies.
literature indicates some common trends, The observed lowering of IQ scores has
there are a number of inconsistent findings, raised discussion of whether this reflects a
which make a clear profile difficult to define. true downward shift, or whether a small
This is likely to be a result of the variable subset of children who perform poorly on
phenotypic expression seen in NF1, but also measures of intellectual functioning lower
in part to methodological differences across the overall group mean (North, 2000).
studies. For example, in studies attempting Although a subset of children will always
to investigate the impact of an NF1 gene perform poorly on testing, the majority of
mutation on cognition, children with NF1 studies examining IQ in NF1 find cohort
have been compared to unaffected siblings scores to be normally distributed, but with
in a pairwise design, to unaffected controls the characteristic downward shift. As such,
from the general population, or to a norm- it appears that the observed lowering of IQ
referenced group. scores reflects a true downward shift in IQ,
rather than a subset of individuals skewing
the mean. This is further supported by evi-
General Intellectual Functioning
dence from a relatively large cohort study re-
Historically, reports of intellectual function- porting that 61% of children with NF1 (n =
ing in patients with NF1 overestimated the 81) obtained Full Scale IQs at least 10 points
prevalence of mental retardation, with some lower than those of their siblings without
studies suggesting rates of 30% (Samuels- NF1 (Hyman et al., 2005). Although a few
son & Axelsson, 1981). These early studies studies have reported that children with
often obtained their subjects from mental in- NF1 display significantly lower Performance
stitutions and hospitals, resulting in a biased than Verbal IQs (Eliason, 1986; Legius, De-
sample skewed toward severe NF1-related scheemaeker, Spaepen, Casaer, & Fryns,
manifestations, with mildly affected cases 1994), the majority have not replicated this
clearly underrepresented (Cole & Myers, finding (e.g., Ferner, Hughes, & Weinman,
1978; Crowe et al., 1956). These studies also 1996; Hyman et al., 2005; Moore, Slopis,
tended to rely on crude measures of intelli- Jackson, De Winter, & Leeds, 2000; North
gence, such as the number of years of school- et al., 1995).
Visual–Spatial Language
and Perceptual Skills
Early studies in NF1 focused much effort on
Visual–spatial deficits are among the most understanding nonverbal aspects of the dis-
common and severe impairments associated order, giving little attention to verbal-based
with NF1 and constitute a core feature of abilities. Mazzocco and colleagues (1995)
the NF1 cognitive phenotype. Characterized were among the first researchers to under-
by a difficulty organizing and accurately intake a detailed examination of language
terpreting visual information, poor perfor- skills in children with NF1. They compared
mance on the Judgment of Line Orientation 19 children with NF1 to their siblings on a
(JLO) test is a consistent feature across all number of language tasks. The children with
studies of the NF1 cognitive phenotype (e.g., NF1 obtained significantly lower scores on
Hyman et al., 2005; Moore et al., 2000; tests of vocabulary, picture naming, written
Ozonoff, 1999; Schrimsher, Billingsley, Slo- vocabulary, receptive language, and verbal
pis, & Moore, 2003). For example, Hyman reasoning than their unaffected siblings did.
and colleagues (2005) reported that 56% A deficit in phonological processing, particu-
of children with NF1 performed at least larly phoneme segmentation, was also iden-
one standard deviation below the mean on tified in the NF1 group; this is an important
JLO. Others have reported mean scores for finding, given that phonological skills are a
NF1 cohorts to fall more than two standard recognized precursor of literacy skills. Dilts
deviations below their unaffected siblings and colleagues (1996) compared 19 children
(Hofman, Harris, Bryan, & Denckla, 1994; with NF1 to their siblings on the Clinical
Joy, Roberts, North, & de Silva, 1995). As Evaluation of Language Fundamentals—
JLO does not involve fine motor coordina- Revised test. They reported that 58% of
tion or a timed response, it is thought to be children with NF1 failed this screening
particularly sensitive to the visual–spatial test, compared to a failure rate of 16% in
difficulties in NF1. The point has been the control group. Combined expressive and
raised that JLO relies on elements of execu- receptive language deficits were identified in
tive functioning (an area also believed to 26% of the sample with NF1, while 32%
be commonly impaired in NF1; see below), displayed pure expressive language impair-
such as using visual working memory and ment. Pure receptive language deficits were
visual tracking skills to encode a line of one not identified in the cohort with NF1.
orientation and compare it to an array of These earlier findings have since been
orientations (Cutting, Clements, Lightman, replicated across a large number of studies
Yerby-Hammack, & Denckla, 2004; Levine (e.g., Billingsley, Slopis, Swank, Jackson, &
et al., 2006). The specific cluster of deficits Moore, 2003; Hyman et al., 2005). Given
observed across multiple visual–spatial and the wide range of language skills implicated,
perceptual tasks, however, provides strong a global language deficit has been widely ac-
evidence of a true visual–spatial deficit. The cepted as a key feature of the NF1 cognitive
evidence for visual–spatial deficits has been phenotype. It is important to note, however,
further strengthened by studies demonstrat- that NF1-related language deficits rarely
ing impaired performance on the JLO task occur in isolation (Ozonoff, 1999). A ma-
after controlling for IQ and performance jority of children with NF1 who experience
on fine motor tasks (Hyman et al., 2005). language difficulties are more likely to have
Apart from JLO, other common measures concurrent difficulties in other cognitive do-
of visual–spatial and perceptual function- mains, such as visual–spatial impairment
ing sensitive to these deficits in children with (North, 2000).
NF1 include the Block Design subtest of
the Wechsler intelligence scales, the Beery–
Executive Function and Attention
Buktenica Visual–Motor Integration test,
and the Rey–Osterrieth Complex Figure An area of increasing interest and recogni-
Test (Hyman et al., 2005; Kayl & Moore, tion is the presence of executive impairments
2000; Legius et al., 1994; Mazzocco et al., in children with NF1. Executive function re-
1995; Schrimsher et al., 2003). fers to a collection of interrelated cognitive
and behavioral skills that are responsible for bined subtype, 32% with the predominant-
goal-oriented activity, such as planning, at- ly inattentive subtype, and only 3% with
tention, inhibition, cognitive flexibility, orga- the predominantly hyperactive–impulsive
nization, and self-monitoring (Lezak, 1995). subtype. These proportions mirror those
It is well established that the frontal lobes, reported for the general population with
and in particular the prefrontal cortex, play ADHD, suggesting that the underlying pro-
an important role in cognitive aspects of ex- cesses associated with attention difficulties
ecutive function. It is generally recognized in NF1 may be similar to those associated
that children with NF1 experience executive with ADHD and that analogous treatment
impairments; complex attention, working strategies may thus be applied to children
memory, spatial planning, and organiza- with comorbid NF1 and ADHD (e.g., Maut-
tion are typically implicated. Early studies ner, Kluwe, Thakker, & Leark, 2002).
highlighted a depressed Freedom from Dis-
tractibility Index on the Wechsler intelli-
Memory
gence scales, which incorporates aspects of
attention, sequencing, and verbal working Although the presence of memory deficits in
memory (e.g., Eliason, 1986). North and children with NF1 remains an area of con-
colleagues (1995) described their cohort as troversy, memory in general is thought to be
having poor problem-solving skills and poor spared in children with NF1 (e.g., Hofman
learning of material presented in an unstruc- et al., 1994; Hyman et al., 2005; Joy et al.,
tured manner. One study suggested that 60% 1995). Indeed, the memory problems that
of their patient sample displayed features of have been reported may more accurately re-
executive dysfunction, including deficits in flect primary language or visual–spatial im-
the ability to copy a complex figure in an or- pairments than memory deficits per se. Fur-
ganized manner (Chapman, Waber, Bassett, thermore, because of the significant overlap
Urion, & Korf, 1996). A further study re- between executive function and memory,
ported that although executive deficits were particularly working memory, future studies
highly correlated with IQ, spatial planning will need to separate the interrelationships
impairments were greater than predicted by among language, executive function, and
IQ (Hyman et al., 2005). memory (Levine et al., 2006).
It has been suggested that poor inhibition,
complex attention, planning, and organiza-
Social Cognition
tion in children with NF1 contributes to a
profile resembling attention-deficit/hyperac- Concerns regarding social skills and peer
tivity disorder (ADHD) (Levine et al., 2006; interaction have often been reported in the
North et al., 1995; Ozonoff, 1999; Ward & NF1 literature. Common descriptions in this
Gutmann, 2005). Approximately 40% of literature include “shy,” “loner,” “awkward
children with NF1 meet Diagnostic and Sta- around peers,” and “having difficulty form-
tistical Manual of Mental Disorders, fourth ing relationships with peers.” However, very
edition, text revision (DSM-IV-TR) criteria few studies have explored these issues in de-
for ADHD (Hyman et al., 2005; Koth, Cut- tail. Parent and teacher questionnaires ex-
ting, & Denckla, 2000). ADHD is charac- ploring behavior and social skills consistent-
terized by developmentally inappropriate ly reveal that children with NF1 experience
levels of hyperactivity, impulsivity, and inat- greater levels of anxiety, withdrawal, depres-
tention. This triad of symptoms forms the sion, and somatic complaints; are subjected
basis for the three main subtypes of ADHD to more teasing; and have poorer overall so-
(inattentive, hyperactive–impulsive, and cial skills (Barton & North, 2004; Johnson,
combined). The most commonly reported Saal, Lovell, & Schorry, 1999; Prinzie et al.,
problem areas in NF1 are inattention and 2003). A handful of studies have also inves-
impulsivity (North et al., 1995). Indeed, tigated self-concept in children with NF1
Hyman and colleagues (2005) reported that (Barton & North, 2007; Counterman, Say-
out of 31 children with NF1 who met DSM- lor, & Pai, 1996; Dilts et al., 1996). The most
IV-TR criteria for ADHD (39% of the total recent of these found that although children
sample), 65% were classified with the com- with NF1 experience a poor self-concept for
physical/sporting abilities, they report an in- psychomotor abilities, and social skills in
flated self-perception of their academic abili- the presence of intact verbal skills (Rourke,
ties, suggesting a lack of metacognition (i.e., 1988). NLD is thought to emerge in children
skills to evaluate their own abilities) in this with disordered right-hemisphere networks
area (Barton & North, 2007). The impact of (from deterioration or destruction of white
executive impairments on self-concept (and matter), or with a lack of access to such sys-
social cognition in general) remains unclear tems (e.g., callosal agenesis; Rourke, 1988).
and needs to be addressed in future studies. Although children with NF1 display certain
aspects of the NLD syndrome, there has
been a trend away from this conceptualiza-
Academic Achievement and LD
tion with a greater recognition of language
Given the breadth and severity of NF1- impairment in NF1. In fact, current under-
related cognitive impairment, it is not sur- standing suggests that NF1 is not related to
prising that children with the disorder are SLD; impairments are evident in mathemat-
at significant risk of academic underachieve- ics, single-word reading, reading comprehen-
ment, with the reported frequency of LD sion, and spelling when children with NF1
estimated to fall between 20% and 70% are compared to unaffected siblings and chil-
(Brewer et al., 1997; Hyman, Shores & dren from the general population (e.g., Cut-
North, 2006). The breadth of this range is ting, Koth, & Denckla, 2000; Hyman et al.,
due to the lack of a standard definition of 2005; Watt, Shores, & North, 2008).
LD. The term learning disability typically In order to appropriately treat LD in NF1,
refers to scores on tests of academic achieve- it is important to understand the cognitive
ment that are “substantially below” those and language impairments that underlie
expected for children of similar age, level various types of LD. Although very little is
of schooling, and level of intelligence. How- known about the relationship between cog-
ever, the application of this definition varies nitive impairment and mathematical LD in
from study to study. Whereas some report NF1, a handful of studies have attempted to
absolute levels of performance, others di- understand the underlying cause of reading
agnose LD based on a discrepancy between disability (Cutting et al., 2000; Mazzocco et
IQ and academic achievement (e.g., Hyman al., 1995; Watt et al., 2008). Those that have
et al., 2005). Hyman and colleagues (2006) typically report deficits in measures correlat-
made the distinction between specific learned with reading achievement. For example,
ing disability (SLD), or academic difficulties Cutting and colleagues (2000) reported that
in the presence of normal IQ, and general rapid naming and phoneme segmentation
learning disability (GLD), associated with were delayed. Similarly, Mazzocco and col-
low IQ and delayed academic achievement leagues (1995) also reported deficits in basic
(more than one standard deviation below the linguistic abilities of phonological memory
normative mean). The authors reported that and phoneme segmentation. A recent study
20% of their NF1 cohort (n = 81) exhibited by Watt and colleagues (2008) demonstrat-
SLD, 32% GLD, and 48% typical academic ed that despite average levels of general intel-
achievement. Of note, there was a highly sig- lectual functioning, 50% of children in their
nificant gender effect in the group with SLD cohort (15 of 30) met the diagnostic criteria
(15 out of 16 were males). Thus males with for specific phonological dyslexia; that is,
NF1 appear to have a much greater risk for they demonstrated impaired nonword read-
SLD, whereas females with NF1 are at no ing (e.g., ganten), but reading of irregular
greater risk of SLD than those in the general words (words that do not follow spelling-
population (Hyman et al., 2006). to-sound rules; e.g., island) fell within the
As early studies into the cognitive profile normal range. These findings suggest that a
of children with NF1 focused primarily on significant proportion of children with NF1
the nature of visual–spatial and perceptual experience a specific difficulty in employing
impairments, it had been proposed that chil- spelling-to-sound rules to assemble a pro-
dren with NF1 could be primarily character- nunciation when reading, possibly as a result
ized as having nonverbal learning disability of difficulties in phonological awareness.
(NLD)—a syndrome consisting of impaired As no studies have examined the efficacy
mathematics, visual–spatial skills, complex of interventions on cognitive impairments or
LD in NF1, the next logical step is to vali- are expressed early in life, and that they ap-
date remediation techniques in this group. pear to mirror the difficulties identified in
From a clinical perspective, there is currently school-age children (i.e., attention, motor,
no suggestion that the management of NF1- and language difficulties).
related LD needs to differ from techniques Although these two cross-sectional stud-
employed in the general population who ex- ies highlight the presence of developmental
perience similar deficits (North et al., 1995). delays in young children with NF1, the tra-
As such, tools for the remediation and man- jectory of the observed difficulties is unclear.
agement of ADHD and LD that have been We are currently conducting a longitudinal
effective in general paediatric populations study of a cohort of very young children
may also benefit children with NF1. It is with NF1 (ages 5–40 months) to ascertain
critical that future research not only focus how delays identified in very young children
on the categorization and subtyping of chil- develop over time, and also to identify early
dren with NF1, but also address ways of predictors of future academic failure. Early
minimizing the impact of specific cognitive identification will not only enable appropri-
difficulties on learning, and examine the ate assessment and intervention as early as
potential benefits of standard remediation possible, but will also be the key to targeting
practices for children with NF1. patients for specific and preventative thera-
pies as they become available, ultimately im-
proving the long-term outcomes of children
Developmental Considerations with NF1.
Only a handful of studies have examined
In studies that have investigated the cogni- cognitive functioning in adults with NF1.
tive functioning of children with NF1, most Although early cross-sectional data suggest-
have focused on children ages 6–16 years. ed an improvement in cognitive performance
Thus little is currently known about cog- from childhood to adulthood (Riccardi &
nitive development in very young children Eichner, 1986), most subsequent evidence
with NF1. To the best of our knowledge, indicates a stable profile. In the only lon-
only two studies have reported specifically gitudinal study bridging childhood and
on the functioning of children under 6 years adulthood, Hyman and colleagues (2003)
of age. Legius and colleagues (1994) grouped prospectively followed 32 patients with
children with NF1 into three age ranges: 17 NF1 and 11 unaffected sibling controls.
months to 4 years (n = 7), 4 years to 6 years Both groups underwent baseline neuropsy-
(n = 7), and 6 years to 16 years (n = 31). In the chological assessments in childhood (mean
youngest age range, 6 of 7 children demon- age 12.6 years) and were reassessed after an
strated a delay in language and motor skills, 8-year period (mean age 20.1 years). There
and 4 of 7 children exhibited mild develop- was no improvement in cognitive ability as
mental delay. For children ages 4–6 years, the children with NF1 developed into adult-
their general intellectual functioning was hood.
in the average range, with significantly bet-
ter verbal than nonverbal abilities. Three of
these children were receiving remedial teach- Pathogenesis of Cognitive Deficits
ing; two had speech disorders; and attention
difficulties were also identified. In the sec- The presence of cognitive deficits in NF1
ond study, Samango-Sprouse and colleagues has led to an interest in understanding the
(1994) assessed 90 infants and toddlers with neurobiological basis of the NF1 cognitive
NF1. Young children were reported to have phenotype. Investigations have consistently
depressed cognitive abilities, as well as ab- found little or no relationship between clini-
normal neuromotor and perceptual motor cal variables and the degree of cognitive im-
development. Problem-solving skills were pairments of NF1. For example, factors such
described as monochromatic (i.e., one strate- as gender, presence of macrocephaly, clinical
gy was used excessively), and a more passive severity, or mode of inheritance (familial or
interaction style was also reported. Taken sporadic) do not correlate with or predict
together, the results of these two studies sug- cognitive dysfunction (e.g., Hyman et al.,
gest that NF1-related cognitive impairments 2005; North et al., 1995). Current research,
however, provides strong evidence for a rela- hallmark feature of NF1. T2H commonly
tionship between cognitive dysfunction and occur in the basal ganglia, cerebellum, brain-
(1) structural brain anomalies and (2) altered stem, thalamus, and subcortical white mat-
biochemical pathways as a direct result of a ter, and are currently thought to represent
loss of neurofibromin. Below, we discuss evi- areas of increased water content within the
dence for both. myelin or dysplastic areas of white matter
formation. As such, T2H may be a radiolog-
ical marker of more extensive white matter
Abnormal Brain Structure
abnormality in individuals with NF1 (Di-
Consistent findings in the neuroimaging lit- Mario & Ramsby, 1998; North et al., 1995).
erature are now providing insight into brain– T2H are estimated to be present in 55–90%
behavior relationships in NF1. One of the of children with NF1; however, it has been
most robust findings in the literature is that predicted that with increasingly sensitive im-
children with NF1 have larger brains than aging techniques, the prevalence is likely to
their typically developing peers do (Green- approach 100% (Gill, Hyman, Steinberg, &
wood et al., 2005; Moore, Slopis, Schomer, North, 2006). Although they are not associ-
& Jackson, 1996; Said et al., 1996). Although ated with any mass effect, focal neurologi-
this enlargement appears to be primarily local deficits, or macrocephaly, there has been
calized to increases in white matter volumes, much debate over their relative contribution
there is suggestion of increased gray matter to cognitive impairment. A number of large
volume in posterior regions (Greenwood et studies using clinic-based samples and quan-
al., 2005). A number of studies have found titative neuropsychological measures found
correlations between gray matter proper- a significant association between a lowering
ties and cognitive function; however, due to of IQ and the presence of T2H (e.g., Denckla
the diverse nature of the research questions, et al., 1996; North et al., 1994). However,
firm conclusions concerning the role of gray others have not (Bawden et al., 1996; Legius
matter and cognitive impairment cannot be et al., 1995). The reasons for these contra-
drawn (Greenwood et al., 2005; Moore et dictory findings are most likely to be dif-
al., 2000; Said et al., 1996). ferences in inclusion criteria, small sample
Other studies have targeted the influence sizes, age variations of cohorts, differences
of more specific NF1-related neuroanatomi- in subject populations (e.g., age variations of
cal abnormalities on cognition. A relation- cohorts), and differing methods of quantify-
ship has been established between corpus ing T2H.
callosum volume and cognition. Specifically, Of the three studies that have reported
larger corpus callosum volumes have been on location of T2H, all consistently found
associated with greater severity of visual– that thalamic T2H were associated with
spatial impairment and LD (Moore et al., significantly lower IQ (Goh, Khong, Leung,
2000), whereas smaller volumes have been & Wong, 2004; Hyman, Gill, Shores, Stein-
associated with more severe attention prob- berg, & North, 2007; Moore et al., 1996).
lems in children with NF1 and ADHD (Kayl, Hyman and colleagues (2007) reported that
Moore, Slopis, Jackson, & Leeds, 2000). although the presence and number of T2H
Billingsley and colleagues (2003) examined were not associated with IQ, discrete T2H
the neural correlates of language and read- located in the thalamus were associated with
ing dysfunction in NF1. They found that severe and generalized cognitive impairment.
children with NF1 displayed greater sym- Thus the specific locations of T2H may be
metry of the planum temporale—a structure more precisely linked to the lowering of IQ
located on the on the superior surface of and other specific cognitive functions than to
the temporal lobe within the sylvian fissure, their number or presence. The apparent rela-
which is thought to play a role in mapping tionship between thalamic T2H and cogni-
auditory phonemes onto visual graphemes. tive impairment is not surprising, given that
This mirrors structural abnormalities ob- infarction, tumor, and trauma studies have
served in dyslexic children from the general demonstrated clear links between thalamic
population. lesions and impairments in memory, execu-
Focal areas of high intensity observed on tive and visual–spatial function, language,
T2-weighted MRI (T2H) are considered a and attention.
Animal Models and Abnormal +/– mice exhibit cognitive impairments, but
Ras Functioning the other carriers display normal cognitive
performance. Furthermore, remedial train-
The NF1 gene encodes the protein neurofi-
ing of impaired mice on the water maze task
bromin, which has several known biochemi- can alleviate the learning deficit.
cal functions, including activation of the ras Although these experiments suggest that
GTPase. Thus partial or complete loss of an increase in active ras could be responsible
neurofibromin results in the up-regulation for the Nf1 +/– mouse cognitive phenotype,
of ras signaling, which has been proposed this assertion has been reinforced by studies
to underlie many of the phenotypes associ- that manipulated levels of active ras. Costa
ated with NF1. Defective ras signaling has and colleagues (2002) bred Nf1 +/– mice to
been suggested to affect neural development, mice deficient in active ras (K-ras +/– mice)
migration, and apoptosis, resulting in ab- and tested both groups on a hidden water
normal cortical and white matter structure maze task. Genetic manipulation to reduce
(Billingsley et al., 2003; North, 2000; North ras resulted in equivalent performance be-
et al., 1997). This hypothesis may explain tween the wild-type mice and Nf1 +/– /K-ras
the absence of focal neurological signs in the +/– mice, suggesting that learning impair-
presence of high-frequency cognitive dys- ments in Nf1 +/– mice may be caused by ex-
function. It also provides sound theoretical cessive ras activity.
explanation for decrements in performance Active ras has also been inhibited in Nf1
on neuropsychological measures with in- +/– mice via pharmacological manipulation.
creased task complexity. To achieve this, Nf1 +/– mice were given lo-
An important experimental model to ex- vastatin, an agent commonly used to treat
amine the cognitive corollary of a partial or hyperlipidemia in children and adults, which
complete loss of neurofibromin is the Nf1 has been shown to cross the blood–brain
+/– mouse model. Importantly, human and barrier and decrease p21ras isoprenylation
mouse forms of neurofibromin are highly ho- and activity in the brain. Li and colleagues
mologous (98% sequence similarity), as are (2005) tested whether lovastatin could re-
the promoter sequences of the gene, suggest- verse cognitive and behavioral deficits in Nf1
ing that both the biochemistry of the protein +/– mice compared with a placebo control
and the transcriptional regulation of the gene group. After several days of treatment, the
are conserved across species. Mice heterozy- Nf1 +/– mice treated with lovastatin dem-
gous for a mutation in the NF1 gene (Nf1 +/– onstrated improved performance relative to
mice) demonstrate cognitive and behavioral the placebo group on tasks of visual–spatial
abnormalities that resemble the impairments learning and attention. Not only did lovas-
observed in humans. These cognitive impair- tatin result in a functional improvement, but
ments are not related to an increase in tumor slice preparations indicated that lovastatin
predisposition and do not appear to be as- also rescued defects in long-term poten-
sociated with any structural abnormalities tiation, an increase in synaptic strength be-
in the brain. Compared to their unaffected tween two neurons contributing to a cellular
littermates, Nf1 +/– mice experience difficul- mechanism of learning and memory (Cooke
ties on hippocampal-dependent tasks, such & Bliss, 2006). These results provide further
as the Morris water maze, and also on tasks evidence that ras modulation by neurofibro-
of attention and motor coordination. min is essential for learning and memory in
Notwithstanding the clear differences be- Nf1 mice, and they are potentially very sig-
tween mice and humans, there are distinct nificant for the development of treatments
cross-species similarities in the learning defi- for NF1 in humans.
cits caused by NF1 mutations. NF1 mutations
seem to affect some brain functions more
than others. For example, whereas visual– Areas for Further Research
spatial learning, attention, and motor coor-
dination are impaired, other forms of learn- Over the past 15 years, we in this field have
ing, such as classical conditioning, appear to achieved a much greater understanding of
be intact (Silva et al., 1997). The phenotypic the NF1 cognitive phenotype and identi-
expression is also variable: 40–60% of Nf1 fied possible radiological markers for cogni-
tive impairments. Many important issues, Barton, B., & North, K. (2004). Social skills of
however, remain to be addressed. For ex- children with neurofibromatosis type 1. Devel-
ample, we need a better understanding of opmental Medicine and Child Neurology, 46,
specific neuropsychological impairments of 553–563.
Barton, B., & North, K. (2007). The self-concept of
memory, language, and executive function. children and adolescents with neurofibromatosis
Given the relatively heterogeneous nature of type 1. Child: Care, Health, and Development,
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control groups when appropriate. Careful nonverbal cognitive deficits in children with neu-
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patients needs to be undertaken, so that fu- mental Neuropsychology, 18, 784–792.
ture intervention studies can be specifically Billingsley, R. L., Slopis, J. M., Swank, P. R., Jack-
son, E. F., & Moore, B. D. (2003). Cortical mor-
targeted. As areas of cognition continue to
phology associated with language function in
be investigated, it is also critical for neuro- neurofibromatosis type I. Brain and Language,
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brain imaging techniques to be incorporated tions into tuberous sclerosis and Recklinghausen’s
into future studies. Not only do these meth- neurofibromatosis: Contribution to elucidation
ods hold promise to uncovering the neural of inter-relationship and eugenics of syndromes.
basis of NF1-related cognitive impairment, Acta Psychiatrica et Neurologica Scandinavica,
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be implemented as early as possible. for learning disabilities are sex-specific. Ameri-
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C h a p t e r 18
Sickle Cell Disease
Julien T. Smith
David A. Baker
The term sickle cell disease (SCD) refers gous condition of SCD is present. Several
to a broad category of chronic hematologi- heterozygous forms exist, with sickle hemo-
cal disorders that includes sickle cell ane- globin C disease (HbSC), sickle beta-plus
mia (SCA), as well as other specific genetic thalassemia (HbS/ß+), and sickle beta-zero
presentations of the disease. SCD is an au- thalassemia (HbS/ß°) being the most com-
tosomal recessive genetic pathology of the mon variants. However, approximately 65%
hemoglobin (the oxygen-binding molecules of individuals affected by SCD possess the
of the blood), which affects approximately homozygous state (HbSS), the most severe
72,000 people of African, Mediterranean, genotype; several heterozygous conditions
Caribbean, South and Central American, account for the rest of the SCD population
Arab, and East Indian descent in the United (Wang, 2007). Moreover, those who inherit
States alone and is the most prevalent genet- the “sickle cell trait” have one normal beta-
ic hematological disorder worldwide (Ash- globin gene and one sickle beta-globin gene
ley-Koch, Yang, & Olney, 2000; National (HbS), making them trait carriers (HbAS)
Heart, Lung, and Blood Institute, 1996). but generally asymptomatic, except in rare
In the United States, the disease affects ap- and extreme circumstances (Ashley-Koch et
proximately 1 in 350–700 African American al., 2000). Infants with SCD are protected
and 1 in 1,000–1,400 Hispanic American from abnormal hemoglobin effects by the
newborns annually (National Heart, Lung, presence of fetal hemoglobin through about
and Blood Institute, 1996; Wang, 2007). 3 months of age. Adult hemoglobin com-
The most severe form of SCD is SCA, which pletely replaces fetal hemoglobin within the
presents when two copies of the hemoglo- first 3–6 months after birth. In individuals
bin variant (HbSS) compose the beta-globin with SCD, the adult hemoglobin is obviously
gene. The beta-globin locus is a group of impaired, and the negative effects of the dis-
genes on the short arm of chromosome 11, ease take hold in early childhood. Evidence
responsible for hemoglobin protein synthe- suggests that children who exhibit more
sis. When only one copy of the hemoglobin acute symptoms earlier in life display a more
variant (HbS) combines with a copy of an- clinically severe disease course (Miller et al.,
other beta-globin gene variant, a heterozy- 2001).
338
Sickle Cell Disease 339
Pathophysiology implicated in the CNS complications related

to SCD (Prengler, Pavlakis, Prohovnik, &
The rigidity and dysfunction of erythrocytes Adams, 2002).
(red blood cells) are central to the pathophys-
iology of SCD. In an individual with SCD,
HbS allows crystal formation on the eryth- Cerebrovascular Accidents :
rocytes after releasing oxygen, leaving them Overt and Silent Strokes
less stable, unable to bond oxygen proper-
ly, more rigid, and with a shorter lifespan Cerebrovascular accidents (CVA), or stroke,
(10–20 days). During the deoxygenation is the most broadly documented form of
process in the vasculature, the presence of neurological injury in patients with SCD
abundant HbS molecules causes the collapse (Schatz & Puffer, 2006, 2007). According to
and sickling of the red blood cells (i.e., they the Cooperative Study of Sickle Cell Disease
become sickle-shaped). Because sickled cells (CSSCD), a longitudinal, multicenter study
are rigid, they are unable to pass through involving over 4,000 patients, the likelihood
the vasculature properly, and interfere with that a child with SCA will have a stroke is
the blood flow by clumping together and be- 11% before age 20. Furthermore, of all pa-
coming lodged in the vessels. The collection tients with SCD, 6–11% will experience a
of many of these trapped sickled cells can stroke prior to age 15, with peak incidence
cause vaso-occlusion by blocking blood flow occurring between 2 and 5 years of age
and preventing the oxygenation of cells. Ac- (Ohene-Frempong et al., 1998). Silent stroke
cumulations of sickled cells lead to increased (see below) appears even more prominent in
viscosity or slowed movement of blood, re- this population, with prevalence rates rang-
ferred to as sludging, as the healthy, oxygen- ing from 15% to 27% (Balkaran et al., 1992;
ated blood cells cannot pass around the rigid Schatz & Puffer, 2007); variations in imag-
cells or effectively move through the viscous ing techniques account for such a wide range
fluid. Moreover, red blood cells in SCD also of rates (Schatz & Puffer, 2007). Approxi-
appear to have an increased binding affinity mately two-thirds of children who have one
for the vascular endothelium, with stronger stroke have another stroke, 80% of which
affinity evident in more severe clinical cases occur within 36 months without therapeutic
(Ballas & Mohandas, 1996; Lonergan, intervention. Seventy-five percent of the chil-
Cline, & Abbondanzo, 2001). dren who experience a CVA have a cerebral
Another complication of SCD is the re- infarction, while 20% have an intracerebral
duced oxygen-carrying capacity of eryth- hemorrhage. For uncertain reasons, chil-
rocytes that occurs when HbS polymerizes dren are more likely to experience infarct,
into the collapsed state. Low oxygenation whereas adults are more likely to experience
can lead to acidosis and ischemis necrosis. hemorrhage (Ohene-Frempong et al., 1998;
Certain tissues are particularly susceptible Pavlakis, Prohovnik, Piomelli, & Devivo,
to the negative effects of low oxygen and 1989; Ris & Gruenich, 2000). The Stroke
blockage, including organs such as the lungs, Prevention Trial in Sickle Cell Anemia per-
spleen, kidneys, and liver, as well as the cen- formed in the 1990s, as well as more recent
tral nervous system (CNS). studies, have shown that children with ab-
Given the extensive vasculature in the normal transcranial Doppler ultrasonog-
brain and the resulting neuropathology re- raphy (TCD) velocities who receive regular
lated to SCD, several theoretical models of blood transfusions have a 90% lower risk of
the processes causing neurological damage stroke (Adams et al., 1998; Lee et al., 2006).
have been proposed. For instance, Hillery Red blood cell transfusion therapy clearly
and Panepinto (2004) have proposed that reduces the risk of recurrent stroke, but this
neuropathology in SCD is caused by several therapy is accompanied by its own risks and
cascading and interrelated events, including uncertainties, as well as questions of wheth-
increased red cell adhesion, damage to the er and when it can be safely stopped (Lee et
vessel wall, inflammation, abnormal vaso- al., 2006; Pegelow, 2001).
motor tone/control, and increased activa- Strokes can occur either overtly or covertly,
tion of the coagulation system. Therefore, with obvious or subtler CNS injury that may
both large and small vessels are commonly not be easily identified through standard neu-
rological exam (Fowler et al., 1988; Mercuri susceptible to cerebral hypoperfusion and
et al., 1995; Swift et al., 1989). Overt strokes subsequent damage, especially between the
are defined as having an acute onset of motor anterior and middle cerebral arteries (Pav-
symptoms that persist for at least 24 hours, lakis et al., 1988; Wang, 2007). Reduced
as well as clear evidence of neurological in- pressure from large-vessel disease (lesions of
jury in neuroimaging. During childhood, the the intima [inner lining] in major arteries)
majority of overt hemorrhagic strokes result causes slower flow rates of blood between
from large-artery vasculopathy (Pegelow, small vessels in watershed regions and in-
2001). Overt strokes commonly occur in the creases risk of hypoperfusion. The chronic
frontal and parietal lobes, which are supplied anemia and hemodynamic insufficiency of
by the internal carotid artery and middle or SCD lead to vulnerability and “inadequate
anterior cerebral arteries. Overt stroke typi- perfusion in border zone regions presenting
cally involves more than 40 cubic centimeters a mechanism for cerebral infarction” (Pavla-
of brain tissue, whereas smaller volumes are kis et al., 1988, p.128). The most common
usually associated with silent stroke (Schatz sites of CVA or stroke are the internal ca-
& Puffer, 2007). rotid artery, the anterior and middle cerebral
Silent cerebral infarct (SCI) or silent stroke arteries, and their boundary zones (Craft,
is defined as brain lesions that are detect- Schatz, Glauser, Lee, &c DeBaun, 1993);
able on magnetic resonance imaging (MRI), these serve the middle and superior frontal
but without evidence of overt neurologi- gyri, as well as the temporal and parietal
cal impairment upon physical examination cortex, all common sites of stroke (Schatz
(Pegelow et al., 2002). With rapid improve- & Puffer, 2007). Whereas overt stroke is as-
ments in neuroimaging techniques, SCI has sociated with worse cognitive outcomes, the
been found to be the most prevalent mecha- milder extent of neurological injury in silent
nism of neurological injury in children with stroke is offset by the higher prevalence rate
SCA, occurring in as few as 15% and as many and associated risk factor for future overt
as 35% of cases (Bernaudin et al., 2000; Bu- stroke (Schatz & McClellan, 2006). Ongo-
chanan, DeBaun, Quinn, & Steinberg, 2004; ing, subtle neurological deficits caused by
Pegelow et al., 2002; Steen, Emudianughe, et silent strokes, ischemia, and hypoxia are
al., 2003; Switzer, Hess, Nichols, & Adams, most frequently identified in the territory of
2006). Furthermore, Wang and colleagues penetrating arteries, the deep white matter,
(2001) found that approximately 10% of a and striatum. Subtle cerebral impairment
sample of children under age 6 had evidence resulting from silent stroke may be evident
of previous SCI. Using more sensitive MRI only as mild sensory deficits, soft signs, or
technology (thin-slice T1- and T2-weighted higher-order cognitive deficits. Several stud-
sequences and fluid attenuated inversion re- ies, including the CSSCD, have found neu-
covery sequence), Steen, Emudianughe, and ropsychological differences between chil-
colleagues (2003) found a 35% prevalence of dren with SCD who have had overt stroke,
silent stroke, particularly in the parenchyma silent stroke, and no known stroke (see the
of the brain (supportive tissue consisting of more extensive neuropsychological discus-
nerve and glial cells). sion below). Overall, the clinical impact of
With improved radiological technology, SCI is not as subtle as was once believed.
the processes and subtleties of CNS injury Children with silent strokes have an in-
in patients with SCD are now better un- creased risk for future overt strokes or new
derstood. Using MRI, magnetic resonance MRI lesions (Miller et al., 2000; Pegelow et
angiography (MRA), TCD, and in some in- al., 2001). Risk factors for SCI include low
stances computerized tomography, research- pain rate, a history of seizures, and a leu-
ers have found that damage can occur in kocyte count over 11.8 × 109/L (Kinney et
minute veins, arterioles, and surrounding al., 1999). In addition to these risk factors,
tissue (Adams et al., 1988, 1992; Armstrong there appears to be a genetic predisposition
et al., 1996; National Institutes of Health, to stroke in individuals with SCD, as sibling
1986; Pavlakis et al., 1988; Ris et al., 1996; studies have found that a disproportionate
Wiznitzer et al., 1990). Arterial border zones number of siblings without SCD experience
(so-called “watershed regions”) are most stroke (Driscoll et al., 2003).
Nonstroke-Related Causes age. Hogan, Pit-ten Cate, Vargha-K hadem,

of Neurological Compromise Prengler, and Kirkcham (2006) found a
significant association among decreased
In the past 10 years, improvements in im- oxygen saturation, increased cerebral blood
aging technology have enhanced under- flow velocity, and lower Full Scale IQ in an
standing related to potential disease-related adolescent sample with SCD. Furthermore,
causes of cognitive challenges in SCD. Clear- differences in the composition of gray mat-
ly, children who have experienced obvious ter on T1-weighted MRI have been identi-
physiological complications are at increased fied in the thalamus, caudate, and cortex of
risk; however, children who are experienc- children with SCD (Steen et al., 1998, 1999,
ing silent strokes, metabolic insufficiencies, 2004; Steen, Eminudianughe, et al., 2003)
and chronic oxygen deprivation are also and were presumed to represent diffuse in-
at increased risk for reduced neurocogni- jury secondary to hypoxia from chronic ane-
tive functioning. There are indicators that mia. Moreover, decreased corpus callosum
children with SCD who have no significant size was found in a small sample of children
MRI abnormalities still display lower scores with SCD who had no visible infarcts (Schatz
on tests of intellectual functioning, although & Buzan, 2006).
these differences in many cases are not sta- The early literature suggested that local
tistically significant (Schatz, Finke, Kellet, impairments in glucose metabolism and
& Kramer, 2002; Steen et al., 2005; Steen, perfusion may also be culprits in the non-
Miles, et al., 2003). Furthermore, cognitive stroke-related neurocognitive effects of SCD
impairment has been identified in children (Rodgers et al., 1988), and more contempo-
without evidence of stroke in clinical his- rary research has supported this. Glucose
tory or neuroimaging (Schatz, Finke, et al., metabolism studies using positron emission
2002; Steen et al., 2005); this may be asso- tomography (PET) or perfusion MRI have
ciated with severity of anemia (Bernaudin supported the earlier hypothesis, showing
et al., 2000; Schatz, Craft, et al., 2004) or that such impairments are associated with
inadequate perfusion (Kirkham et al., 2001; lower intellectual scores (Kirkham et al.,
Oguz et al., 2003). Most supportive are the 2001; Powars et al., 1999; Reed, Jagust, Al-
findings that severe anemia seems to be as- Mateen, & Vichinsky, 1999), although the
sociated with cognitive challenges including impact on particular neurocognitive func-
deficits in intellectual ability, verbal skills, at- tions is less clear.
tention, and working memory (Bernaudin et
al., 2000; Brown et al., 1993; Schatz, Finke,
& Roberts, 2004; Steen, Xiong, Mulhern, Developmental Considerations
Langston, & Wang, 1999; Steen, Miles, et
al., 2003). There is also evidence that higher Although most of the clinical manifestations
blood flow velocity in the midcerebral artery of SCD are not apparent until early child-
is associated with lower verbal function- hood, Wang and colleagues (1998), using
ing, as well as with weaker sustained atten- MRI and MRA, found mild CNS abnormal-
tion and executive skills (Kral et al., 2003). ities in a sample of very young children (ages
Schatz and Puffer (2007) conclude from 7–48 months) with SCA and developmental
these data that for children without stroke, delays and MRI and MRA abnormalities.
disease severity (marked by abnormal TCD This has drastic ramifications for the ensu-
and severe anemia) is associated with cogni- ing development of children with SCD.
tive dysfunction. The first 2 years of life are a critical pe-
Furthermore, functional imaging studies riod of brain development, during which
also support findings that diffuse brain in- glial proliferation, myelination, dendritic
jury occurs within SCD without evidence of branching, and development of synaptic
stroke. Kennan, Suzuka, Nagel, and Fabry connections are abundant, and vulnerabil-
(2004) found evidence that the brains of ani- ity to neurological compromise is profound.
mal models with SCD are less protected from Neurological insult during this period may
the effects of oxygen deprivation, resulting have long-term cognitive and behavioral
in diffuse and chronic CNS oxygen short- consequences because optimal brain activity
is interrupted during an imperative growth several social and environmental factors in-
period. Medical and educational profession- teract with the neurological condition.
als often overlook this debilitation, as com-
pensatory strategies develop with physical
recovery and time, and these can obscure Specific Neuropsychological
underlying deficits temporarily or in spe- Impairments
cific situations. Neurological injury is often
Attention, Impulse Control,
viewed as an acute illness that ends at about
and Processing Speed
the time of discharge from the hospital, and
long-term sequelae are not linked to the It is critical to understand the complicated
original injury. Early injury, however can labyrinth of the attention system and its re-
lead to a globally compromised CNS that lationships to neurological dysfunction. Be-
has been forced to reconstruct the interactive cause of the variable nature of stroke and
neuronal network. Theories of neurologi- chronic hypoxia in children with SCD, any
cal maturation suggest that the developing one level or multiple levels of attention skill
brain is plastic, or malleable to alterations can be compromised. Dissecting attention
in functional area. The concept of plasticity skill levels and identifying specific deficits
implies that the functions of a damaged area are vital to selecting the most efficacious in-
of the brain can be “reassigned” to another, terventions.
undamaged area. Although this is immedi- Both attention and impulse control appear
ately effective in enabling an individual to particularly vulnerable to the neurocogni-
regain a certain level of skill, it can lead to tive impacts of SCD, and deficits in these are
longer-term problems when the area of the often associated with frontal lobe abnormal-
brain that has taken over a specific ability is ity. Early studies of attention skills in chil-
called upon to perform its original function. dren with SCD that did not examine physi-
According to Teuber’s so-called “crowding ological findings found notable attention
principle” (Woods & Teuber, 1973), recov- and behavioral problems (Burlew, Evans, &
ery by reassignment occurs at the expense Oler, 1989; Hurtig & Park, 1989; Hurtig &
of other abilities. When functions are shifted White, 1986). In a study using a visual ori-
in an attempt to compensate, areas become enting task (Craft, Schatz, Glauser, Lee, &
congested and less efficient. Early injury DeBaun, 1994) in children with SCD who
therefore jeopardizes long-term develop- had experienced stroke, those with bifrontal
mental progress, although this may not be injury showed more impulsivity than children
immediately evident. with diffuse lesions, who had increased reac-
Further clarification of the impact of SCD tion time; both groups were more impaired
on brain development is provided by research than children with SCD without stroke and
in early nutritional issues. Multiple or severe sibling controls. More recent studies have re-
hypoglycemic episodes, or severe malnutri- peatedly documented problems in attention
tion in early development, can compromise and concentration skills in pediatric patients
brain growth (Swift et al., 1989). Iron de- with SCD compared to peers and/or sibling
ficiency anemia in the critical CNS growth controls (Brandling-B ennett, White, Arm-
period can clearly compromise long-term strong, Christ, & DeBaun, 2003; Brown et
cognitive development; the effects include al., 1993, 2000; Craft et al., 1993; Fowler et
reduced attention, fatigue, behavioral prob- al., 1988; Kral et al., 2003; Schatz, Brown,
lems, and poor academic achievement. Iron Pascual, Hsu, & DeBaun, 2001; Schatz,
deficiency anemia can also lead to neuro- Craft, Koby, & DeBaun, 2004). Patients
logical soft signs, such as poor coordination with histories of both overt and silent stroke
and balance. Given the probability of early have often been found to evidence the most
neurological involvement, a neurodevelop- attention challenges (Schatz & Puffer, 2007).
mental perspective appears essential when it Noll and colleagues (2001), found signifi-
comes to conceptualizing the impact of SCD cantly lower scores in specific measures of
on a child (Schatz & McClellan, 2006). A attention (mental processing, working mem-
neurodevelopmental approach is useful in ory, rapid novel learning, verbal repetition,
integrating how SCD expresses itself over and error-prone behavior) in children with
the course of a child’s development, and how SCD than in matched controls. However,
findings of disease-specific attention impair- cluded that slower response speed is not a
ments have not always been supported (Craft core feature of SCD (Schatz, Finke, & Rob-
et al., 1993; Nabors & Freymuth, 2002; erts, 2004). The rate at which a child pro-
Tarazi, Grant, Ely, & Barakat, 2007). Mul- cesses input can have a strong impact on at-
tiple dimensions of the illness, including its tention, as slower speeds are likely to lead
socioeconomic, psychosocial, and neuropsy- to the appearance of inattentiveness, failure
chological aspects, are likely to contribute to to fully process all available input, and inac-
challenges in attention function. curate working memory. Slower processing
Many studies have identified physiological thus has a negative impact on academic per-
correlates of attention and self-regulatory formance as well as social success.
difficulties in SCD. Craft and colleagues Deficits in impulsivity and self-regulation,
(1993) found higher levels of impulsivity/ as well as in intellectual functioning (see
intrusive errors and reduced self-regulation below), are likely to be associated with in-
in subjects with anterior lesions than in a creased externalizing behavioral challenges
healthy sibling control group. The severity (Schatz & McClellan, 2006; Thompson et
and persistence of chronic hypoxia (anemia, al., 2003). Children with poor self-regulatory
sleep hypoxia, reduced pulmonary function) control and limited problem-solving abili-
in SCD seems to be associated with impair- ties are likely to have greater difficulties in
ments of attention and working memory navigating the academic and social environ-
(Bernaudin et al., 2000; Brown et al., 1993; ments, with weaker coping skills and frus-
Noll et al., 2001; Schatz, Finke, & Roberts, tration tolerance than their peers. Deficits
2004; Steen et al., 1999; Steen, Miles, et al., in vigilance and impulse control have other
2003). Patients with increased frontal lobe strong academic implications (Nabors &
involvement, regardless of pathophysiology, Freymuth, 2002): They may affect learning,
may be more likely to evidence attention and referral for resources, and teacher–student
self-regulatory impairments that interfere relationships.
with multitasking skills (Berkelhammer et Even in the absence of identifiable tissue
al., 2007). Damage to the anterior forebrain injury, deficits in verbal working memory
is a common finding; it has a negative im- and processing speed have been identified
pact on broad aspects of attention, memory, (Bernaudin et al., 2000; Schatz, Finke, et
and other executive skills, as well as on spe- al., 2002; Steen et al., 2003). Deficits in au-
cific functions of selective attention, vigi- ditory processing (Schatz & Roberts, 2005)
lance, shifting set, planning, organization are likely to impair initial attention and
of thought/behavior, and error monitoring subsequent encoding of verbal information,
(Brown et al., 2000; Craft et al., 1993; De- interfering with immediate and sustained at-
Baun et al., 1998; Schatz et al., 1999; Schatz tention to verbal input as well as with so-
& Puffer, 2007). There is also evidence that cial information processing. An early report
higher blood flow velocity in the midcerebral from the CSSCD (Wang et al., 2001) found
artery is associated with lower verbal func- significantly lower performance on mea-
tioning, and specifically with weaker audi- sures of working memory and new learning
tory working memory (Kral et al., 2003), in children with HbSS who had experienced
which can interfere with auditory attention silent infarcts, compared to those without
and processing. abnormal imaging.
Strokes, like many other neurological in- The prevalence of identified attention dif-
juries, commonly result in difficulties with ficulties in neuropsychological testing and
attention and concentration (DeBaun et al., behavioral reports suggests the importance
1998; Schatz et al., 1999). Interestingly, at- of screening for these issues, beginning quite
tention seems to be affected regardless of early in life. There are presently few reliable
the volume of injury from stroke (Schatz et measures to assess specific attention func-
al., 1999), and is thus apparently a highly tion in very young children, but constructs
vulnerable neurocognitive construct in the such as response latency or duration of vi-
pathophysiology of SCD. Whereas some sual focus might be targeted and measure-
research has identified stroke-associated ments developed. DeBaun and colleagues
impairments in visual processing speed (Na- (1998) found patient performance on the
bors & Freymuth, 2002), others have con- Test of Variables of Attention (McCarney
& Greenberg, 1990) to be highly sensitive or other less obvious pathophysiological as-
to identification of previously unidentified pects of SCD is still developing. Recent de-
silent stroke, suggesting that this may be an velopments in MRI technology have shown
important screening tool for identifying at- greater sensitivity in identifying subtle focal
tention challenges and potential silent stroke brain injury, although comprehension of the
in this population. neurocognitive correlates to particular le-
sion sites or types has not completely caught
up. Conclusions in this area are additionally
General Intellectual and
complicated by a young brain’s ability to re-
Neurocognitive Development
organize function.
Many early studies compared the intellectual To best understand the causal factors of
status of patients with SCD and healthy peers; cognitive challenges in SCD, identifying the
however, discrepancies were commonly con- developmental pattern of onset as well as
founded by racial, economic, disease-state- the most vulnerable patient subgroup(s) or
related, or cohort issues. For this reason, time period(s) is critical. It is also essential
research began to turn toward comparing to early identification and specified inter-
patients with SCD to their healthy siblings, vention that might ameliorate the negative
to control for these threats to internal va- impact. Thus far, evidence related to the de-
lidity. Even with such controls, subsequent velopmental impact of SCD has been incon-
studies continued to find lower overall scores sistent. There were some earlier findings that
in intellectual development in children with the neurocognitive impact of SCD becomes
SCD who had experienced stroke (Fowler et amplified with age (Brown et al., 1993;
al., 1988; Gold, Johnson, Treadwell, Hans, Fowler et al., 1988; Wang et al., 2001), but
& Vichinsky, 2008; Kramer, Rooks, & Pear- research attempting to identify specific age-
son, 1978; Listianingsih, Hariman, Griffith, related dynamics did not come to any firm
Hurtig, & Keehn, 1991; McCormack et al., conclusions (Noll et al., 2001; Steen et al.,
1975), as well as those who had not (Schatz, 1999; Swift et al., 1989; Wasserman, Wili-
Finke, et al., 2002; Steen et al., 2005, Steen, mas, Fairclough, Mulhern, & Wang, 1991).
Miles, et al., 2003). More recent studies have begun to elucidate
Early researchers knew that CNS pathol- age-related factors in the intellectual func-
ogy was associated with SCD. As previously tioning of children with SCD. Evidence of
stated, hypothesized mechanisms leading silent stroke or arterial stenosis has been
to neurocognitive impairment in children identified in the MRIs of even very young
with SCD included microinfarction, anemia children (4 years and under) (Wang et al.,
and related ischemia, and nutritional defi- 1998), and declines in cognitive perfor-
ciencies (Brown, Armstrong, & Eckman, mance have been recognized in the young-
1993; Powars, Wilson, Imbus, Pegelow, est patients with SCD, including preschool-
& Allen, 1978). But they also understood age children (Tarazi et al., 2007), toddlers
that other factors were affecting cognitive (Thompson, Gustafson, Bonner, & Ware,
performance, such as recurrent school ab- 2002), and infants (Hogan et al., 2005).
sence, socioeconomic status, the impact of The magnitude of IQ difference from peers
a chronic illness on family functioning, and increases from toddlerhood to preschool
illness-related psychological issues (mood, age (Schatz & Roberts, 2007; Thompson
adjustment, coping skills, etc.) (Hurtig & et al., 2002), as well as from late childhood
Park, 1989; Hurtig & White, 1986). Un- into early adolescence (Hogan et al., 2006;
derstanding which mechanisms place chil- Schatz, Finke, et al., 2002; Wang et al.,
dren with SCD at what type of neurocog- 2001). Researchers have increasingly recog-
nitive risk is persistently evolving, but still nized that subtle physiological consequences
not fully realized. Schatz and colleagues of the illness, along with the psychosocial
(1999) even suggested that specific cognitive impact of SCD (living with a chronic ill-
profiles might be associated with various ness, painful crises, school absence, socio-
CNS lesion sites. The general neurocogni- economic status, financial burdens, etc.),
tive impact of stroke in patients with SCD jointly lay the foundation of compromised
appears well accepted and understood, but neurocognition that appears to begin quite
understanding of the impact of silent stroke early in life.
Early concerns that the pathological sickle Intellectual testing also revealed significantly
cell hemoglobin might be related in and of it- lower Full Scale IQ scores (borderline range)
self to lower intellectual status have received than in sibling controls (low-average range)
various levels of support in research find- in children with normal conventional MRI
ings. It was known early that the gene for as well as quantitative MRI. Further sup-
abnormal hemoglobin had less of an impact porting these findings was a study by Pow-
on patients who had heterogeneous states of ars and colleagues (1999), who compared
SCD or who were carriers of the trait, and groups of children who had either no neuro-
a logical presumption seemed to follow that logical symptoms or only soft neurological
they were also less neurocognitively compro- signs, using MRI and PET scans along with
mised than those with the homogeneous gen- neurocognitive assessment. Children with
otype. However, as mentioned previously, normal MRI and abnormal PET scans had
some trait carriers are susceptible to health IQ scores that fell in the low-average range
complications in rare instances, which leads (one standard deviation below the popula-
to this question: Are there neurocognitive tion norm), whereas the children with nor-
deficits associated with being an SCD trait mal MRI and PET scans had IQs within the
carrier? Wasserman and colleagues (1991) average range. Additional neuropsychologi-
matched patients with SCD to sibling con- cal deficits were identified in school achieve-
trols on intellectual, academic, and neurop- ment and psychomotor speed.
sychological measures. Siblings with sickle This recognition of the risk of subtle neu-
cell trait (HbAS) performed no differently rological impact and consequent neurocogni-
from normal-hemoglobin siblings (HbAA); tive sequelae began to spur significantly more
this supported the findings of previous re- research in the subsequent decade. Gold and
searchers (Kramer et al., 1978; McCormack colleagues (2008) found that 82% of their
et al., 1975), who had hypothesized that the sample of patients with SCD and evidence of
abnormal hemoglobin found in SCD and stroke had Full Scale IQs one or more stan-
sickle cell trait was not the primary factor dard deviations below the mean, whereas
in lower intellectual and academic perfor- 50% of those with silent stroke scored one
mance. However, later research again sug- or more standard deviations below the mean
gested that sickle cell trait might predispose for Verbal IQ, and 62.5% of those with si-
carriers to an increased risk of vascular ab- lent stroke scored one or more standard de-
normalities and stroke (Steen, Emudianughe, viations below the mean for Performance
et al., 2003). IQ. However, for children with SCD and no
In one of the landmark studies examining evidence of infarct, 45% still scored one or
the impact of silent stroke on neurocogni- more standard deviations below the mean
tive functioning, Armstrong and colleagues for Verbal IQ, and 35% scored one or more
(1996) found that children with SCD and standard deviations below the mean for Per-
a history of overt stroke had significantly formance IQ (compared to 16% in the gener-
lower neuropsychological scores than chil- al population). An increasing amount of re-
dren with silent strokes or children without search has thus examined the prevalence and
MRI abnormality. However, children with potentially subtle neurocognitive impact of
silent strokes had significantly lower scores understated pathophysiology in a high per-
than children without MRI abnormality in centage of patients with SCD by early adoles-
arithmetic, vocabulary, visual–motor speed, cence (Bernaudin et al., 2000; Brown et al.,
and coordination. Such findings were among 2000; Wang et al., 2001). One study (Knight,
the first to bring to light the possibility that Singhal, Thomas, & Serjeant, 1995) found
children without overt stroke remained at significantly lower IQ in adolescents with
risk for neurocognitive deficits, and that neu- HbSS, which was attributed to the effects of
ropsychological testing might identify the early nutritional deficits on physical growth
weaknesses even in the absence of positive and cognitive development. Unfortunately,
neuroimaging findings. Steen and colleagues there has been little subsequent research on
(1998) used quantitative MRI to identify en- how micronutrient deficiencies in SCD may
cephalomalacia in the cortical gray matter of be related to neurocognitive development.
patients with SCD who had normal clinical In a large prospective study, Bernaudin
exams and normal conventional MRI scans. and colleagues (2000), found significant-
ly impaired Full Scale and Performance sensitive neuroimaging in an attempt to di-

IQs in a combined sample of patients with rectly evaluate the specific pathophysiology
SCD and a history of overt stroke, and of SCD outside of stroke.
language-specific IQ deficits in those with Early neurological injury is commonly
silent strokes. A more unexpected finding associated with neurodevelopmental chal-
was that the Verbal, Performance, and Full lenges, particularly a failure to maintain a
Scale IQs were also impaired in patients developmental pace similar to that of peers.
who had severe chronic anemia or throm- The concept of plasticity suggests that cog-
bocytosis. Given this finding, the authors nitive impairment resulting from injuries
questioned the potential impact of early use that occur early has greater opportunities
of hydroxyurea (a medication that increases for recovery over time and can benefit from
blood concentrations of fetal hemoglobin, compensatory effects, although at the ex-
which reduces erythrocyte sickling) on the pense of other skills (Woods, 1980; Woods
long-term intellectual scores of SCD pa- & Teuber, 1973). However, neuronal pro-
tients. Indeed, Puffer, Schatz, and Roberts liferation and differentiation are active pro-
(2007) found significantly higher scores on cesses in children under the age of 2, and
tests of verbal comprehension, fluid reason- injury occurring during these phases is com-
ing, and general cognitive ability in children monly associated with poorer neurodevelop-
with SCD who were taking hydroxyurea mental outcome than injury occurring dur-
than in those who were not. Test perfor- ing the synaptic pruning phases (ages 2–7)
mance was presumed to be associated with (Schatz & McClellan, 2006). Early damage
improved CNS oxygenation and reduced to neuronal structure and organization has
fatigue or episodes of pain. As the recogni- a long-term negative impact on neurocogni-
tion of the early neurocognitive impact of tive operation, leading to greater functional
SCD has increased, early identification and cognitive and behavioral impairment over
intervention are being advocated. The use of time. Impairments in the cognitive skills
chronic transfusion therapy not only clearly that are not expected early in development
reduces risk of subsequent stroke, but may can be difficult to identify or discriminate at
also interrupt the developmental neurocog- first; however, these deficits become greater
nitive regression noted in many patients with liabilities as the comparative peer group nat-
SCD (Kral et al., 2006). Early identification urally acquires the integrative capacities that
of neurocognitive issues has been advocated come with myelination and learning.
and even recommended by numerous re- The cumulative impact of the pathophysi-
searchers to identify patients who are at risk ology of SCD must be considered along with
of or already evidencing early signs of neu- development. Undoubtedly, stroke has an
rocognitive compromise (Armstrong et al., immediate and long-term negative impact
1996; Gold et al., 2008). on neurocognitive functioning. However,
Studies examining the intellectual func- repeated neurological insults of any type are
tioning of patients with SCD have not con- typically associated with increasing cogni-
sistently used neuroimaging as a criterion tive, learning, and behavioral difficulties.
for subject selection, and have sometimes Children who have experienced at least one
relied only on information from medical re- stroke have an average subsequent reduction
cords to determine stroke history. Because in IQ scores of 10–15 points (Schatz et al.,
children with unidentified silent strokes may 2001; Schatz & McClellan, 2006; Schatz &
have been included in such studies, there Puffer, 2007; Wang et al., 2001), and those
have been concerns that their findings might with larger lesions have more significant IQ
overestimate the true negative neuropsy- decrements than those with minimal enceph-
chological impact of SCD. However, in a alopathy do (Schatz, White, Moinuddin,
meta-analysis, Schatz, Craft, and colleagues Armstrong, & DeBaun, 2002). Such changes
(2002) found the effect size of inclusion of in intellectual functioning are likely to affect
patients with unidentified silent strokes to academic, social, and occupational access,
be small and probably noncontributory to performance, and attainment. Unfortunate-
group differences. Nevertheless, recent stud- ly, SCD is a disease of recurrent risk and in-
ies have begun to define subject populations jury. Just as the effects of repeated traumatic
with more caution, while additionally using brain injury are diffuse in nature, recurrent
silent infarcts seem to be associated with may contribute to changes in intellectual per-
declines in general intellectual functioning formance. Using voxel-based morphometry,
over time, which probably result from more Baldeweg and colleagues (2005) identified
specified neurocognitive impairments (Kral deep anterior and posterior white matter ar-
et al., 2003, 2006; Schatz et al., 1999). In terial border zone abnormalities in children
addition, the relationship between the extent both with and without identifiable silent in-
or recurrence of neurological damage and farct. In addition, these children were found
cognitive impairment is proportional. The to have lower IQ scores, regardless of the
impact of repeated silent stroke and non- presence of visible lesions. Using data from
stroke-related neurological impairment may the CSSCD, Wang and colleagues (2001)
relate both to its diffuse nature and to the found that over 10 years of data collection,
level of cumulative impairment (Armstrong there was a progressive decline in IQ scores
et al., 1996; Bernaudin et al., 2000; Wang for children with SCD even when their MRI
et al., 2001). findings were normal. Gold and colleagues
Thompson and colleagues (2003) docu- (2008) also found that children without
mented reduced cognitive functioning over evidence of infarct evidenced more intellec-
the period of 6 months to 3 years of age tual challenges than the normal population.
in children with SCD. Schatz and Roberts Findings of lower IQ in children without ab-
(2007) also identified age-related decline normal neuroimaging has raised questions
from 12 to 40 months of age in language and regarding other pathophysiological factors
motor skills in patients with SCD. Further- inherent in SCD that might have an impact
more, declining IQ scores with age have been on neurocognitive development. Chronic hy-
extensively documented in the SCD literature poxia to the brain has been repeatedly impli-
(Kral et al., 2003; Steen et al., 2005; Wang cated as a subtle cause of reductions in neu-
et al., 2001). With the goal of determining rocognitive performance over the course of
the meaning, rather than only the presence, development. Hogan and colleagues (2006)
of SCD’s effects on cognitive functioning, found that lowered IQ was a function of ab-
Schatz, Finke, and colleagues (2002) con- normal oxygen delivery to the brain (result-
ducted a large meta-analysis of studies that ing from reduced oxyhemoglobin saturation
examined cognitive performance over time and increased cerebral blood flow velocity),
in children with SCD. They found a reliable although the relationship between cerebral
consistency in multiple studies identifying blood flow velocity and IQ was significant
a decrement (4–5 standard score points) in only for Verbal IQ scores. Recently, Hogan
intellectual test scores in the absence of cere- and colleagues (2006) found that children
bral infarct—fi ndings that have been; subse- with SCD as young as 3–9 months of age
quently confirmed (Steen et al., 2005, Steen, evidenced higher indicators of neurocogni-
Miles, et al., 2003). The authors concluded tive dysfunction that were correlated with
that reductions over time were related to the hematocrit, suggesting an early onset of
pathophysiological impact of SCD as well as neuropsychological impairments from that
the impact of chronic illness on neurocog- pathophysiology of SCD. Excluding sub-
nitive development. Kral and colleagues jects with silent infarcts by use of MRI,
(2006) additionally found evidence that chil- Bernaudin and colleagues (2000) and Steen
dren without a history of overt stroke are at and colleagues (1999) still found a notable
risk of cognitive decline with age not only relationship between hematocrit and cogni-
in global intellectual functioning, but also in tive functioning. Higher values of cerebral
specific skills (e.g., verbal memory, sustained blood flow velocity, as measured by TCD,
attention, cognitive flexibility, and visual– have been found to be associated with lower
motor integration). Confirming the findings scores in verbal intelligence and executive
of developmental regression in children with abilities (Kral et al., 2003).
SCD, Schatz and Buzan (2006) also found The increased level of neurocognitive vari-
that age had a negative correlation with inability (rather than only performance defi-
tellectual test scores in children with SCD cits) in children who have experienced silent
compared to those without. stroke, have larger volumes of tissue involve-
Unidentified neurological injury in patients ment, or have abnormal MRI abnormalities
with SCD who have normal neuroimaging is an important finding of studies examining
intellectual functioning (Grueneich et al., memory functions. Their findings indicated

2004; Ris, Grueneich, & Kalinyak, 1995; a specific relationship between frontal lobe
Schatz et al., 1999). In children with SCD compromise and attention and other execu-
who have no evidence of overt CNS disease, tive impairments, as well as between diffuse
the same level of variability has not been injury and visual–spatial and language im-
identified (Noll et al., 2001). Clearly the pairments.
presence of CNS pathology, even if uniden-
tified, is related to some level of global dys-
Academic Achievement
function. In any neurologically based cog-
nitive dysfunction, it is often the variability There is a historically strong link between
that is the fundamental disability. Children school attendance and academic achieve-
with SCD have subtler, but broader and less ment in the general population. Children
predictable, neurocognitive profiles that are with chronic illness overall have lower lev-
not promptly identified by grades, classroom els of academic achievement than their peers
performance, or criterion-based test scores. without such illness, even in the absence
This variability and lack of predictably can of learning disabilities (Martinez & Erci-
unfortunately prolong identification of defi- kan, 2009); this is often attributed to days
cits and delay intervention because subtle of illness and number of absences. Many
impairments are missed or misattributed students with SCD will miss a considerable
to another factor (e.g., immaturity, gender, number of school days or have SCD-related
school absence). Such a risk emphasizes difficulties within the classroom environ-
the importance of early and thorough neu- ment (Cant-Peterson, Palermo, Swift, Bebee,
ropsychological assessment of individual & Drotar, 2005). However, some research
strengths and weaknesses, to inform and specifically on SCD has indicated that fac-
guide cognitive and academic intervention. tors other than school absence seem to con-
Variability in cognitive development may tribute to reduced academic achievement.
also be partially explained by the economic The number of missed school days has been
hardship that many children with SCD ex- associated with lower scores on intellectual
perience. A disproportionate number of chil- tests in children with SCD (Wasserman et
dren with SCD come from families in lower al., 1991); however, even prior to begin-
socioeconomic brackets, and poverty has a ning school, children with SCD evidence
well-documented impact on neurocognition lower performance in kindergarten readi-
in general and on developmental regression ness and academically relevant skills, with
with age in particular (Brown et al., 1993; or without a history of stroke (Chua-Lim,
Gustafson, Bonner, Hardy, & Thompson, Moore, McCleary, Shah, & Mankad, 1993;
2006). The psychosocial impact of poverty Steen et al., 2002). Schatz (2004) reviewed
has yet to be clearly discriminated from the the academic attainment (which he defined
neurological impact of SCD. as grade promotion and need for remedial
Importantly, researchers have begun to services) of a population of children with
raise the issue that relying solely on IQ tests SCD who had no neurological documen-
as broad measures of the cognitive challeng- tation of stroke; he found that, compared
es present in SCD is not very likely to be sen- to peers, children with SCD had increased
sitive to specific neurocognitive dysfunction levels of grade repetition, and their achieve-
(Grueneich et al., 2004; Schatz et al., 1999). ment was significantly lower than their cog-
Global IQ measures are also not as sensi- nitive performance. Cognitive ability and
tive to age-related changes as are measures days of illness were predictors of attainment
of specific abilities, particularly memory problems. Psychosocial and disease-related
and executive functions (Steen, Miles, et al., factors (e.g., pain management, medical ap-
2003; Steen et al., 2005). Recognizing that pointments, self-esteem, delayed puberty
intellectual measures may provide a weak as- and growth, medication regimens, and fa-
sessment of specific cognitive deficits, Schatz tigue) can also affect not only attendance,
and colleagues (1999), used more specific but even attention and social and cognitive
neuropsychological measures to assess four performance in school (Bonner, Gustafson,
constructs of neurocognitive performance: Shumacher, & Thompson, 1999). Thus, al-
attention/executive, spatial, language, and though attendance is a key factor in achieve-
ment, the neurocognitive and psychosocial from neurocognitive to psychosocial factors.

factors within SCD potentially play a large Missed school days, physiological needs
role in the educational success (and probably (temperature regulation, adequate hydration,
in the subsequent occupational attainment) fatigue, etc.) and learning difficulties can im-
of this population. pair academic performance on a daily basis,
It is not difficult to draw a connection and ultimately can decrease overall achieve-
between the pathophysiology of SCD and ment and attainment. Stroke-associated
potential academic difficulties. Studies have impairments have indeed been identified in
indeed often found that children with SCD reading, math, and spelling achievement,
are more likely to be receiving some form of compared to that of peers (Nabors & Frey-
academic intervention, from special educa- muth, 2006; Schatz et al., 2001). Wang and
tion services to grade retention (Kral et al., colleagues (2001) found that patients with
2003; Schatz et al., 2001). Some studies ex- HbSS and silent infarcts had significantly
amining neuroimaging results and academic lower academic scores in math and read-
functioning have identified a relationship ing, as well as lower Verbal, Performance,
between abnormal findings and academic and Full Scale IQs, than patients without
difficulties (Armstrong et al., 1996; Kral et MRI abnormalities over a 5-year span. Both
al., 2003; Schatz et al., 2001), though oth- stroke-related and non-stroke-related neu-
ers have not (Brown et al., 2000; Gruenich rocognitive impairment are likely to impair
et al., 2004). Overt stroke appears to have long-term academic performance, psychoso-
a greater impact on academic achievement cial success, occupational attainment, and
than on intellectual functioning, particular- psychological functioning well into adult-
ly in mathematics (Armstrong et al., 1996; hood. The significant reduction in IQ scores
Schatz & Puffer, 2007; Wang et al., 2001). for children who have experienced stroke
Wang and colleagues (2001) found that chil- affects their academic attainment in 80%
dren with silent infarct scored lower than of cases (Schatz et al., 2001; Schatz & Mc-
those without evidence of infarct on aca- Clellan, 2006; Wang et al., 2001); however,
demic measures, but also found an average a large proportion of children with SCD and
decline of 0.9 points per year in children no history of stroke also have neurocogni-
with SCD and no evidence of infarct. tive challenges that create academic needs,
Certainly neurocognitive impairment does and these children may not be identified as
not occur in every student with SCD, but for in need of intervention (Cant-Peterson et al.,
those who do have these effects, awareness, 2005).
accommodation, and intervention are criti- The impairments in attention and mem-
cal to long-term educational success. Chil- ory that are among the most commonly
dren with various forms of SCD—across all reported neurocognitive consequences of
age groups and those with and without a neurological injury may be associated with
history of stroke—have high rates of learn- lower general academic performance in SCD
ing difficulties; these reflect the direct influ- (Schatz & Puffer, 2007). In particular, new
ence of neurocognitive challenges, as well as learning and organizational challenges are
the incidental effects of chronic illness and noted and compromise both acquisition as
recurrent school absences. Regardless of the well as access to previously learned informa-
source of their learning challenges, these tion. Lower skills in auditory discrimina-
children must be identified, as they have in- tion have been identified in students with
creased needs for academic accommodation. SCD screened for kindergarten readiness,
Measures of academic achievement have and these deficits may be associated with
been used in students with SCD to deter- difficulties in auditory attention, working
mine severity, CNS impact, and functional memory, and language processing within
outcome of the disease. However, measur- the classroom (Schatz, 2004; Steen et al.,
ing achievement along with academic at- 2002). The persistence of these impairments
tainment as defined above provides a more can lead to progressive changes in academic
inclusive appraisal of the educational impact achievement over time, particularly in com-
of SCD (Schatz, 2004). parison to peers. As peers progress through
The causes of academic difficulties are developmental refinement of learning tech-
unquestionably multifactorial, stemming niques and independent organization, and
develop increased capacity for focal and sus- math scores than those with silent infarct.
tained attention, children with neurological Children with silent infarcts consistently
compromise who are impaired in achieving had lower math scores than those with nor-
such developmental milestones fall further mal MRI scans, although differences were
and further behind their peers. not always significant. Noll and colleagues
The effects of SCD on reading acquisi- (2001) found significantly lower written cal-
tion and achievement have been the cause of culation scores in children with SCD than
some concern. Deficits in reading have been in controls. Many studies have included
repeatedly identified in children with SCD only screening of written calculation, rather
compared to matched peers (Brown et al., than more comprehensive assessments of full
1993; Fowler et al., 1988; Nabors & Frey- mathematical abilities (mental and written
muth, 2002; Noll et al., 2001; Sanders et al., computation, word problems, applied math,
1997; Swift et al., 1989), and children with sequential problem solving, etc.), so iden-
SCD who have had silent infarct have been tifying specific contributors to arithmetic
found to have lower reading achievement challenges will contribute to understanding
than those without (Armstrong et al., 1996; these deficits more specifically. Cohen and
Gold et al., 2008). Specifically (and predict- colleagues (1994) found that children with
ably), a history of left-hemisphere stroke has SCA who had experienced right-hemisphere
been associated with lower reading compre- stroke had difficulties in arithmetic skills, but
hension and spelling achievement scores in that those with left-hemisphere stroke had
children with SCD (Cohen, Branch, McKie, difficulties specifically in math calculation.
& Adams, 1994). Gold and colleagues (2008) Nabors and Freymuth (2002) also found that
found lower single-word reading and reading written calculation was consistently the low-
comprehension scores in children with overt est academic score (along with reading and
and silent stroke than in those without evi- spelling) in children with SCD, either with
dence of infarct. A weaker core vocabulary or without stroke. Although the differences
has been frequently identified, and certainly were deemed not statistically significant, the
may contribute to reduced reading skill (Noll authors did not discuss the clinical signifi-
et al., 2001; Schatz, 2004; Schatz, Craft, et cance of the findings that all children with
al., 2004; Wang et al., 2001). Auditory pro- SCD scored lower in mental and written
cessing (discrimination of phonemes) and calculation than sibling controls did. Many
reduced attention may also contribute to re- other studies have found low math scores in
ductions in early acquisition of reading skills patients with SCD, although these have not
(Schatz, 2004; Steen et al., 2001). Cognitive always been significantly discrepant from
difficulty alone cannot be held responsible those of controls (Fowler et al., 1988; Kral et
for the lower reading acquisition and perfor- al., 2003; Ogunfowara, Olanrewaju, & Ak-
mance of children with SCD; environmental enzua, 2005; Wasserman et al., 1991). Schatz
and family factors also must be considered. (2004) found in his meta-analysis that mean
Reading skills require conjoint development math scores on screening measures (typical-
of phonemic awareness, fluency, and listen- ly involving only written calculation) were
ing comprehension skills that are applied to most often lower, but that the effect size was
written text in the framework of frequent nonsignificant. Studies assessing both writ-
practice. Consequently, such factors as fam- ten calculation and applied math problems
ily literacy skills, access to books, and par- might provide more information regarding
ent–child interaction will have an impact on these common difficulties. Swift and col-
readiness to read and long-term reading pro- leagues (1989) found a clinically significant
ficiency; these may be areas of vulnerability discrepancy in both calculation and applied
in this population because of its dispropor- math scores between children with SCD and
tional level of lower socioeconomic status. controls. Wang and colleagues (2001) found
Math difficulties have also been commonly that scores in broad math skills were lower
identified in studies examining the academic than in broad reading, that children with
impact of SCD. Armstrong and colleagues stroke scored significantly lower on math
(1996) found that children with SCD with tasks than those with silent stroke did, and
overt stroke had significantly lower mental that both groups scored significantly lower
calculation, written calculation, and applied than those with normal MRI.
Similar to intellectual functioning over psychologists, special educators, and school

time, there appears to be a risk of decline in nurses, who can advocate for these children’s
math achievement over time in patients with needs within the school and classroom. In
SCD (Wang et al., 2001); again, this may be fact, it would best benefit the broad popu-
associated with challenges in school atten- lation with SCD to be screened for specific
dance, but also with neurocognitive issues neuropsychological functioning, in order for
in attention, problem solving, and psycho- those in need to access state-funded early
motor speed. However, prevention of stroke intervention services prior to the age of 3,
and intervention after stroke may serve a and have access to special education services
protective factor. Kral and colleagues (2006) after age 3 according to the 2004 Individu-
found that performance on math and visu- als with Disabilities Education Improvement
al–motor integration tasks was stronger in Act (Armstrong, 2005). The routine use of
patients who were receiving chronic transfu- screening measures throughout school may
sion therapy after stroke than in those who help to identify students with SCD who
were not. would benefit from intervention at a younger
Among educators, there may be inad- age, and this in turn may decrease academic
equate awareness of the academic risks as- and behavioral issues that are usually exac-
sociated with chronic illness generally, and erbated with age. However, many families of
certainly SCD specifically. Consequently, children with SCD may not have access to,
resource allocation may be lacking (Day & or may not have the knowledge to seek out,
Chismark, 2006). If the number of days out- neuropsychological assessment either pri-
side the classroom is correlated with weak vately or through their local schools (Cant-
attainment, individualized academic inter- Peterson et al., 2005). Preventative measures
ventions in multiple environments may be (e.g., parent education about the neurocog-
quite critical to optimal academic achieve- nitive and academic issues and risks in SCD,
ment. Children with SCD who miss school as well as school- and family-based interven-
due to illness may benefit from increased in- tion programs to minimize environmental
dividual interventions either while hospital- risks and maximize academic achievement)
ized, while homebound, or on their return have begun, but more are needed. Koontz,
to the classroom, to minimize the negative Short, Kalinyak, and Noll (2004) success-
impact of absence combined with learning fully pilot-tested a school-based intervention
challenges. program intended to educate peers and teach-
School districts in geographic areas that ers about SCD. The intervention resulted in
have high populations of children with SCD increased knowledge and perceived comfort
are more familiar with these children’s prob- in peers and teachers, as well as fewer school
lems of pain crises, decreased stamina, need absences in the students with SCD.
for medically based accommodations, and
school absences. However, less ethnically di-
Sensory, Motor, Visual–Spatial,
verse school districts may not be as informed
and Visual-Perceptual Skills
or experienced. In addition, educational
definitions or state laws may not reflect cur- An increased presence of fine motor, tactile,
rent scientific and medical knowledge about visual-perceptual, and visual–motor integra-
the direct impact of SCD on brain function. tion impairments has been found in children
The fact that the pathophysiology of SCD is with SCD, although the data are variable
associated with neurological injury may not and sometimes have not isolated the con-
be known to school personnel, and conse- struct of fine motor skills from those of spa-
quently some of these children may be served tial and perceptual abilities for comparison.
under Section 504 accommodation plans Visual–spatial deficits do appear to occur
as students with health issues, rather than more frequently than language deficits, re-
under individualized education programs gardless of age at injury (Armstrong et al.,
as children with academically relevant dis- 1996; Bernaudin et al., 2000; Schatz et al.,
abilities and health concerns. Parents and 1999; Wang et al., 2001). Several studies
medical providers may need to shoulder the have also noted that children with SCD have
responsibility of sharing this information significantly poorer performance on mea-
with school personnel, particularly school sures of visual–motor integration and atten-
tion (Schatz, Finke, et al., 2002; Wasserman global impairment in verbal abilities (expres-
et al., 1991). Schatz, Craft, Koby, and De- sive language, verbal and auditory memory,
Baun (2000) found that patients with SCD oral reading) consistent with aphasia. [PC6]
who had silent infarcts but no evidence of On the other hand, children with specific
overt infarct obtained lower visual–spatial right-hemisphere stroke have been found to
and visual–motor scores than sibling con- evidence relative sparing of verbal functions
trols, who evidenced no abnormalities. (Schatz, Kraft, et al., 2004).
Spatial organization and processing defi- Although this and other studies have found
cits have also been found to be more likely in impaired language function in children with
children with SCD who have a history of dif- SCD, not all are specifically related to left-sid-
fuse injury (Craft et al., 1993; Schatz et al., ed cerebral injury. Hariman, Kirkham, Hur-
1999). Language skills are associated with tig, and Keehn (1991) identified low-average
left-hemisphere control in the majority of to impaired levels of language functioning in
the population, whereas visual–spatial func- children with a history of nondefined stroke,
tions are subsumed under multiple integra- and concluded that there were more psy-
tive brain regions. Visual–spatial functions chosocial than physical consequences. Post-
are consequently often considered “more stroke reductions in Full Scale IQ, reading,
vulnerable” to any neurological injury. Al- spelling, and written language all clearly
though larger lesions are clearly associated suggests an underlying language weakness.
with identifiable impairment, many children Listianingsih and colleagues (1991) found
may have subtle deficits that negatively af- reduced language functions in children with
fect their abilities to attend to, organize, and SCD who did not have a documented his-
sequence visual information, and to under- tory of stroke, suggesting the possibility of
stand relationships, directionality, dimen- either inherent neuropathology or the oc-
sionality, and orientation; these deficits can currence of silent stroke. Wasserman and
subsequently impair their ability to under- colleagues (1991) also found language dif-
stand charts, copy from the board, or line up ficulties on the Luria–Nebraska, but did not
math problems. Overt stroke, even regard- find supportive evidence of language com-
less of specific location, appears to have a promise on the Wechsler Intelligence Scale
greater impact on Performance IQ than on for Children—Third Edition. Cohen and
Verbal IQ (Armstrong et al., 1996; Bernau- colleagues (1994) found significantly lower
din et al., 2000; Wang et al., 2001). Craft verbal function in a combined SCD group
and colleagues (1993) found that children with stroke than in either a sibling control
with silent diffuse stroke showed signifi- group or an age-referenced normative group.
cantly more impairment on spatial measures Children with abnormal MRI findings have
than did either children with anterior lesions been found to make more errors during rapid
or healthy siblings. Understandably, injury naming (Brown et al., 2000), although the
in the posterior parietotemporal regions, as role of processing speed, impulsivity, poor
well as the total volume of the stroke, has inhibition, and poor self-monitoring in such
been associated with the severity of subse- a task should also be considered.
quent visual spatial impairments (Craft et Interestingly, in a survey of parents of in-
al., 1993; Schatz et al., 1999). fants and preschoolers with SCD, there was
more reported concern about physical devel-
opment than about language development
Language Skills
(Gentry, Hall, & Danier, 1997). However,
Although Verbal IQ deficits have frequently language developmental milestones at young-
been reported for school-age children with er ages may not be generally understood by
SCD, a more specific profile of language nonprofessionals, and may thus be underre-
abilities in SCD has become clearer within ported. Because academic skills are highly
the past decade. Available studies suggest dependent on receptive and expressive abili-
that both lesion volume and location are ties, language-based impairments that may
associated with specific language deficits be present at the beginning of formal school-
(Berkelhammer et al., 2006). As expected, ing are likely to have a negative impact on
Cohen and colleagues (1994) found that acquisition of reading, spelling, and writing
patients with left-hemisphere stroke had a skills as well as social-interactive abilities.
More subtle language-based impairments that higher blood flow velocity in the mid-
may not be apparent until later years, when cerebral artery is associated with lower ver-
both academic and social demands increase bal functioning, as well as with weaker sus-
and become more complex. Schatz and Rob- tained attention and other executive skills
erts (2007) found that a disease-related im- (Kral et al., 2003).
pact on language factors was not statistically
supported, although the authors did find
Organization, Sequencing, Learning,
that younger groups showed higher language
and Memory
functioning than older groups, indicative of
age-related language decline. The authors The evidence of weaker attention in children
determined that although detailed language with diffuse and anterior stroke suggests
factors at toddler and preschool ages may be that the process of acknowledging, acquir-
too subtle to detect with current measure- ing, organizing, retaining, and recalling in-
ments, indications of language issues may formation is likely to be compromised. The
be present at these early ages. At the time ability to learn and access knowledge from
of kindergarten entry, children with SCD memory requires a sequence of attending,
already evidence significantly lower skills in organizing, planning, and storing informa-
auditory discrimination—a skill that is criti- tion in an efficient and accessible style. If a
cal to developing the foundational phonic child cannot attend efficiently, then impair-
abilities for reading and spelling, as well as ments in learning and memory are likely
receptive language and attention (Steen et to result, but these may or may not reflect
al., 2002). Given the high rates of attention specific memory deficits. Weak organization
and other executive impairments in SCD, and sequencing can subsequently interfere
language-based difficulties may be associat- with efficient learning and memory. Mem-
ed with difficulties in verbal working memory impairments are sometimes presumed
ory and auditory processing (Bernaudin et when another underlying deficit occurs in
al., 2000; Schatz, Finke, et al., 2002; Schatz a related neuropsychological function. True
& Roberts, 2005; Steen, Miles, et al., 2003). memory deficits should be isolated from
Schatz, Puffer, Sanchez, Stancil, and Rob- other impairments that lead to reduced
erts (2009) compared language-processing learning efficiency, as the interventions are
skills (semantic, syntactic, and phonologi- likely to be different.
cal processing) of 5- to 7-year-old children Frontal regions play a major role in mem-
with SCD at high or low neurological risk to ory and learning, including skills of organi-
the skills of peers without SCD. Children at zation, planning/strategy development, and
high risk evidenced deficits in all language- mental manipulation of information that
processing domains, whereas those at low facilitate encoding and access from long-
risk did not evidence any language deficits. term storage. Consequently, the association
This brings into question the possibility of of memory and executive skills is quite im-
disease-related factors that may affect lan- portant in general neurocognitive function.
guage development, as well as highlighting Frontal lobe injury in SCD may have a spe-
the early-onset negative impacts that can cific impact on learning and memory, which
occur in SCD. Multiple studies have reported would have broad neurodevelopmental im-
findings of developmental regression in lan- plications. Anterior forebrain lesions have
guage-based skills over time in patients with been specifically associated with commonly
SCD (Schatz & Roberts, 2003; Thompson et identified deficits in memory, attention, and
al., 2002; Wang et al., 2001); however, these executive skills in general (Schatz & Puffer,
findings have also been associated with psy- 2007).
chosocial and environmental risk factors, In particular, verbal working memory
rather than with disease severity alone. has been repeatedly found to be particu-
Severe anemia has been implicated in re- larly impaired in patients with SCD. White,
duced verbal skills, attention, and working Salorio, Schatz, and DeBaun (2000) found
memory in children with SCD (Bernaudin et that working memory deficits were specific
al., 2000; Brown et al., 1993; Schatz, Finke, to the type and location of infarct in SCD.
& Roberts, 2004; Steen et al., 1999; Steen, For children with SCD and diffuse infarcts,
Miles, et al., 2003). There is also evidence verbal working memory span was reduced
in comparison to that of controls with SCD Other Executive Functions

and without infarct. For those with ante-
Executive functions are those operations
rior or posterior infarcts, the ability to re-
that direct and regulate thought and be-
hearse longer segments of verbal informa-
havior, including obvious social pragmat-
tion was negatively affected in comparison
ics and behavior, as well as subtle cognitive
to controls. Reed and colleagues (1999)
demonstrated verbal memory deficits in processes and integration and management
each of their subjects, who were also found of various skills. Young children are not ex-
to have white matter lesions on PET scans. pected to have adequate self-regulation, as
Reduced efficiency in rehearsing verbal in- their managerial/self-monitoring skills are
formation during initial learning, and poor under development. Inappropriate execu-
retrieval of verbal information, have both tive skills are often viewed as immaturity,
been identified; these would clearly have attention-deficit/hyperactivity disorder, or
an impact academic achievement and prog- delayed social development, and children
ress (Brandling-Bennett et al., 2003; White, with such problems are expected to “catch
Saloria, Schatz, & DeBaun, 2000). Frontal up” with time. Children who have experi-
lobe injury in SCD has also been related to enced early CNS injury often recover acutely
difficulties with manipulating verbal infor- and appear to perform adequately or to have
mation in working memory and to poorer only subtle deficits in preschool and primary
retrieval of verbal information on memory grades. Families and medical personnel often
recall trials (Brandling-B ennett et al., 2003; focus on the apparent recovery from acute
White et al., 2000). Kral and colleagues injury and unintentionally downplay subtle
(2003) found that abnormal TCD measures impairments in comparison to the original
were predictive of weaker auditory working trauma. Some children are seen as awkward
memory. Noll and colleagues (2001) com- or different, but not “impaired,” and conse-
pared children with SCD and no evidence of quently do not receive interventions during a
stroke with peers without a chronic illness, critical period of development. It is not until
finding significantly reduced working mem- later grades, when the executive functions
ory, speed of novel learning, and both verbal are socially and academically demanded,
and visually based short-term recall in the that the impairments become more obvi-
group with SCD. Specific strategic memory ous and less tolerable to peers, parents, and
processing deficits have also been found in teachers. Increasing social, behavioral, and
children with SCD who had frontal lobe in- academic problems, unregulated by an im-
farct (Brandling-Bennett et al., 2003). Poor- paired executive system, pose greater threats
er long-term episodic memory, novel verbal to successful development.
learning, short-term independent recall of As noted earlier, notable evidence of fron-
verbal information, and working memory tal lobe abnormalities has been found in
were found in children with SCD who had patients with SCD and stroke (Brown et al.,
frontal infarct, compared to those without 2000; Gold et al., 2008). Reports regard-
evidence of infarct. Recognition and cued ing the number of patients who have sus-
recall were consistent between groups, high- tained frontal lobe damage are remarkable:
lighting the negative impact of SCD-related Schatz and colleagues (1999) identified 86%
impairment on new learning. Whereas the of their subjects with stroke as having sus-
group with SCD–frontal infarct and the tained frontal injury; Brown and colleagues
controls had similar strategy development (2000) reported that 96% of children with
during new learning, the former group did overt and silent stroke had sustained fron-
not subsequently use these strategies during tal lobe damage; and a more recent study
independent recall and were dependent on found that 59% of patients diagnosed with
cued recall strategies to access knowledge. infarct had sustained cortical frontal lobe
Children receiving chronic transfusion ther- damage (Gold et al., 2008). Examining cor-
apy who also had higher TCD values per- tical thickness at various age levels, Kirk and
formed better on verbal memory tasks (Kral colleagues (2009) found notable thinning in
et al., 2006), which is consistent with the multiple cortical areas, particularly in the
presumed role of oxygenation in learning adolescent group. The precuneus and pos-
and memory. terior cingulate gyrus were most affected.
Although neuropsychological data were not resulting from days of illness, academic at-
collected, the authors presumed that corti- tainment issues, and frequency of school
cal and subcortical connections between the absence. Deficits in facial recognition and in
parietal and frontal lobes might be at the auditory and visual processing of emotions
foundation of many executive impairments (vocal prosody, facial expressions) have been
in SCD. The precuneus region of the parietal identified in children with overt stroke (Boni,
lobe has high connectivity and has been im- Brown, Davis, Hsu, & Hopkins, 2001).
plicated in such higher-order cognitive tasks Children who experienced overt stroke were
as visual representation, episodic memory found to have more difficulty in interpreting
retrieval, perspective taking, and internal ambiguous verbal and nonverbal cues, which
representation of self (Cavanna & Trimble, would probably negatively affect their re-
2006), all of which involve executive skills. sponses to the increasingly socially complex
Schatz and Buzan (2006) found that ante- situations that occur with development. In
rior corpus callosum volume in patients with addition, children with SCD and stroke had
SCD did relate to deficits in attention and more difficulty reading facial expressions
executive skills (particularly motor control). and decoding emotional tone from voices
Higher blood flow velocity in the area of the than those with SCD and normal MRI find-
midcerebral artery has also been associated ings had (Boni et al., 2001). Furthermore, as
with weaker sustained attention and execu- mentioned previously, deficits in processing
tive skills (Kral et al., 2003). speed can also impair social skill develop-
Although the findings have been variable, ment in this particular population.
deficits in specific executive skills such as se- Identified neurocognitive challenges in
lective attention, problem solving, planning, SCD are presumably associated with subse-
decision making, judgment, and set shifting quent neurobehavioral difficulties. In fact,
have been recurrently identified (Gold et al., lower intellectual abilities can result in poor
2008; Schatz et al., 2001; Schatz, Finke, et coping skill development. On the other hand,
al., 2002). Higher levels of deficits in execu- higher levels of intellectual functioning have
tive functions are also consistently found been associated with lower reported levels of
after stroke in patients with SCD (Cohen et externalizing behavior problems (Schatz &
al., 1994). Schatz and Roberts (2007) used re- McClellan, 2006; Thompson et al., 2003).
sponse delay as a measure of executive func- Moreover, language deficits are often asso-
tion in toddlers and preschool-age children ciated with children’s difficulties in under-
with high- and low-neurological-risk SCD. standing verbal expectations and responding
The younger age group and lower-risk SCD to directions, as well as properly expressing
group made fewer errors, indicating better themselves. Children with attention impair-
working memory; they also evidenced better ments have difficulties in self-regulation and
self-regulation and “low-intensity pleasure” motivation that can also affect behavioral
(soothability and self-entertainment ability) compliance and response to intervention.
than the older and higher-risk groups did. Lastly, the broad area of executive deficits
Such findings are indicative of early-onset (see earlier discussions) can interfere with
self-regulatory difficulties that could play a behavioral compliance and frustration toler-
role in the development, learning, and be- ance.
havior of children with SCD. As noted throughout this chapter, general
neuropsychological functioning in SCD has
been found to be associated with socioeco-
Neurobehavioral and
nomic status (Brown et al., 1993; Schatz
Psychosocial Functioning
& Roberts, 2007; Thompson et al., 2002;
Perspective taking and other social and Wang et al., 2001). It is critical to consider
emotional processes have received less atten- the combined impact of disease state, bio-
tion than other neurocognitive challenges in medical risk factors and psychosocial risk
SCD. Social-cognitive deficits in SCD might factors because research has yet to identify
be presumed from the neurocognitive im- a predictable and consistent relationship.
pairments identified in attention, working Psychosocial factors have sometimes been
memory, language, and processing speed, as found to be better predictors of neuropsy-
well as the more psychosocial impairments chological performance than disease sever-
ity for preschool-age children (Tarazi et al., illness and a neurodevelopmental disorder;
2007), whereas Schatz, Finke, and colleagues researchers, clinicians, educators, and fami-
(2002) found that disease severity was a lies are all improving their grasp of the risks
predictor of cognitive functioning for chil- posed by SCD, as well as the interventions
dren in a low-socioeconomic status group. needed to optimize development. Clearly,
According to a review by Schatz and Puffer however, there is much more to understand.
(2007), there are more notable neurocogni- With the acknowledgment that the neu-
tive and academic challenges resulting from rocognitive effects of SCD can begin as early
stroke related to SCD than there are behav- as 6 months of age, there need to be more
ioral difficulties. Previous assessments of routine cognitive assessments of patients
behavioral issues in SCD have relied heavily with SCD in the clinics in which they are
on maternal report and have used measures managed, within their pediatricians’ care, or
that may be less sensitive to the unique fac- even in the educational setting. Routine as-
tors associated with neurological compro- sessment for early neurocognitive challenges
mise. The presence of behavioral challenges would open the doors for earlier intervention,
may actually be higher than is currently potentially decreasing the negative impact of
discussed in the literature. Given the high the disease on functional cognitive skills, and
rates of academic difficulties/attainment thus improving the developmental trajectory.
problems, economic disadvantage, stressors Because days out of school are so highly cor-
of living with chronic illness, and other neu- related with academic achievement, there
ropsychological limitations, the absence of is an obvious need for educational adapta-
behavioral challenges would be unexpected tions and accommodations to be provided
and quite different from other populations within the context of the variables inher-
with similar stressors. ent in chronic illness. Provision of adapted
Although many children with chronic ill- academic tutoring within the hospital and
ness have been found to have adjustment and home settings might minimize or alleviate
mood difficulties, rates of depression have the impact of missed instructional time. Im-
been found to be comparatively highest in proved education of academic personnel and
children with SCD (Key, Brown, & Marsh, students has already been shown to have a
2001). More specifically, these children have positive impact on the functional daily status
also been reported to have increased rates of children with SCD; such efforts require
of feelings of hopelessness. However, Yang, further investigation and implementation,
Cepeda, Price, Shah, and Mankad (1994) as well as expansion into the broad range of
noted years ago that fatigue and physical care providers, including families.
complaints may lead to higher false-positive There has been a notable expansion of
rates of depression in children with SCD. knowledge about the neuropsychological
Depressive and anxiety disorders are more impact of SCD in recent years. However, the
widespread among medically involved chil- complexities of the brain–illness relation-
dren and teenagers than among their peers, ship are great, and will be best understood
and comorbidity may have a negative im- by continuing this intensive pace of inves-
pact on medical outcomes and quality of life tigation. Neurologically based deficits that
(Benton, Ifeagwu, & Smith-W hitley, 2007). lead to specific areas of neurocognitive func-
Nonetheless, assessing emotional status in tion need to be better elucidated and perhaps
children and adolescents with SCD is ex- predicted. The impact of early identification
tremely important in the overall conceptual- of neurocognitive impairment on cognitive
ization of their neuropsychological profile. rehabilitation and its outcomes is also as yet
unknown in SCD. In addition, the role of
early treatment interventions in optimizing
Future Directions neurocognitive development, particularly
in Neuropsychological Research therapies such as hydroxyurea, needs to be
more fully investigated.
The understanding of the developmental The cultural implications of how patients
and neurocognitive impact of SCD has ad- with SCD are managed, educated, and sup-
vanced significantly in the past decade. SCD ported in the community require more in-
is now better conceptualized as a chronic vestigation as well. The mere fact that the
population of patients with SCD has such a Bernaudin, F., Verlhac, S., Freard, F., Roudot-
high rate of economic disadvantage explora- T horaval, F., Benkerrou, M., Thuret, I., et al.
tions, so that our understanding of how to (2000). Multicenter prospective study of children
interact most effectively with these families with sickle cell disease: Radiographic and psycho-
metric correlation. Journal of Child Neurology,
will be improved. How this population is
15, 333–343.
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our culture. Hopkins, K. (2001). Social information process-
ing and magnetic resonance imaging in children
with sickle cell disease. Journal of Pediatric Psy-
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C h a p t e r 19
Down Syndrome
Heather Cody Hazlett

Julie Hammer
Stephen R. Hooper
Randy W. Kamphaus
Down syndrome was named after the phy- Genetic and Familial Issues
sician John Langdon Down, who in 1866 Related to Etiology
published a description of patients he iden-
tified as “Mongolian.” In addition to de- Down syndrome is classified as one of the
lineating the physical features of this syn- chromosomal disorders, meaning that the
drome, Down noted that these individuals syndrome has been traced to malformations
were responsive to training and could ben- in the genes of individuals who display the
efit from intervention (Carr, 1995). Interna- syndrome. There are actually several differ-
tional prevalence rates of Down syndrome ent types of Down syndrome, with the most
are reported to be approximately 8.32 per prevalent being trisomy 21 (94%), where
10,000 live births (Cocchi et al., 1988). This there is actually a third chromosome 21 in
estimate is higher than earlier ones, due to addition to the usual two (Prescott, 1988).
efforts to screen pregnant women over the Trisomy occurs in approximately 4% of
age of 35, who are felt to be at greater risk all pregnancies, making it the most com-
for giving birth to a child with Down syn- mon chromosomal abnormality in humans
drome. Nonetheless, because approximately (Hassold, Sherman, & Hunt, 1995). Genetic
70% of babies born with Down syndrome anomalies have also been found on chromo-
are born to younger mothers, and because some 21, in particular band q22. Specific re-
some women may refuse screening (Carr, gions of chromosome 21 have been mapped
1995; Sadovnick & Baird, 1992), this figure and are associated with the various features
is still high. Gender differences are evident, of Down syndrome. Currently, approxi-
in that males commonly outnumber females mately 25–40 genes have been mapped to
(the sex ratio is 1.3:1); this may be due to a chromosome 21 through techniques such as
higher mortality rate in females during in- gene linkage. This is one reason for the wide
fancy (Carr, 1995). range of individual variation found in the
362
Down Syndrome 363
population with Down syndrome (Koren- dactyly, and a wide space between the first
berg, Pulst, & Gerwehr, 1992). Other types and second toes (Pueschel, 1992b). Certain
of Down syndrome consist of translocation features have been found to change over
21, mosaicism, and partial trisomy 21 (Cole- time. For example, the epicanthal folds and
man, 1988; Pueschel, 1992b). Translocation large neck may become less noticeable over
21 results when one part of chromosome 21 time, while other features (e.g., a fissured
has been transferred to a different location. tongue and dental problems) become more
Mosaicism occurs when not all of the cells problematic with increasing age (Pueschel,
display the chromosomal trisomy, although 1992b). The intellectual disability evident
a majority do display trisomy 21. Some re- with Down syndrome may range from mild
search indicates that individuals with this to profound (according to the American As-
condition have higher mean cognitive scores sociation on Intellectual and Developmental
than those with trisomy 21. Disabilities classification), which adds to the
Relative risk for giving birth to a child heterogeneity of this population.
with Down syndrome is approximately 1%,
plus the amount of risk associated with the
Ophthalmological Concerns
mother’s age during pregnancy. The risk
for having a child with Down syndrome Ophthalmological problems can be major
increases exponentially with maternal age. disabilities for individuals with Down syn-
For example, a 20-year-old mother has a 1 drome. The most common causes of loss of
in 1,923 chance of giving birth to an infant vision are cataracts and acute keratoconus.
with Down syndrome, whereas the chance Functionally, individuals may suffer from
for a 49-year-old mother is 1 in 12 (Prescott, amblyopia, strabismus, blepharitis, and high
1988). Prenatal procedures, such as amnio- refractive errors, which if untreated may be
centesis and chorionic villi sampling, can be debilitating (Catalano, 1992; Niva, 1988;
used to screen for Down syndrome. The eti- Tsiaras, Pueschel, Keller, Curran, & Giess-
ology behind the maternal age effect has not wein, 1999). Fortunately, medical interven-
yet been determined, although it appears to tion is available for all of these conditions;
be related to an increase in trisomy at con- therefore, parents, teachers, and health pro-
ception rather than a decrease in the ability fessionals should be aware of these potential
to abort a trisomic fetus naturally (Hassold difficulties and seek medical evaluation to
et al., 1995). determine the nature of the ophthalmologi-
cal needs.
Medical Concerns
Oral Problems
and Comorbid Disorders
Since the maxilla and mandible are smaller in
Although Down syndrome is primarily persons with Down syndrome than in most
known as one of the chief causes of intellec- individuals, the tongue may appear to be
tual disabilities, it also includes distinctive larger than normal. As a result of the smaller
physical characteristics, as Down noted in oral cavity and relatively larger tongue, oral
his 1866 report. These may include brachy- hygiene may be difficult. In addition, indi-
cephaly (broad head), a delay in the closure viduals with Down syndrome may have a
of the fontanels, hypoplasia of the midfacial furrowed tongue or cleft palate, which may
bones, obliquely placed palpebral fissures, further complicate oral health. The tongue
epicanthal folds, depressed nasal bridge, protrusion also contributes to the split, in-
hyper- or hypotelorism, Brushfield spots flamed lips that are commonly seen in these
(i.e., white spots on the periphery of the iris), individuals. Other common problems in-
an overlapping or folding of the helix of the clude malocclusions, anomalies in the denti-
ear, thickened lips, tongue protrusion and/ tion (e.g., congenitally missing teeth, delayed
or fissured tongue with increasing age, short eruption of teeth, delayed shedding of pri-
and broad neck, umbilical hernias, broad mary teeth), and periodontal disease (e.g.,
and stubby hands and feet, a single palmar gingivitis is seen in almost all persons with
transverse crease, partial or complete syn- Down syndrome) (Vigild, 1992).
Cardiac Problems Gastrointestinal Anomalies

The prevalence of congenital heart malfor- A number of gastrointestinal anomalies are
mations in persons with Down syndrome associated with Down syndrome, but among
has been reported to be as high as 50% (for the most common are esophageal atresia,
trisomy 21), and cardiac anomalies remain tracheoesophageal fistula, duodenal atresia
the main cause of death, especially in the or stenosis, and Hirschsprung disease (Levy,
first few years of life (Marino, 1992). The 1992). The etiology of these conditions can
most common types of anomalies found in be traced to malformation during embry-
these children are defects in the atrioven- onic development. A child with esophageal
tricular canal. These anomalies produce an atresia may have difficulty breathing, due
increased risk of congestive heart failure. to the increased production of oropharyn-
Certain types of cardiac defects result in de- geal secretions. Children may also exhibit a
creased pulmonary blood flow, which may balky cough as a result of tracheoesophageal
contribute to pulmonary artery hypertension fistula. Both of these conditions are compli-
and pulmonary vascular obstructive disease cated by gastroesophageal reflux. Corrective
(Howenstein, 1992; Suzuki et al., 2000). surgery is available for these anomalies, and
Early diagnosis and corrective surgery may therefore early detection and intervention
improve survival rates to 80–90% of chil- should prevail. Beasley, Allen, and Myers
dren who may otherwise fail to reach their (1997) reported that despite treatment, in-
15th year (Marino, 1992). A survival rate as dividuals with Down syndrome who have
high as 87.8% was reported for individuals esophageal atresia have a high mortality,
with Down syndrome who had surgery for perhaps due to the other physical anoma-
cardiovascular lesions. In contrast, a surviv- lies associated with Down syndrome. There
al rate of 41.4% was reported for those who have been some claims that children with
did not undergo surgery (Hijii, Fukushige, Down syndrome have difficulty with ab-
Igarashi, Takahashi, & Ueda, 1997). sorption of some foods (e.g., protein, fat,
and vitamins). In that regard, Pueschel and
colleagues (1999) found that approximately
Respiratory Concerns
3.8% of children with Down syndrome have
Respiratory problems may result from the celiac disease.
physical abnormalities observed in children
with Down syndrome. For example, the
Dermatological Conditions
small oral cavity and hypoplasia of the mid-
facial region create problems with airways. Although there is no dermatological condi-
In addition, lungs in individuals with Down tion that is characteristic of Down syndrome,
syndrome have been found to be smaller than several conditions are seen frequently (>50%)
average (Howenstein, 1992). Pneumonia con- in this population. These maladies include
tinues to be one of the major causes of death, dry skin, atopic dermatitis, fungal infections
and there is an overall predisposition for con- of the feet and nails, and mucosal anomalies
tracting infectious diseases in the lower re- (e.g., inflammation of the lip, scrotal tongue)
spiratory tract. Lower respiratory tract infec- (Benson & Scherbenske, 1992). Ercis, Balci,
tions have also been linked to the increased and Atakan (1996) found that 40.8% of
mortality rates in this population. These con- children with Down syndrome had palmo-
ditions are related to the many structural and plantar hyperkeratosis (hardened/dry skin
functional disorders associated with Down on the palms of the hands and/or soles of the
syndrome (Howenstein, 1992). Sinus infec- feet); 30.9% had seborrheic dermatitis (ecze-
tions and chronic rhinitis are common, and ma, dandruff); 20% had a fissured tongue;
cases of bacterial pneumonia and viral infec- 12.6% had cutis marmorata (discolored skin
tions are typically more severe in these indi- that may appear “marbled”); 11.2% had a
viduals. Sleep apnea, which is characterized geographic tongue (inflammation of the
by snoring, restless sleep, interrupted breath- tongue); and 9.8% had xerosis (dry skin).
ing while asleep, mouth breathing, and day- With proper treatment, these conditions
time somnolence, has also been reported. should not become disabling.
Down Syndrome 365
Other Physical Difficulties activity by causing severe discomfort, which

in turn contributes to decreased mobility and
In infancy and early childhood, ear infec-
physical activity. Other orthopedic difficul-
tions are a significant problem for indi-
ties may arise from cervical spine instability
viduals with Down syndrome. This is an
in the atlanto-occipital and atlantoaxial re-
important medical concern, since frequent
gions (Frost et al., 1999). Persons with Down
ear infections are known to contribute to
syndrome may suffer from severe scoliosis
developmental delays in language skills. The
and typically have problems with collapsing
cause for the increased number of ear infec-
flat feet and bunion deformity (Pueschel &
tions may be related to the abnormalities of
Solga, 1992). Additional difficulties result
the ear that are associated with Down syn-
from hypotonia, or low muscle tone, which
drome. For this reason, hearing should be
is considered to be a major universal charac-
closely monitored and screened semiannual-
teristic and is related to delays found in gross
ly through age 8 (Downs & Balkany, 1988).
motor development.
Disorders of the liver, such as hepatitis,
have been linked to Down syndrome. In-
dividuals with Down syndrome who are Neurological and Psychiatric
institutionalized are at particular risk for Conditions
contracting hepatitis B. Proper hygiene
Neurological Conditions
and immunization may provide protection
against hepatitis B. In addition, persons with Down syndrome has been found to interfere
Down syndrome seem to be susceptible to with the fetal development of the central ner-
leukemia (Scola, 1992). vous system and to result in brain abnormali-
The genitourinary system may also be af- ties. These abnormalities include a reduction
fected in persons with Down syndrome. Re- in the total number of neurons throughout
search has identified smaller-than-normal several cortical areas, abnormalities within
kidneys, obstructive lesions along the uri- the neurons themselves, and abnormalities
nary tract, and difficulty with uric acid and in the ability of the neurons to communicate
creatinine clearance (Ariel & Shvil, 1992). with each other (Florez, 1992). Although
Additional characteristics involve the geni- brain weight at birth is close to normal, brain
talia. One commonly observed character- weight for children with Down syndrome
istic has been hypogenitalism, particularly tends to fall in the below-average range over
with males. In addition, trisomy 21 has been time. This condition may be related to a re-
found to be concomitant with other sex- duction in the neuronal density in cortical
related syndromes, such as Klinefelter, XYY, areas and decreased dendritic arborization
XXX, and Turner syndromes. At one time (Florez, 1992). The most affected area of the
it was hypothesized that hypospadias and brain in persons with Down syndrome is the
cryptorchidism were also linked to Down cerebral cortex, where the reduction in the
syndrome, but more recent findings have dis- number of neurons, existence of dendritic
proven such reports (Ariel & Shvil, 1992). In spines, and poor synaptic connections con-
females, there may be the occurrence of hy- tribute to difficulties in cognitive and learn-
permenorrhea or menorrhagia with the onset ing processes (e.g., attention, information
of puberty (Elkins, 1992). This problem may processing, integration, short- and long-term
be due to a number of factors, such as hypo- memory, and language skills) (Florez, 1992).
thyroidism and/or obesity, both of which are Research using magnetic resonance imag-
associated with Down syndrome. Neuromus- ing (MRI) to examine the brains of adults
cular abnormalities are commonly reported with Down syndrome and dementia indi-
in cases of Down syndrome, and often these cated the presence of smaller total brain, left
contribute to the increased mortality rates hippocampus, and left amygdala volumes,
within this population. Among the problems compared to nondemented individuals with
reported, subluxation and dislocation of the Down syndrome (Pearlson et al., 1998). In
cervical spine, hip, and patella are the most addition, the adults with Down syndrome
life-threatening (Pueschel & Solga, 1992). and dementia showed more generalized at-
Each of these conditions may impede physical rophy than their peers.
Other neurological problems that some lescents. Coe and colleagues (1999) found
children with Down syndrome face are sei- that children with Down syndrome had sig-
zure disorders. Increased rates of seizure nificantly more behavior problems on parent
disorders have been associated with Down and teacher ratings than matched controls
syndrome, with prevalence rates reported without intellectual disabilities had; there
as high as 33% in some studies (Pueschel, were particular concerns in the areas of at-
1992b). Most seizures will begin before age tention, conduct problems, and social with-
1 (40%) or after individuals reach their 30s drawal.
(40%). Finally, Einfeld, Tonge, Turner, Parmenter,
and Smith (1999) examined the longitudinal
course of behavior and emotional problems
Psychiatric Conditions
in young children with Down syndrome and
Previous research by Myers (1992) showed found that these children had considerably
the other psychiatric conditions that can be fewer behavior problems than children with
comorbid with Down syndrome. She found Prader–Willi syndrome and Williams syn-
in children under the age of 20, that exter- drome. In addition, behavior problems did
nalizing problems such as attention-deficit/ not change significantly over time for any of
hyperactivity disorder, oppositional defiant the syndromes. By contrast, McCarthy and
disorder, conduct disorder, and aggressive Boyd (2001) found that the early childhood
behaviors accounted for most of the distur- factors of presence of a psychiatric disor-
bances. In persons over age 20, aggressive der and family environment did not predict
behaviors, major depressive disorder, and adult psychopathology in young individuals
stereotypic behaviors were reported most with Down syndrome.
frequently. Myers also stated that although
children and adolescents with Down syn-
Systemic Problems
drome show lower risk for developing a
psychiatric disorder than other individuals Persons with Down syndrome have a higher
with intellectual disabilities, they are still at susceptibility to bacterial infections, malig-
greater risk than the general population. nancies, and autoimmune disturbances, as a
More recently, Dykens (2007) made simi- result of a mild immune deficiency (Ugazio,
lar observations about children with Down Maccario, & Burgio, 1992). Further com-
syndrome, again noting that they tend to be plications result from several hematological
at lower risk for significant psychopathology abnormalities that are unique to Down syn-
than other groups of children with intellec- drome. These irregularities include transient
tual disabilities. In fact, Dykens and Kasa- myelodysplasia in infancy (the presentation
ri (1997) found that children with Down of which resembles congenital leukemia),
syndrome scored significantly lower on the red cell macrocytosis, and increased suscep-
Child Behavior Checklist than children with tibility to leukemia (Lubin, Cahn, & Scott,
Prader–Willi syndrome and other nonspe- 1992). At one time, Down syndrome was
cific intellectual disabilities. Despite the felt to be caused by generalized endocrine
suspected lower rates of psychopathology in failure; however, the majority of persons
individuals with Down syndrome, children with Down syndrome do not suffer from
and adolescents can still manifest behav- endocrine dysfunction (Pueschel & Bier,
ioral and emotional problems. For example, 1992). On the other hand, the prevalence
Dykens, Shah, Sagun, Beck, and King (2002) rate for endocrine disturbances is greater
found that although externalizing behavior for those with Down syndrome than for the
was lower across community and clinic sam- general population. Among the most com-
ples of children and adolescents with Down mon findings are problems related to thy-
syndrome, internalizing behaviors were sig- roid functioning, specifically hypothyroid-
nificantly higher in older adolescents ages ism (Pueschel & Bier, 1992). This condition
14–19 years, with particular increases in may predispose individuals with Down syn-
withdrawal. In fact, increases in withdrawal drome to become overweight, particularly
were found in 63% of community-based when it is paired with the presence of hy-
adolescents and 75% of clinic-referred ado- potonia.
Down Syndrome 367
Mortality do; however, their special needs may re-

quire some environmental supports in order
The greatest likelihood of death resulting
for them to achieve their developmental
from medical complications, such as con-
milestones. Developmental stages generally
genital anomalies, circulatory problems, and
mimic those found in normal children in the
respiratory illness, occurs during the first
domains of sensorimotor functioning, con-
year of life, with ages 1–9 being the largest servation, and mastery of space, time, and
age group at risk for early death (Sadovnick moral judgment, although these skills are
& Baird, 1992). With advances in medical acquired at a slower rate (Hodapp & Zigler,
treatment and early intervention for such 1990). This finding was supported by the
difficulties, survival rates should improve in work of Tingey, Mortensen, Matheson, and
the future. Doret (1991), who found that infants and
When Down originally characterized this young children with Down syndrome were
syndrome in 1866, he commented on the more similar to normal children on the Per-
shorter life expectancy for these individuals. sonal, Social, and Adaptive domains of the
This phenomenon held true until the 1940s, Battelle Developmental Inventory, and less
when average life expectancy rose from ap- similar in the Communication and Cogni-
proximately 9 years to 12 years of age. It tive domains. This discrepancy was found to
was estimated in the 1990s that about 44% widen as the children’s age approached 36
of the children born between 1952 and 1981 months.
would live to be at least 60 years old (Carr,
1995; Sadovnick & Baird, 1992). More re-
cent estimates of life expectancy for males Temperament
and females with Down syndrome were 61.1 Biological studies have found that children
years and 57.8 years, respectively (Glasson et with Down syndrome may be less reactive
al., 2003). Although the shorter life expec- to novelty, and thus may appear more pas-
tancy was at one time accounted for by the sive or less generally reactive, than other
congenital heart defects that often accompa- children of similar age (Ganiban, Wagner,
ny Down syndrome, this reason has not been & Cicchetti, 1990). In many other regards,
substantiated in research comparing individ- however, children with Down syndrome dis-
uals with Down syndrome who did not have play the same temperamental variability as
heart defects to a matched group with intel- any other children. Zickler, Morrow, and
lectual disabilities but not Down syndrome Bull (1998) found that infants with Down
(Sadovnick & Baird, 1992). Strauss and syndrome were rated as more active, less
Eyman (1996) noted in their large sample of intense, and more distractible, and tended
individuals with Down syndrome that up to to demonstrate more approach behaviors,
age 35, mortality rates were comparable to when compared to typically developing in-
those for a sample of individuals with intel- fants. When maternal ratings of tempera-
lectual disabilities; however, after age 35, mental qualities for children with Down
the mortality rates for the group with Down syndrome are compared to maternal ratings
syndrome increased at a greater rate than for for nondisabled children, the descriptions
the group with intellectual disabilities. appear to be relatively similar. However,
mothers of a group with Down syndrome
have reported lower adaptability and a
Developmental Course greater need for stimulation for their chil-
dren (Vaughn, Contreras, & Seiter, 1994). A
Although the majority of children with study of older children and adolescents with
Down syndrome display delayed motor func- Down syndrome, using maternal and teach-
tion, cognitive development, and language er ratings of temperamental characteristics,
acquisition, there are individual variations found that mothers perceived their children
in rate and level of achievement. Children as less active, more predictable, more posi-
with Down syndrome experience a period of tive in mood, less persistent, and more dis-
rapid growth and development during their tractible (Gunn & Cuskelly, 1991). Mothers
first 3 years of life, much as other children and teachers agreed on which children were
viewed as easy or difficult overall, but the re- age 40 do show the characteristic features
ports of individual characteristics constitut- of Alzheimer disease in the central nervous
ing these categories varied for the two sets system. These features consist of cortical
of raters. Ratekin (1996) found that children atrophy, neurofibrillary tangles, and neu-
with Down syndrome were rated by their ritic plaques (Lai, 1992; Mufson, Benzing,
mothers as being higher in approachability, & Kordower, 1995). Visser, Aldenkamp,
distractibility, and mood, but lower in per- van Huffelen, and Kuilman (1997) found an
sistence, than typically developing children increasing prevalence rate for dementia in a
were rated by their mothers. group with Down syndrome. After age 40,
prevalence rates were about 11% between
ages 40 and 49, but increased up to 77%
Cognitive Development
between ages 60 and 69. Other studies have
Given that most children with Down syn- observed that adults with Down syndrome
drome suffer from some degree of intellectu- over the age of 50 are at substantial risk for
al disability (mild, moderate, severe, or pro- the development of dementia associated with
found), the degree of cognitive development Alzheimer disease (e.g., Holland, Hon, Hup-
that may be evident depends in part on how pert, & Stevens, 2000; see Zigman & Lott,
severe the cognitive deficits may be. The dif- 2007, for a review).
ficulty of using many standardized tests to Efforts to find a genetic link between
evaluate a child with intellectual disabilities, Down syndrome and Alzheimer disease have
and the problems with obtaining longitudi- had mixed results, with some indication that
nal data, make research in this area difficult a gene for Alzheimer disease may be located
to generalize to a population that is known on the long arm of chromosome 21. The de-
for its heterogeneity. Although standardized mentia resulting from Alzheimer disease is
intelligence tests have been found to be use- difficult to establish in persons with intel-
ful in classifying an individual as having in- lectual disabilities, especially in severe cases;
tellectual disability or not, they are of more therefore, clinical studies attempting to es-
limited utility in discriminating between tablish the presence of dementia in Down
the various levels of intellectual disabilities syndrome populations are difficult to carry
(Kamphaus, 1993). For example, children out. Moreover, hypothyroidism, poor nutri-
with mosaicism have been found to score tion, and depression may all masquerade as
10–30 points higher on IQ measures than dementia, and all are common problems for
those with trisomy 21, and have demonstrat- persons with Down syndrome. This scenario
ed normal visual-perceptual skills as well makes differential diagnosis hard to accom-
(Fishler & Koch, 1991); however, Wishart plish. The clinical dementia associated with
(1995) cautions that, generally speaking, Alzheimer disease does, however, become
there is no fixed “ceiling” of cognitive de- evident in persons with Down syndrome
velopment for individuals with Down syn- who live to be 50 or older. The symptomatic
drome, and that learning for this population presentation is essentially the same as that
should continue well beyond adolescence. for groups without Down syndrome, but it
Perhaps the most consistent finding re- may appear to be somewhat exaggerated,
garding cognitive development in children due to the physical and cognitive features al-
with Down syndrome is that there is a gen- ready associated with Down syndrome (Lai,
eral slowing, or perhaps decline, in their 1992).
rate of development as they get older (Carr,
2005). Early accounts of Down syndrome
Language Development
portrayed a general decline in IQ over the
lifespan. Carr (1995) summarized this re- Language is closely linked to cognitive abili-
search and found that there is actually little ty, in that the rate and degree of language at-
evidence that IQ, memory, or practical skills tainment will depend heavily on the amount
deteriorate significantly before the age of 50. of cognitive deficit that exists. Some factors
In addition, fewer than 50% of individu- that lead to delays in language acquisition
als with Down syndrome show clear signs are related to the physical characteristics
of dementia; however, many individuals associated with Down syndrome. Problems
with Down syndrome who live to be over with otitis media, cognitive dysfunction
Down Syndrome 369
(e.g., memory, attention, arousal), and visual Down syndrome found that receptive and
disturbances may impede a child’s ability to expressive language skills, along with the-
gather auditory and visual cues concerning ory of mind, were more severely impaired
language. Compared to children without in- than in individuals with fragile X syndrome
tellectual disabilities, children with Down (Abbeduto et al., 2001).
syndrome acquire language skills more
slowly than other motor or cognitive skills.
Social Development
In addition, language development fails to
proceed at a consistent pace, but occurs in Because of the motor, perceptual, cogni-
spurts, with a great deal of development oc- tive, and language delays that children with
curring before the age of 7 (Fowler, 1988). Down syndrome exhibit, their ability to gain
This discrepancy can first be seen in infancy social competence may also be diminished.
and grows larger as children become older. For this reason, they may seek out develop-
For example, although the rate of vocabulary mentally matched rather than age-matched
learning in children with Down syndrome is children for peer interactions. Play develop-
typically consistent with their developmen- ment has been reported to follow develop-
tal age, it does not progress at a rate that is mental trajectories as well (Beeghly, Perry,
consistent with their other cognitive skills or & Cicchetti, 1989). Earlier hypotheses that
consistent in relation to that of typically de- children with Down syndrome are more so-
veloping peers (Miller, 1995; for reviews, see ciable than other children with intellectual
Abbeduto, Warren, & Conners, 2007, and disabilities, and that this feature is a defin-
Roberts, Price, & Malkin, 2007). Recent ing quality of the whole group, have not been
studies have examined significant predictors definitively supported by research, although
of language outcomes in children with de- some gender differences in sociability have
velopmental disabilities and in children with been described. Ruskin, Kasari, Mundy, and
Down syndrome in particular, and have Sigman (1994) found that young children
found that parental responding significantly with Down syndrome paid more attention to
predicted language skills (Brady, Marquis, people during a social interaction paradigm
Fleming, & McLean, 2004; Yoder & War- than did mental-age-matched controls, dem-
ren, 2004). More specifically, language pro- onstrating a greater focus of attention to the
duction appears to be more impaired than social cues provided. However, when pre-
language comprehension. Within expressive sented with ambiguous stimuli paired with
language, the grammatical/syntactical com- either positive or negative facial expressions
ponents of language rather than the lexical or from their parents, toddlers with Down
nonverbal aspects seem to show the greatest syndrome were found to display signifi-
impairments (Fowler, 1988; Miller, 1995). cantly less appropriate responses (e.g., they
Children with Down syndrome have been responded with positive affect to negative
described as having a specific language im- expression) than did mental-age-matched
pairment characterized by fewer total words controls (Knieps, Walden, & Baxter, 1994).
used in an utterance, fewer number of differ- Therefore, although children with Down
ent words used, and less than average length syndrome may be as socially responsive as
of utterance (Chapman, Seung, Schwartz, & other children, they fail to learn socially ref-
Bird, 1998). When adaptive behaviors were erenced cues. These social-cognitive skills
assessed with the Vineland Adaptive Behav- are essential to interpersonal skills and mak-
ior Scales in a group of children with Down ing friendships.
syndrome from 1 to 11½ years of age, a rela- In a study on social-cognitive under-
tive weakness in communication (compared standing in children with Down syndrome,
with daily living and socialization skills) was Wishart (2007) found that in certain learn-
found (Dykens, Hodapp, & Evans, 1994). ing contexts (e.g., collaborative learning),
Within the communication domain, there the children with Down syndrome worked
was more deficiency in expressive language alongside other children, but engaged in more
than in receptive language. This finding is parallel working than collaborative working
supported by Miller’s (1995) work. More on a shared task. In addition, Wishart found
recently, an examination of the linguistic relative weaknesses in emotional recognition
and cognitive profile of individuals with in children with Down syndrome. Similarly,
Landry, Miller-Loncar, and Swank (1998) in children with Down syndrome, with the
found that children with Down syndrome most frequently cited causal factors being
have a more difficult time than control chil- the hypotonia and hyperflexia that can be
dren transferring goal-directed play skills seen in almost all of these children. There
used with their mothers in a joint play ses- are individual variations in both the qualita-
sion to independent play situations. In other tive and quantitative aspects of motor skills.
words, children with Down syndrome ben- Dunst (1988) concluded that sensorimotor
efit from structured (directed) play, but have development in children with Down syn-
trouble using these skills on their own and drome, despite their slower rate of develop-
may continue to need structured play time. ment, was more like that of children without
intellectual disabilities. In a cross-sectional
study of 6- to 16-year olds with Down
Growth and Motor Development
syndrome, using a range of manual tasks,
Individual factors (e.g., cardiac and skeletal Thombs and Sugden (1991) found evidence
problems, hypotonia, obesity, vision and for an increased use of precision grips among
hearing disturbances, and perceptual prob- older children. In addition, the older children
lems) may have an impact on the growth and were found to be faster on the speeded tasks.
motor development of any child with Down The authors concluded that on measures of
syndrome. Aspects of significance are height speed, strategies, and types of grip, there are
and weight. Prenatally, fetuses with Down general developmental advances across age
syndrome have been found to be smaller groups. Children with Down syndrome may
than fetuses without disabilities. The largest display difficulty with gross and fine motor
deficit appears between birth and 36 months skills, balance, posture, strength, and flex-
of age, where statistical differences have ibility (Brandt, 1996; Jobling, 1998), and
been found between children with Down subsequent interventions should be tailored
syndrome (both males and females) and nor- to the children’s individual needs, based on
mal controls, with the children with Down their medical and health conditions. An ex-
syndrome being smaller than average. Poten- cellent review of the literature on motor de-
tial factors affecting growth in infancy may velopment in children with Down syndrome
include prematurity, cardiac disease, and was provided by Block (1991) approximately
genetics. During middle childhood, growth 20 years ago, and it continues to be perti-
rates become closer to normal, although ado- nent to the present.
lescents experience smaller pubertal growth
spurts as well as delayed onset of menses for
females (i.e., later than the typical onset of Cognitive, Emotional,
10–14 years) (Elkins, 1992). They will, how- and Behavioral Presentation
ever, have normal development of secondary
Cognitive Presentation
sex characteristics. By adulthood, individu-
als with Down syndrome are typically two As noted earlier, a wide range of cognitive
standard deviations below normal in height abilities can be observed in individuals with
(Cronk & Anneren, 1992). Individuals with Down syndrome, creating a heterogeneous
Down syndrome are commonly found to be population. Interestingly, females have been
overweight because of excessive weight gain found to have higher intellectual function-
during infancy and childhood (Cronk & ing than males in both childhood and adult-
Anneren, 1992; Rubin, Rimmer, Chicoine, hood (Carr, 1995). Many arguments have
Braddock, & McGuire, 1998). The etiology been made regarding this finding, but to date
of this weight gain has not yet been deter- there are no established conclusions about
mined conclusively, though there are some the presence of gender differences. When
indications that it may be a factor of hypo- compared to other groups of children with
thyroidism and/or hypotonia. Although their developmental disabilities, those with Down
metabolic rates do not differ from normal, syndrome may not appear to be that differ-
individuals with Down syndrome have less ent in the classroom. One study comparing
body mass and slower growth, and therefore the cognitive skills of adolescents with Down
require fewer calories (Pipes, 1992). syndrome to those of children with cerebral
In general, motor development is delayed palsy or nonspecific intellectual disabilities
Down Syndrome 371
found no significant differences between cles and related congenital abnormalities of

any of the groups (Smith & Phillips, 1992). the oral–peripheral region.
The group with Down syndrome did fail to
show progress in language acquisition on a
Emotional Presentation
second assessment, but they also displayed
some gains in cognition and copying skills, As noted earlier, individuals with intellectual
compared to the group with nonspecific in- disabilities demonstrate greater susceptibil-
tellectual disabilities. Other cognitive defi- ity to stressors than the general population
cits noted in children with Down syndrome and can show a wide range of emotional ex-
include limited memory functioning (par- pressions. The developmental delays and lan-
ticularly for spatial stimuli), reduced task guage impairments associated with intellec-
persistence and distractibility, slowed reac- tual disabilities may contribute to the finding
tion time and information-processing speed, that individuals with Down syndrome are at
and difficulty with reasoning and judgment slightly greater risk for emotional problems
(Gibson, 1991). than the general population (Myers, 1992).
As noted above, almost all of the literature Children with Down syndrome will experi-
on Down syndrome discusses some type of ence challenges in school, occupational, and
language difficulty, particularly expres- social functioning, and these challenges may
sive language impairments, as constituting be manifested as mood disturbances (anxi-
a hallmark of this disorder. Children with ety or depression), physical complaints, so-
Down syndrome have been found to have cial withdrawal, or work inhibition (Myers,
delayed acquisition of language skills that 1992). Although depression in children with
is not commensurate with their mental age. Down syndrome has not been well docu-
This deficit may be due to the presence of mented in the literature, adults have been
central auditory processing abnormalities. found to exhibit depression to a greater ex-
For example, dichotic listening studies have tent than children. The prevalence of major
found that individuals with Down syndrome affective (mood) disorders in adults with in-
have reversed hemispheric dominance (right- tellectual disabilities has been estimated to
rather than left-hemisphere dominance) for be about 1–3.5% (Myers, 1992).
processing speech (Dahle & Baldwin, 1992).
Research using volumetric MRI measures
Behavioral Presentation
has found that individuals with Down syn-
drome have a smaller left planum temporale Cuskelly and Dadds (1992) performed a
(a region associated with language function- study of mother, father, and teacher ratings
ing) than controls (Frangou et al., 1997). of behavior problems in children with Down
The implications of a smaller planum in in- syndrome compared to their siblings. On
dividuals with Down syndrome are still un- the Revised Behavior Problem Checklist, all
clear, however, as the authors were unable raters reported that the group with Down
to find a direct relationship between size and syndrome exhibited significantly more total
performance on their language testing. behavior problems and significantly more
Due to their neurological abnormalities, attention/immaturity problems than their
individuals with Down syndrome will dis- siblings. There were also significant gender
play reduced short-term memory and will differences as viewed by the raters. Mothers
have greater difficulty recalling auditory than reported the same level of problem behav-
visual information (Florez, 1992). Difficul- iors for each gender, whereas fathers report-
ties in language development involve (1) an ed that the girls displayed more problems,
asynchrony in language production relative and teachers experienced greater problems
to language understanding and other cogni- with boys. In an interesting follow-up study,
tive skills; (2) an onset of productive deficits Cuskelly and Gunn (1993) found that moth-
that coincides with vocabulary growth; (3) ers of children with Down syndrome re-
a slowness in the development of syntactic ported significantly more conduct problems
skills; and (4) heterogeneous language devel- in the female siblings than mothers who
opment for the population (Florez, 1992). In did not have a child with Down syndrome
addition, difficulties with articulation may reported in their daughters. This finding
be exacerbated by hypotonia of facial mus- may indicate that mothers of children with
disabilities may have some misperceptions described. For example, children with Down
regarding “typical” behavior. It may also syndrome were found to exhibit a general
show that siblings of children with Down deficit in their sequential processing, al-
syndrome, especially girls, could experience though selected deficits in simultaneous pro-
greater adjustment problems and should be cessing have also been noted (Hodapp et al.,
considered to be at risk for showing a variety 1992). In general, variability has been found
of behavioral difficulties. within this population, and failure to engage
in tasks and response variability are factors
that can add to the instability of findings
Key Assessment Issues and Tools (Wishart & Duffy, 1990).
At present, a number of well-standardized
The diagnosis of Down syndrome is typical- measures exist that can aide the examiner in
ly made at or before birth (35%), or within gaining a reliable estimate of a child’s intel-
the first 2 years of life (46%), although there lectual functioning. A description of these
are some cases where a diagnosis has been tasks is beyond the scope of this chapter,
made after the third year (Quine & Rut- but suffice it to say that most contemporary
ter, 1994). For this reason, most children measures of cognitive functioning are multi-
enter preschool with a diagnosis. However, dimensional in nature. For example, the dif-
as Quine and Rutter (1994) found, parents ferent dimensions provided by the Stanford–
are often not provided with detailed expla- Binet Intelligence Scales, Fifth Edition (Roid,
nations of their children’s impairments and 2003) will provide not only the opportunity
the associated features of these. Health care to gain an overall estimate of intellectual
professionals and school personnel should functioning (IQ), but an initial breakdown
be aware of the need for education that par- of specific cognitive functions as well (Fluid
ents and families may require to be informed Reasoning, Knowledge, Quantitative Rea-
participants in their children’s medical care soning, Visual–Spatial Processing, Working
and related treatments. Memory). Knowing the level and pattern of
Often parental reports constitute a chief cognitive abilities should provide additional
source of assessment information regarding information with respect to describing the
the developmental status of children with cognitive topography of Down syndrome,
disabilities such as Down syndrome. When as well as the profile of relative strengths
rating scales and interview data are being and weaknesses that may be present. This
employed, estimates of a child’s functioning profile of abilities can also be complemented
must sometimes rely on the judgment of the by more in-depth assessment using neurop-
parent who completes the forms. In a study sychological testing procedures in an effort
comparing maternal and professional esti- to examine the specific cognitive dimensions
mates of developmental status among chil- in more detail (various executive functions,
dren with disabilities, it was concluded that different kinds of memory, etc.).
mothers provided higher estimates of ability
across all developmental domains (Sexton,
Behavioral Assessment
Thompson, Perez, & Rheams, 1990). Ad-
ditional findings showed that maternal and There are no characteristic behaviors as-
professional ratings were highly correlated, sociated with Down syndrome. Rather, the
with children’s intellectual functioning being full range of behaviors seen in nondisabled
the most significant variable contributing to children may be exhibited by children with
this correlation. In other words, mothers and Down syndrome. Obstinacy, aggression,
professionals tended to agree more closely withdrawal, and self-injurious behaviors are
when children’s intellectual functioning was among the most frequently seen behaviors,
closer to average. and they are also the ones that elicit the most
frustration from parents and educators. Be-
havior management techniques such as posi-
Cognitive Assessment
tive and negative reinforcement have been
In addition to the general intellectual defi- shown to be effective in decreasing problem
cits that are present in most children with behaviors and increasing target behaviors.
Down syndrome, specific deficits have been In a study using descriptive analysis to as-
Down Syndrome 373
certain the function of problem behaviors and remediation should also take place as
in a small sample of children with intellec- early as possible, with routine developmen-
tual disabilities, contingent reinforcement tal surveillance being provided throughout
and teaching functionally equivalent behav- the school years.
iors were found to be effective in reducing Over the years, numerous treatments have
problem behaviors for these children (Lalli, been sought to help “cure” various dysfunc-
Browder, Mace, & Brown, 1993). In additions caused by Down syndrome. Whereas
tion, because the students were required to some of these treatments have sought to
communicate their requests, they concur- improve intellectual functioning and others
rently improved their verbal skills. have attempted to alleviate physical condi-
tions, they are considered unconventional,
and practitioners may wish to familiarize
Medical Assessment
themselves with these in order to discuss
and Intervention
them competently with parents who show an
Approximately 20 years ago, the National interest in these therapies. Some of the more
Down Syndrome Society (NDSS) sponsored popular of these are as follows: (1) pituitary
a conference on health care in Down syn- extract, given to improve intellectual and
drome, where suggestions were made for social development; (2) glutamic acid; (3)
important medical interventions (Lott & thyroid hormone, given to improve intellec-
McCoy, 1992). It was recommended that tual functioning; (4) 5-hydroxytryptophan,
during the neonatal period and early infan- given to improve behavioral and motoric
cy, there should be an attempt to establish functioning; (5) dimethyl sulfoxide, given
chromosomal karyotype, communicate the to improve behavior and learning; (6) sicca
diagnosis to parents, and refer parents to cells (fetal cell therapy), given to increase
available support groups. In addition, sev- intellectual functioning and growth; (7) vi-
eral types of screenings were recommended, tamins, minerals, enzymes, and hormones,
based on the known health concerns for chil- administered to treat intellectual disabili-
dren with Down syndrome. These included ties; and (8) facial plastic surgery, intended
screening for cataracts, blockages in the gas- to improve characteristic features (for de-
trointestinal tract, congenital heart disease, tailed reviews, see Pueschel, 1992a; Roizen,
thyroid dysfunction, and hearing problems. 2005). Parents may be willing to try these
It was advised that these exams should con- alternative therapies, despite evidence that
tinue annually into early adulthood. The demonstrates their lack of efficacy. Often
NDSS also advocated enrolling these chil- parents are influenced by positive expecta-
dren in early intervention programs. These tions of improvement and may attribute any
recommendations have set the stage for cur- change to the therapy. However, at all times,
rent clinical practice standards, with many the health and best interest of a child should
of the original recommendations remaining remain the primary focus.
in force.
During the preschool and school years,
early efforts should focus on remediating Options for Treatment
common orthopedic problems (e.g., bun- of Psychosocial, Educational,
ions, severe flat feet, dislocated hips) and and Emotional Problems
dental problems, as well as on providing ad-
ditional vaccinations (e.g., against influenza, Infants with Down syndrome commonly
pneumococcal infections, and hepatitis B) display delays in gross and fine motor, cog-
for at-risk children. Special behavioral pro- nitive, personal, social, emotional, and lan-
grams may be beneficial to improve self-help guage development (Dmitriev, 1988). These
skills, communication, and nutrition, as well areas may be improved with training, and
as to ameliorate problems related to aggres- certain characteristics of children with
sion, self-injurious behavior, and school ad- Down syndrome facilitate such education.
justment. For example, some children with These factors include the following: (1) In-
Down syndrome display food behavior prob- fants with Down syndrome are more like
lems, such as throwing or hoarding food normal infants than not and will respond to
(Pipes, 1992). Psychoeducational evaluation social gestures; (2) they will respond posi-
tively to physical assistance (e.g., shaping) motivation levels and deficient learning.
while learning; (3) they are reinforced by Fewell and Oelwein (1991) examined the ef-
their own successes; and (4) they have higher fectiveness of the Model Preschool Program,
receptive than expressive language skills and which focused on children with Down syn-
good visual discrimination (Dmitriev, 1988). drome and developmental delay. They found
Interventions should also include a child’s that of the six skill areas emphasized (gross
family, since there are some indications that motor skills, fine motor skills, cognition, re-
maternal responsiveness to a preschooler ceptive communication, expressive commu-
with Down syndrome may be improved nication, and social/self-help skills), the chil-
by the existence of available maternal sup- dren with Down syndrome made gains in
ports (Lojkasek, Goldbert, Marcovitch, & all areas, with the exception of gross motor
MacGregor, 1990). The effectiveness of early skills on the Classroom Assessment of Devel-
intervention programs for children with dis- opment Skills. However, on the Battelle De-
abilities has not gone without debate, since velopmental Inventory, expressive language
available research is often plagued by meth- in addition to fine and gross motor skills
odological flaws. Shonkoff, Hauser-Cram, failed to show developmental improvements.
Krauss, and Upshur (1992) reviewed the Nonetheless, the project presented evidence
existing literature on the effects of early that early intervention could be successful in
intervention services, and concluded that some areas of development.
most programs for infants and toddlers with Behavioral interventions designed to in-
disabilities are only moderately effective in corporate functional communication train-
producing short-term benefits as measured ing have been shown to be effective (Arn-
by traditional cognitive or developmental dorfer, Miltenberger, Woster, Rortvedt, &
measures. However, other studies suggest Gaffaney, 1994). Although the number of
that longer, more intense interventions may families involved in this study was limited,
be more effective in the age range from birth the researchers utilized behavioral inter-
to 5 years. Not only has functioning been views, direct observation, and experimental
found to be closer to typical development analysis to determine the functions of the
with early infancy training programs, but children’s problem behaviors. The research-
there are indications that early entry into ers then used functional communication
intervention programs is more cost-effective training as an intervention. This procedure
than later entry into such programs (Warf- involved teaching a child a response that
ield, 1994). In other words, the earlier that resulted in the same desired consequence as
treatment for developmental skills is avail- a problem behavior. Others have endorsed
able for infants, the better. the use of naturalistic teaching to gain ac-
Dmitriev (1988) has advocated an inter- quisition of targeted skills (Fox & Hanline,
disciplinary training model for effectively 1993). A methodology of this nature would
teaching children with Down syndrome—a involve using the natural environment, nat-
model in which medical, educational, and ural consequences, and child initiation to
parental participation is essential. The edu- teach new tasks. However, both approaches
cational program should also include parent need to be researched empirically in order
training in behavior management and devel- to determine whether these methods are
opmental concerns. Developing a sequence truly successful. In another experiment de-
of tasks and skills to be obtained will provide signed to increase vocal responsiveness in
parents with a hierarchy of skills required preschoolers with Down syndrome, positive
for their child to master certain developmen- reinforcement (PR) was found to be success-
tal goals. In one study, Wishart (1991) found ful (Drash, Raver, Murrin, & Tudor, 1989).
that, compared to nondisabled infants, those Children were trained using PR alone, PR
with Down syndrome made inefficient use of combined with dimming of lights, and PR
the cognitive abilities that they did have and combined with visual screening. All condi-
would often remain passive even when a task tions were successful in increasing vocal
was within their ability level. The implica- responsiveness, with the two methods com-
tions are that the delayed developmental rate bining PR with other techniques producing
seen in children with Down syndrome may the most improvement. It should be noted
be due to an interaction between inadequate that a commonly used reinforcer (food) was
Down Syndrome 375
not employed, in an effort to create a more task mastery behaviors than either the typi-
socially valid paradigm. The results indicate cal 2-year-olds or 3-year-olds. The devel-
that behavioral management techniques may opmentally disabled groups completed only
be employed successfully to teach language half as many tasks successfully as the typi-
skills. A small-scale study with three school- cal children. In addition, both groups had
age children focused on increasing phono- higher rates of interaction with the teacher
logical awareness found that training could (i.e., more frequent demands for assistance).
improve literacy skills (Kennedy & Flynn, Compared to the other children with intel-
2003). Specific skills trained included allit- lectual disabilities, the children with Down
eration detection, phoneme isolation, spell- syndrome actually made fewer requests of
ing of orthographically regular words, and the teacher and peers, but their requests
rhyme detection. were more successful. These findings in-
Skills that preschool programs should dicate that children with Down syndrome
concentrate on in order to increase inde- may benefit from working within a buddy
pendence include separation from parents, system, given that they experience lower
eating and drinking, handwashing, toilet- task mastery but relatively advanced social
ing, gross and fine motor skills, social skills, interaction skills. Some research has indi-
and language acquisition (see Love, 1988, cated that developmental gains in children
and Oelwein, 1988, for model instructional with Down syndrome are not associated
plans). Cuskelly, Zhang, and Gilmore (1998) with time spent in an integrated classroom,
advocate training self-regulation skills, such and in fact that slightly higher gains in ex-
as the ability to delay gratification and mas- pressive language are made in nonintegrated
tery motivation, early in development to help settings (Fewell & Oelwein, 1990).
foster greater independence later in adult- The use of computers to teach language
hood. Principles of applied behavior analy- skills has been advocated as another teach-
sis are often successful when instructors ing tool (Meyers, 1988). In this forum, the
are attempting to teach such tasks as feed- computer provides structure and scaffold-
ing, toileting, cessation of habitual tongue ing for the acquisition of spoken and written
protrusion, and gross and fine motor skills. language skills such as vocabulary, spelling,
Since the developmental age of children with comprehension, and sentence construc-
Down syndrome often lags behind their tion. Language intervention, as advocated
chronological age, it is necessary to main- by Miller (1995), should be family-based.
tain an awareness of which activities a child Parents and siblings should encourage com-
is ready to perform successfully. munication about daily activities and events,
Placement in a regular classroom may and should be responsive to a child’s inter-
also improve academic attainment in chil- ests and initiation of communication.
dren with Down syndrome. One study of Beginning in adolescence, the child’s emo-
academic attainment in children with Down tional health should be carefully monitored
syndrome ages 6–14 years found that al- for symptoms of depression. Individuals
though cognitive ability level had the great- with Down syndrome are at increased risk
est impact on achievement, type of school for developing major depression and have
attended was the next largest contributing also been noted to develop learned helpless-
factor (Sloper, Cunningham, Turner, & ness (Harris, 1988). Activities to build self-
Knussen, 1990). Additional factors influ- esteem and self-concept, as well as to pro-
encing academic attainment were gender vide training in vocational matters, should
(female), paternal locus-of-control ratings, be initiated during middle or high school.
and chronological age. In a naturalistic Parents and families of children with
classroom setting, 3-year-olds with Down Down syndrome may be in need of support
syndrome were compared to normal 2- and services as well. These children, as a result
3-year-olds, as well as to another group of their cognitive and physical limitations,
with mild to moderate intellectual disabili- may require a great amount of parental care.
ties, on some classroom behaviors (Bronson, Barnett and Boyce (1995) found that parents
Hauser-Cram, & Warfield, 1995). Both of children with Down syndrome devoted
groups of children with developmental dis- more time to child care and spent less time in
abilities were found to perform lower on social activities than parents without a dis-
abled child. Both mothers and fathers made the same desires as nondisabled individuals
accommodations in the amount of time they for developing relationships and becoming
spent doing daily household activities. Single productive adults. Assistance should focus
parents, who were not sampled in this study, on the development of well-rounded persons
may therefore have even greater difficulty re- who can live in the least restrictive environ-
sponding to the needs of children with Down ment possible—whether that means inde-
syndrome. As mentioned earlier, the siblings pendently in the community, in supervised
of children with Down syndrome may be at semi-independent settings, or within group
risk for developing behavior problems and homes.
adjustment disorders. Another study that
examined ratings of parental stress found
that parents of a child with Down syndrome Conclusion
reported more stress than comparison fami-
lies did (Cuskelly, Chant, & Hayes, 1998). Down syndrome is a genetic disorder with a
For these reasons, it is important to provide distinct physical phenotype but a heteroge-
these families with such resources as parent neous presentation of learning, behavioral,
and sibling support groups. and medical conditions. It is the most com-
mon genetic cause of intellectual disabilities,
and some degree of cognitive impairment is
Adolescence and Adulthood present in all individuals with Down syn-
Outcomes drome. Despite a number of medical co-
morbidities, ranging from cardiac defects to
As a child with Down syndrome enters dermatological conditions, improvements in
young adulthood, concerns regarding voca- management and intervention have extended
tion and independent living emerge. Prior to the average lifespan of these individuals. De-
the implementation of Public Law 94-142, pending on adaptive behavior functioning
the Education for All Handicapped Children and cognitive ability, individuals with Down
Act of 1975, vocational training was not syndrome can achieve a degree of indepen-
considered to be an integral part of service dence within a supportive environment.
for adolescents with disabilities. Individuals
should be prepared to function as indepen-
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social and object mastery in children with Down ings of temperament in samples of children with
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Biomedical concerns in persons with Down syn- M. Pueschel & J. K. Pueschel (Eds.), Biomedical
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concerns in persons with Down syndrome. Bal- C., & Kuilman, M. (1997). Prospective study of
timore: Brookes. the prevalence of Alzheimer-type dementia in in-
Sexton, D., Thompson, B., Perez, J., & Rheams, T. stitutionalized individuals with Down syndrome.
(1990). Maternal versus professional estimates American Journal on Mental Retardation, 101,
of developmental status for young children with 400–412.
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Early Childhood Special Education, 10, 80–95. of early intervention services in Massachusetts:
Shonkoff, J. P., Hauser-Cram, P., Krauss, M. W., Implications for policy. Educational Evaluation
& Upshur, C. C. (1992). Development of infants and Policy Analysis, 16, 87–99.
with disabilities and their families: Implications Wishart, J. G. (1991). Taking the initiative in learn-
for theory and services delivery. Monographs of ing: A developmental investigation of infants with
the Society for Research in Child Development, Down syndrome. International Journal of Dis-
57(6, Serial No. 230), 1–17. ability, Development and Education, 38, 27–44.
Sloper, P., Cunningham, C., Turner, S., & Knus- Wishart, J. G. (1995). Cognitive abilities in children
sen, C. (1990). Factors related to the academic with Down syndrome: Developmental instability
Down Syndrome 381
and motivational deficits. In C. J. Epstein, T. Has- Yoder, P. J., & Warren, S. F. (2004). Early predic-
sold, I. T. Lott, L. Nadel, & D. Patterson (Eds.), tors of language in children with and without
Etiology and pathogenesis of Down syndrome. Down syndrome. American Journal on Mental
New York: Wiley-Liss. Retardation, 109, 285–300.
Wishart, J. G. (2007). Socio-cognitive understand- Zickler, C. F., Morrow, J. D., & Bull, M. J. (1998).
ing: A strength or weakness in Down’s syndrome? Infants with Down syndrome: A look at tem-
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Wishart, J. G., & Duffy, L. (1990). Instability of Zigman, W. B., & Lott, I. T. (2007). Alzheimer’s
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Chapter 20
Klinefelter Syndrome
Heather Cody Hazlett

Mario Gaspar De Alba
Stephen R. Hooper
Klinefelter syndrome (KS) is a disorder man, 1970; Schroder, Chapelle, Hokola, &
seen in males, resulting from an abnormal- Virkkunen, 1981). These studies, however,
ity found at the chromosomal level. It was had serious methodological problems be-
first described in 1942 by Klinefelter, Re- cause they were generally conducted with
ifenstein, and Albright, who used the term populations that were already institution-
to describe a small group of infertile men. alized or imprisoned (Cohen & Durham,
More than a decade later, the discovery of 1985). Unfortunately, even some subsequent
an extra X chromosome was used to distin- literature has relied on these early findings to
guish the syndrome further. Consequently, describe individuals with KS as having high
KS is considered a sex chromosome disorder. rates of incarceration and mental problems
Normally, males are born with 46 chromo- (Gilbert, 1993).
somes, with their gender being defined by a More recent research indicates that al-
pairing of an X and a Y chromosome. Males though there may be some significant cogni-
born with KS, however, typically show an tive, psychiatric, or behavioral problems in
XXY pattern. There are some other varia- these individuals, outcomes are not as grim
tions, such as XXXY or XXXXY, and also as the earlier conceptualizations indicated.
cases considered to reflect mosaicism, which Several longitudinal studies have contrib-
is characterized by having a combination of uted to our understanding of developmental
normal and abnormal cells. The prevalence outcomes in KS. For example, large prospec-
of KS has been estimated at between 1 in tive studies conducted during the late 1960s
500 and 1 in 1,000 live-born males (Bojesen, and early 1970s compiled outcome data for
Juul, & Gravholt, 2003; Lanfranco, Kamis- children born with sex chromosome abnor-
chke, Zitzmann, & Nieschlag, 2004). Esti- malities. Bender and Berch (1990) outlined
mates conducted in Denmark of all males the most important findings from this re-
born during a 13-year period have been research. First, children with sex chromosome
ported to be as high as 1 in 426 (Nielsen & disorders appear to display increased risk for
Wohlert, 1991). developmental, language, learning, and be-
Earlier studies of males with KS found an havioral problems, compared to peers with a
increased risk for psychiatric disorders, crim- normal sex chromosome complement; how-
inality, and intellectual disabilities (Forss- ever, their profiles appear relatively benign
382
Klinefelter Syndrome 383
by comparison with earlier stereotypes, thus somic (Pellestor, Andreo, Arnal, Humeau, &
supporting the notion that earlier studies Demaille, 2002). Rather than the normal XY
examined biased samples. Second, there is genotype that signifies the male gender, boys
a great deal of variability in the phenotype with KS will typically display a trisomy or
of children with the same syndrome, and XXY pattern of sex chromosomes. This tri-
family/environmental influences may medi- somy can occur through various errors. If it
ate the amount of dysfunction displayed be- is maternally derived, an XXY genotype can
cause of the significant variability associated be due to an error during meiosis I, meiosis
with KS. It is now widely accepted that the II, or the early mitotic division in the zygote
original description of males with KS is not (this last is referred to as a postzygotic mitot-
entirely accurate and that they can actually ic error). The XXY pattern can result from
present a wide spectrum of phenotypic vari- paternal nondisjunction only during meiosis
ation (Lanfranco et al., 2004). Our descrip- I (Thomas & Hassold, 2003). Roughly 50%
tion of KS in this chapter addresses the most of KS cases are caused by maternal meiotic
recent and well-accepted findings regarding errors, with three-fourths of these reported
these children and their neuropsychological to show significant effects of maternal age
functioning. It must be noted that studies in- (Gardner & Sutherland, 1996). Some have
volving males with KS typically include only reported maternal age to be a contributing
small cohorts, due to the limited number of factor in approximately 60% of a sample
affected individuals identified. Moreover, of males with KS (Drugan, Isada, Johnson,
these findings must be considered carefully, & Evans, 1996b), while others have found
given that an estimated 70–75% of these in- rates of paternal nondisjunction to occur in
dividuals are never diagnosed due to a lack slightly over half (57%) of the cases, with
of clinically significant signs, symptoms, and the exception of those directly linked to ad-
other manifestations (Bojesen et al., 2003; vanced maternal age (Evans et al., 1996).
Lanfranco et al., 2004). Several studies have shown an equal distri-
bution of maternally and paternally derived
KS. Advanced maternal age and, less clearly,
Genetic and Familial Issues paternal age have also been linked to an in-
Related to Etiology creased risk for KS (Lowe et al., 2001). Ap-
proximately 10% of individuals with KS ex-
There are several different types of genetic hibit mosaicism, meaning that not all cells
disorders. These include autosomal domi- examined display the XXY trisomy; instead,
nant disorders (e.g., Huntington chorea), some show a normal XY pattern because the
autosomal recessive disorders (e.g., phe- nondisjunction error occurred after fertiliza-
nylketonuria), X-linked disorders (e.g., tion (Pierce, 1990).
Lesch–Nyhan syndrome), and those that in- KS is one of the most frequently occurring
volve chromosomal abnormalities. KS falls sex chromosome abnormalities in males. In
into this last category, since it is caused by general, the sex chromosome abnormalities
sex chromosome abnormality. The phenom- produce less significant impairments than
enon that results in a chromosomal abnor- those involving autosomal abnormalities
mality is referred to a nondisjunction. This (e.g., Down syndrome, Edwards syndrome).
occurs when a pair of chromosomes fails to Hynd and Willis (1988) noted two hypoth-
separate during either the first or second di- eses for this distinction. One is that the Y
vision of meiosis. When nondisjunction oc- sex chromosome appears to carry only in-
curs, it results in aneuploidy (the absence or formation necessary for gender determina-
addition of a single chromosome—a mono- tion. The second notes that any number of X
somy or trisomy, respectively). Aneuploidy chromosomes greater than the normal one
is the most common type of chromosome appears to become relatively inactive in early
anomaly found in live births or spontaneous fetal development.
abortions, occurring in approximately 3% of A diagnosis of KS can be made by a thor-
all confirmed pregnancies (Evans, Drugan, ough physical exam, by hormone testing,
Pryde, & Johnson, 1996). Some authors and most accurately through genetic testing.
suggest that up to 10–25% of all fertilized Genetic testing is done prenatally by amnio-
human oocytes are either monosomic or tri- centesis or chorionic villus sampling, and
postnatally through karyotyping (Pierce, sequent research has expanded on these

1990). There are no familial indicators that observations. At birth, males have normal
would suggest a higher risk for produc- male genitalia without ambiguity, with oc-
ing a child with KS, although females with casional micropenis and hypospadias (Zeger
trisomy XXX have been reported to be at et al., 2008). As they grow, decreased tes-
greater risk for producing offspring with KS ticular size is the only consistent physical
or XXX, and (in fewer cases) trisomy 21 feature in KS (Visootsak & Graham, 2006).
and monosomy X0 (Drugan et al., 1996b). Cryptorchidism is also seen more frequent-
Advanced maternal age is a risk factor for ly than in healthy controls (Bojesen, Juul,
any pregnancy, and in these cases a prenatal Birkebaek, & Gravholt, 2006). Hormonal
diagnosis of KS may be possible. Advanced disturbances become problematic dur-
paternal age has also been implicated as a ing puberty, as secondary sex characteris-
risk factor for KS (Sloter, Nath, Eskenazi, tics may be diminished by restricted levels
& Wyrobek, 2004). Males with KS display of testosterone (see below). According to
a broad range of characteristic physical fea- Schwartz and Root (1991), KS is the most
tures and hormonal derangements, which common cause of hypogonadism in males.
are discussed below. Many of these may or The testes initially enlarge normally to their
may not be present at birth, and therefore peak size at midpuberty, but as the seminif-
the existence of an extra X chromosome erous tubules (which constitute 85% of the
may not be suspected or discovered until volume in the testes) hyalanize and fibrose,
concerns about genital and pubertal develop- they decrease in size and become firm. Ulti-
ment surface, or later during testing for in- mately, the affected testes are smaller than
fertility (Drugan, Isada, Johnson, & Evans, average—t ypically less than 2.5 cm in diam-
1996a). In an overview of genetic disorders eter, and with a postpubertal volume of less
and their onset, Weatherall (1991) placed than 10 ml (Smyth & Bremner, 1998; Tyler
the average age for first appearance of KS- & Edman, 2004). Facial, axillary, and pubic
related impairments at 5 years. A more re- hair tends to be sparse. Infertility is caused
cent study suggested that fewer than 10% of by progressive destruction of spermatogonia
boys with KS are diagnosed before puberty, during puberty, which leads to azoospermia
and (as noted above) that possibly up to 70% and is one of the primary disabling features
of affected males with KS may never receive of KS (Wikstrom et al., 2004). New assistive
a diagnosis (Bojesen et al., 2003). reproductive technologies, such as sperm
recovery through testicular biopsy and in
vitro fertilization using intracytoplasmic
Medical Concerns sperm injection, have given men with KS
and Comorbid Disorders reproductive options that they did not pre-
viously have; these procedures have resulted
Generally speaking, the sex chromosome in viable pregnancies (Denschlag, Tempfer,
disorders have less of an impact on the phe- Kunze, Wolff, & Keck, 2004; Paduch, Fine,
notype than autosomal disorders do. With Bolyakov, & Kiper, 2008).
autosomal trisomies, as an example, there
may be multiple affected systems and great-
Hormonal Disturbances
er physical anomalies. The sex chromosome
trisomies cause have less global impairment, Among the chief features of this syndrome
but the development and function of the sex are the endocrinological disturbances that
organs, hormonal production, and repro- impair normal genital and sexual develop-
duction are all negatively affected by sex ment. Typically, a postpubertal patient will
chromosome trisomies (Evans et al., 1996). present with low to low-normal serum testos-
terone and inhibin B (marker of Sertoli cell
function), higher concentrations of luteiniz-
Genital Anomalies
ing hormone (LH) and follicle-stimulating
In a review of the literature on the physi- hormone (FSH), and increased estradiol
cal characteristics of KS, Theilgaard (1984) compared to genetically normal males (Lan-
found several classic genital anomalies com- franco et al., 2004; Paduch et al., 2008).
mon among these individuals, and sub- For the most part, authors have agreed that
these hormone levels are normal during ining (Visootsak & Graham, 2006). Increased
fancy and childhood, but recent studies have frequency of obesity has been described,
questioned this assertion. One study found and a tendency toward central obesity was
that 75% of the cohort with KS had testos- found in 75% of affected males in one study
terone levels below the 25th percentile for (Ratcliffe, 1999). A relatively large study of
age (Zeger et al., 2008). Other studies have 55 boys with KS found an increased preva-
presented conflicting information regard- lence of fifth-digit clinodactyly, hypertelor-
ing the levels of testosterone seen during the ism, high arched palate, and elbow dyspla-
hypothalamic–pituitary–gonadal axis surge sia (Zeger et al., 2008). Other associated
that typically occurs in the first months of findings seen more frequently in KS include
life (Aksglaede, Petersen, Main, Skakkebaek, diabetes mellitus, hyperlipidemia, hyperc-
& Juul, 2007; Ross et al., 2005). Regardless, holesterolemia, gallbladder disease, chronic
testicular activity is minimal during typi- pulmonary infection, and peptic ulcer (Zup-
cal childhood development; consequently, pinger, Engel, Forbes, Mantooth, & Claffey,
hypogonadism may remain clinically silent 1967). Hypogonadism in KS may cause an
until the increased hormonal activity and unfavorable change in body composition
expected changes at puberty are not seen. and result in the metabolic syndrome, which
LH stimulates testosterone secretion, while includes abdominal obesity, atherogenic
FSH stimulates the development of sperm dyslipidemia, elevated blood pressure, in-
during puberty. Therefore, although males sulin resistance or glucose intolerance, pro-
with KS will enter puberty at a normal age, thrombotic state, and proinflammatory state
inadequate testosterone secretion eventually (Ishikawa, Yamaguchi, Kondo, Takenaka,
prevents normal puberty from occurring & Fujisawa, 2008). Evans and colleagues
(Styne, 1991). There have been some mixed (1996) found diabetes to occur in 8% of
accounts of thyroid conditions in these chil- their total population of individuals with
dren, with some studies indicating an in- KS, as well as increased rates of elbow dys-
creased rate of congenital hypothyroidism, plasia, elongated limbs, chronic bronchitis,
and others showing no significant findings and poor fine motor coordination. There is
(Schwartz & Root, 1991). also an increased risk of decreased bone min-
eral content due to the androgen deficiency,
which results in osteopenia and osteoporosis
Neurological Findings
(Schwartz & Root, 1991). Some variants of
Some literature indicates that abnormal elec- KS (e.g., XXXY and XXXXY) have been
troencephalograms (EEGs) and seizure ac- associated with short stature or radioulnar
tivity are seen more frequently in males with synostosis (Schwartz & Root, 1991). In
KS than in the general population. Whether general, individuals with 46,XY/47,XXY
or not there is an increased rate of epilepsy mosaicism have fewer phenotypic findings;
in these males has not been determined con- as the number of X chromosomes increases
clusively. Essential tremor has been docu- (XXXY, XXXXY), the frequency of nearly
mented in a greater proportion of men with all phenotypic anomalies increases (Lan-
KS than in genetically normal controls (Har- franco et al., 2004). The one exception is
low & Gonzalez-A legre, 2009). Neuromus- height, which is inversely proportional to
cular findings show that when compared to the number of X chromosomes (Visootsak,
controls, boys with KS have lower scores on Aylstock, & Graham, 2001).
tasks involving fine and gross motor skills, Other nonspecific features include in-
coordination, agility, speed, dexterity, and creased rates of fatigue, venous stasis ulcers,
strength (Robinson et al., 1986; Ross et al., and essential tremor (Schwartz & Root,
2008). 1991). Of the few accounts of cardiac de-
fects associated with KS, these appear to
occur more frequently in the rarer cases of
Other Physical Features
polysomy (e.g., XXXXY) than in the more
Boys with KS are typically taller than aver- common XXY presentation (Elias & Yana-
age because of elongated legs. The height gi, 1981). In addition, the number and sever-
increase is most dramatic between the ages ity of these cardiac defects may be directly
of 5 and 8 years and is due to leg lengthen- correlated with the degree of polysomy. A
study that followed more than 600 men with terns, and motor developmental milestones
KS and documented the cause of death for are not significantly different. As noted ear-
163 of them demonstrated increased mor- lier, an increased height velocity (owing to
tality rates from diabetes, cerebrovascular, greater leg growth seen between the ages of
cardiovascular, pulmonary, and gastroin- 5 and 8 years) has been reported, as well as
testinal diseases, as well as increased risks a tendency toward central obesity (Ratcliffe,
of lung and breast cancer (Swerdlow et al., 1999). It is not until puberty, however, that
2001). Increased morbidity from ischemic more specific disturbances are noted. Bender
heart disease, deep vein thrombosis, pulmo- and Berch (1990) noted that the males in
nary embolism, and intestinal thrombosis their sample displayed reduced sensory–mo-
has also been seen (Bojesen et al., 2006). tor integration and motor strength. Others
Furthermore, the rate of meditational germ have found a variety of motor difficulties,
cell tumors is increased (Volkl et al., 2006). including decreased running speed, overall
Other studies have not shown a significant agility, and dexterity in visual–motor tasks
comorbidity of renal or lymphatic conditions (Ross et al., 2008). Gynecomastia has been
in this population (Evans et al., 1996). noted in a greater percentage of boys with
KS than of controls (Ratcliffe, 1999; Smyth
& Bremner, 1998).
Developmental Course For the purposes of comparison, typical
pubertal development is briefly reviewed.
About two decades ago, Schwartz and Root Normal secondary sexual development in
(1991) outlined common clinical presenta- males involves genital development and
tions of KS at the various developmental pubic hair growth, and features of puberty
stages, and their description remains useful related to the external genitalia may begin to
today. Specifically, during infancy, KS may develop at any time from age 11 to 15 years
be discovered during routine evaluations for (Wheeler, 1991). This process involves the
the presence of cryptorchidism, microphal- growth of the testes, maturation of the scro-
lus, or hypospadias. School-age children tum, and growth of the penis. In males with
may present with learning or behavioral/so- KS, the size of the penis is within normal
cial problems. During adolescents, clinical limits, but often on the smaller side, while
presentations may result from gynecomas- the testes begin to be distinguished by more
tia, delayed onset of puberty, abnormally obviously diminished size and maturation.
tall stature, small testes, or eunuchoid ha- Androgens control pubic hair growth, and
bitus. Adults are most often discovered dur- (as mentioned above) males with KS have de-
ing investigations of infertility, but may be creased androgen production, which results
identified during evaluations for malignan- in diminished or absent pubic hair growth.
cies and/or tumors. Normally, pubic, axillary, and facial hair
growth follows on the heels of genital devel-
opment; in KS, this growth may be delayed,
Physical Development and Puberty
diminished, or absent. During puberty, the
The majority of infants with KS are indistin- voice normally deepens and the bulboure-
guishable from unaffected infants at birth. thral glands enlarge. Both processes may be
However, Diamond and Watson (2004) cited abnormal in KS. In addition, although some
information from an Edinburgh study that breast enlargement is typical in normal ado-
found babies with KS to be smaller in weight, lescence, in KS there may be significant gy-
length, and head circumference than controls; necomastia (also as mentioned above). Other
their head circumference remained between major characteristics of normal pubertal
the 10th and the 25th percentiles. Fifth-fi nger development in males involve alterations in
and/or fifth-toe clinodactyly has also been lean body mass and fat distribution, and
seen in greater frequency (Simpson, 2003). rapid skeletal growth. In KS, fat deposition
Samango-Sprouse (2001) found the presence may be increased centrally, and the distribu-
of decreased muscle tone and delayed ambu- tion may mimic that of girls (e.g., hip and
lation, particularly in those children who had thigh) (Wheeler, 1991). Boys tend to take
not received therapy. In childhood, physical on a eunuchoid body habitus (long legs and
development generally follows normal pat- arms, narrow shoulders, wide hips, etc.).
Therefore, physical features at puberty and Rovet (1982) found evidence for dimin-
may involve absent or diminished growth of ished dermal ridge counts in a group of chil-
facial, chest, and pubic hair. Gynecomastia, dren with KS, indicating that their prenatal
small testes, central obesity, feminine fat dis- growth is slower.
tribution, and poor muscle tone may also be Hemispheric specialization in KS has been
present in these males, although varying de- studied by observing differences in their
grees of these conditions have been reported performance on verbal and nonverbal tasks.
(Pierce, 1990). Schwartz and Root (1991) Netley and Rovet (1984) found that a group
estimate that 30–60% of all children with of boys with KS performed more poorly than
KS will exhibit gynecomastia by late pu- controls on a number of tasks involving lat-
berty, and they place the prevalence of later- eral presentation of material. For example,
developing carcinoma of the breast at 9 in the boys with KS did more poorly on dichotic
1,000. They are careful to note that although stop consonants, whereas their performance
this rate is above that for genetically normal was better than that of controls on dichotic
men and one-fifth the rate for women, the melodies and half-field dots. The authors in-
role of the extra X chromosome in this higher terpreted these findings to mean that boys
risk for carcinoma in KS is unknown. Severe with KS have difficulty in dealing efficiently
gynecomastia is not improved with andro- with information normally preferentially
gen therapy, and mastectomy is often recom- processed by the left hemisphere, and that
mended when there are significant physical their right-hemispheric functions appear
or psychological concerns. Ratcliffe (1999) to play a larger role in both nonverbal and
found that gynecomastia was often transient verbal processing. Overall, when compared
and rarely required surgical correction. to age-matched controls, children with KS
have been found to display diminished left-
hemisphere specialization for language and
Neurological Development
enhanced right-hemisphere specialization for
Two hypotheses regarding neurological de- nonverbal processing (Netley, 1990). This
velopment have been put forth by Bender finding is supported by the fact that language
and Berch (1990) to explain the character- deficits also are seen in females with XXX,
istics seen in sex chromosome disorders. particularly in expressive language and audi-
One hypothesis is that the presence of a sex tory processing (Walzer et al., 1986). A study
chromosome anomaly may alter normal pat- examining dichotic listening performance
terns of brain growth, resulting in abnormal found that for a group with KS compared to
rates of brain tissue growth and matura- a control group, left-hemispheric processing
tion, which in turn will have an impact on was impaired when they were presented with
functioning. This causal pattern, implicated dichotic syllables (Theilgaard, 1984). Nar-
in cases of extra X chromosomes, is that rowing even further the potential structural
the extra chromosome interferes with left- basis for the neuropsychological deficits seen
hemisphere specialization for language, rein KS, a magnetic resonance imaging (MRI)
sulting in decreased language functioning. case–control study of 42 individuals with KS
The second hypothesis involves the impact demonstrated diminished total cerebral vol-
that hormones may have on brain growth ume and all lobar volumes, as well as a larger
and functioning. For example, the abnormal lateral ventricle volume, compared to those
testosterone levels seen in individuals with of controls. The cortex was significantly
KS may be related to their impairments in thinner in the group with KS in left inferior
verbal ability. Bender and Berch have been frontal, temporal, and superior motor regions
careful to point out, however, that neither (Giedd et al., 2007). A smaller study of 10 in-
hypothesis has been proven conclusively dividuals with KS found reduced volume of
with physiological, empirical evidence. Some the left temporal lobe gray matter (Patward-
implications for differences in brain growth han, Eliez, Bender, Linden, & Reiss, 2000),
patterns have been made by studying dermal and another study cited reduced volume of
ridges. These may be used as indicators of the insula, amygdala, hippocampus, cingu-
prenatal growth because they become dif- late, and occipital gyri, as well as diminished
ferentiated during midfetal development right parietal lobe white matter (Shen et al.,
and remain constant from that point. Netley 2004).
Cognitive Development to 100 (Simpson, 2003), but these studies

may not have included sibling controls for
There are distinctions between the cognitive
comparison. Netley (1987) sought to predict
deficits seen in trisomies of the sex chromo-
intellectual attainment in children with KS
some and those associated with the autosomal from observing the psychometric data of
trisomies. Individuals with sex chromosome their siblings. He found that compared to
trisomies may have normal or above-average their siblings, the boys with KS had lower
intelligence, and if intellectual disabilities intelligence test scores, particularly in verbal
are present, they are typically found to be in abilities, although their IQ scores were high-
the mild range. Autosomal trisomies, on the ly correlated with that of their unaffected
other hand, usually result in profound intel- siblings. This would indicate that aptitude in
lectual disabilities (Evans et al., 1996). Gen- young boys with KS might be predicted from
erally, studies have shown that children with that of their siblings. Some have hypoth-
KS may display a wide range of intellectual esized that the presence of an extra X chro-
ability, ranging from mild intellectual dis- mosome is what deflates the verbal skills,
abilities to above-average intelligence. Re- since females with an extra X chromosome
viewing a 37-year prospective study, Bender also display impaired verbal abilities (Cohen
and Berch (1991) noted that the cohort of & Durham, 1985; Netley & Rovet, 1982).
11 persons with KS had normal Verbal IQ Others propose that the extra X chromo-
(VIQ) and Performance IQ (PIQ) scores, al- some represents a risk factor for a specific
though they were skewed lower than those developmental reading disorder (Bender,
of their euploid siblings. Walzer, Bashir, and Puck, Salbenblatt, & Robinson, 1986).
Silbert (1990) found IQs to be 10–15 points In cases of polysomies (e.g., XXXY,
lower than those of typical peers in a group XXXXY), the level of intellectual impair-
of 13 boys with KS. Of these, 11 had dem- ment appears to increase with the number
onstrated learning problems in reading and of additional X chromosomes, with approxi-
spelling throughout their academic histo- mately a 15-point IQ decrease per extra X
ries. In an exhaustive literature review on chromosome (Simpson, 2003). Intellectual
the cognitive profile of boys with KS, Rovet, disabilities are frequent in those individu-
Netley, Keenan, Bailey, and Stewart (1996) als who have four or more X chromosomes
concluded that a chronic cognitive deficit (Gardner & Sutherland, 1996). Behavioral
in verbal abilities and language process- difficulties also appear more frequently in
ing was consistent across 27 independent this population. One case of a child with
research studies. In addition, a pattern of XXXXY has been reported where the child
general underachievement in school and risk did not display severe intellectual disability
for dyslexia was evident in these children. or abnormal social development (Sheridan
Rovet and colleagues conducted their own & Radlinski, 1988); however, the authors
longitudinal study of cognitive functioning noted that early intervention for learning
in KS; they followed 36 boys with KS and and a supportive home environment may
33 sibling controls for 20 years. Their find- have contributed to this atypical presenta-
ings indicated that compared to the controls, tion.
the boys with KS demonstrated significantly
depressed verbal ability contrasted with nor-
mal nonverbal ability. Language Development
Most studies agree that children with KS Young boys with KS have also been noted
have significant deficits in their verbal abili- to display delayed speech and language de-
ties. VIQ scores on traditional measures velopment, with the first words spoken at
(e.g., the Wechsler scales) are generally below between 18 and 24 months versus the more
average, while PIQ scores are within the av- typical 12 months (Simpson, 2003). Specific
erage range (Ratcliffe, Masera, & McKie, deficits have been discovered in the areas
1994). Rovet and colleagues (1996) found of articulation, phonemic processing, word
VIQ scores to be about 20 points lower than finding, language comprehension, verbal
those of unaffected siblings. Newer studies memory, oral expression, and linguistic pro-
estimate that both VIQ and PIQ scores are cessing speed (Geschwind, Boone, Miller,
normal and usually range from the low 90s & Swerdloff, 2000). Language delays have
been demonstrated to last up to 8 or 9 years aggressiveness, alcohol and other substance

of age, and some research indicates that they abuse, arson, criminal behavior, depression,
may continue through adulthood. In the lon- personality disorders, and schizophrenia in
gitudinal study mentioned above, Rovet and persons with KS (Schwartz & Root, 1991).
colleagues (1996) determined that males with As mentioned earlier, however, these stud-
KS had greater difficulty on tasks involving ies possessed methodological flaws. Chiefly,
auditory memory, language comprehen- they were limited to individuals who were
sion, and language expression. This finding already in psychiatric hospitals or penal
supports an earlier report by Leonard and institutions. More recent studies have sug-
Sparrow (1986), who found language delays gested that KS does not appear to be asso-
in a small sample of males with KS. These ciated with criminal behavior or sociopathy
individuals displayed delayed language de- (Wodrich, 2008), and in fact that psychiatric
velopment, limited vocabulary and syntax, problems are rare among men with KS (Ge-
difficulty with verbal concepts, and lack of schwind et al., 2000). Interestingly, the be-
fluency. In the prospective study by Walzer havioral characteristics associated with KS
and colleagues (1986), speech and language (e.g., low activity, high pliancy) have led some
delays were evident by the third year of life. researchers to find that teachers may view
Specifically, parents reported problems with these children as warm, likeable, anxious to
articulation, word finding, sentence forma- please, and helpful. The general tendency of
tion, and expressive language. Assessment of many individuals with KS to withdraw in
these children indicated that whereas recep- novel situations and to be less assertive may
tive language was age-appropriate, deficits tend to cause teachers to view these children
existed in auditory memory and expressive as lazy, unmotivated, or unwilling to try,
language (e.g., syntax, dysnomia, narrative however (Walzer et al., 1986).
production).
Other studies have suggested that men
Academic Performance
with KS have problems with the prosody of
language, as well as the semantic problems Academic difficulties have been found in the
described above. In a Dutch study compar- areas of reading, spelling, and arithmetic;
ing men with KS to 20 controls, the cohort these are probably related to specific lan-
with KS demonstrated relative difficulties guage deficits in the area of auditory–verbal
discriminating emotions in verbal content, processing (Schwartz & Root, 1991). Poor
and even more so in tone of voice (van Rijn school performance is typical in children
et al., 2007). These types of difficulties are with KS, particularly in reading and spell-
more likely to affect the ability to develop ing. In one study, 92% of individuals with
the appropriate social use of language. KS reported difficulties in learning to read,
and 70% had an absolute reading deficit
(Geschwind et al., 2000). Difficulties with
Behavioral, Academic, speech production, language processing, and
and Emotional Presentation sentence structuring are thought to interfere
with both reading and spelling (Mandoki,
Behavioral Presentation
Sumner, Hoffman, & Riconda, 1991). Re-
Behavioral development is felt to be the research looking at the development of reading
sult of certain predispositions and environ- and spelling in KS proposes that the course
mental influences. With children who have follows normal developmental patterns, but
genetic disorders, the physical consequences becomes arrested at some point (Seymour &
of the genetic abnormalities often result in Evans, 1988). Prospective and longitudinal
certain behaviors. However, as with all be- research (Robinson et al., 1986; Walzer et
haviors, the transactional interaction be- al., 1986) indicates that children with KS are
tween the children’s characteristics and their more likely to be referred for special educa-
environment must be considered in the etiol- tion evaluations by their classroom teachers,
ogy of their behavioral presentation (Hynd and also more likely to be enrolled in a learn-
& Willis, 1988). Research studies conducting disability classroom. In their longitudi-
ed in the 1960s and early 1970s with adult nal study, Rovet and colleagues (1996) found
populations tended to find increased rates of boys with KS to perform significantly worse
on measures of word decoding, reading com- lower-than-average activity (Stewart, Bai-

prehension, spelling, written language skills, ley, Netley, Rovet, & Park, 1986). Another
arithmetic, math problem solving, and the study of the psychological nature of adults
acquisition of conceptual knowledge in areas with KS found them to be less teasing and
such as science and humanities. In addition, sarcastic and more submissive than either
the boys with KS were found to perform lower controls or a group of XYY men (Schiavi,
on standardized achievement tests, and they Theilgaard, Owen, & White, 1984).
tended to fall further behind grade and age van Rijn, Swaab, Aleman, and Kahn
level expectations as they grew older. Interest- (2006) have suggested that, compared to ge-
ingly, Rovet and colleagues noted that most netically normal controls, men with KS have
of the boys with KS were equally impaired on greater difficulty with the accurate percep-
measures of reading and arithmetic; howev- tion of social-emotional cues (e.g., angry
er, they characterized the learning disability facial expressions) and experience greater
seen in KS as primarily language-based. The emotional arousal in response to emotion-
specific deficits demonstrated throughout all inducing events; these factors may cause
their findings appeared to reside in the area them to be more influenced by their emo-
of auditory–verbal processing. This hypoth- tions when making decisions under these
esis is supported by earlier research (Bender circumstances. Adding to their difficulty,
et al., 1986), which demonstrated significant men with KS seem to be less able to iden-
impairments in reading recognition, read- tify and verbalize the emotions they experi-
ing comprehension, and auditory short-term ence. These deficits impair social-cognitive
memory in a group of boys with KS. Bender processing and play an important role in the
and colleagues’ (1986) sample was char- social difficulties that have been previously
acterized by average intelligence, language described in this syndrome.
dysfunction associated with slow processing
and poor short-term memory, and a history
Social Problems
of reading difficulty in school.
As mentioned above, men with KS may dis-
play many characteristics that make social
Emotional Presentation
interactions problematic. These include so-
Various prospective studies done within this cial withdrawal, social anxiety, and shyness,
population describe children with KS as less as well as poor interpretation of the emo-
active, less assertive, and more susceptible tional content of facial expressions and ver-
to stress than controls (Bender & Berch, bal communication (Ratcliffe, 1999; Rob-
1990). Temperamentally, these boys are also inson, Bender, & Linden, 1990; van Rijn
depicted as introverted, lacking ambition, et al., 2006). This assortment of traits has
pliant, less sociable, and socially inappro- lead some researches to question whether
priate (Netley, 1990; Wodrich, 2008). In a an increased level of autistic traits exists in
longitudinal study, specific temperamental men with KS. Using the Autism Spectrum
characteristics were observed in a cohort of Quotient, a self-administered questionnaire
XXY males from birth to age 7 (Walzer et that assesses features of the core autistic
al., 1986). Interview and observational data phenotype in adults of typical intelligence,
were obtained on variables such as activity one study found that men with KS displayed
level, intensity of responding, pliancy (e.g., more autistic traits in all domains than con-
easy to manage, assertiveness), approach– trols did. Increased autistic traits were as-
withdrawal, adaptability, and capacity to re- sociated with more distress during social
late. Compared to a control group, the chil- interactions, and consequently less frequent
dren with KS were again consistently rated participation in social interactions (van Rijn,
as lower in activity and intensity, more pli- Swaab, Aleman, & Kahn, 2008). There have
ant, and more withdrawn in new situations. been a few case reports in the literature of a
On the Personality Inventory for Children dual diagnosis of autism and KS (Jha, Sheth,
(Lachar & Gruber, 1994), boys with KS & Ghaziuddin, 2007). Deficits in response
were found to differ significantly from con- inhibition have also been documented (Tem-
trols on ratings of achievement, intelligence, ple & Sanfilippo, 2003) and can have delete-
and development, in addition to ratings of rious effects on social interactions.
Key Assessment Issues a paucity of testosterone causes a pubertal

delay and a delay in the development of some
Several issues are relevant to KS within the secondary sexual characteristics.
context of diagnosis and assessment. First, Testosterone replacement therapy can have
if a diagnosis of KS is made upon birth or many beneficial effects, including regression
shortly thereafter through genetic testing, of gynecomastia, improved development of
both physiological development and learn- masculine secondary sexual characteristics,
ing capabilities can be assessed early and increase in muscle bulk and bone marrow
monitored over the course of the child’s density, increased energy and endurance,
schooling. Developmental surveillance is improved mood and concentration, and de-
critical following an early diagnosis and creased psychosocial problems (Bojesen &
should facilitate early intervention services Gravholt, 2007; Nielsen, Pelsen, & Sorens-
if problems surface. This developmental sur- en, 1988; Simm & Zacharin, 2006). Tes-
veillance should continue as the individual tosterone has been shown to have positive
grows older and can be assessed with more effects on fat mass, muscle mass, and muscle
specific types of tools. This assessment can strength, as well as sexual activity, and it
include comprehensive psychoeducational improves positive aspects of mood in young
testing, which can help determine which, if hypogonadal men (Wang et al., 2000). It
any, impairments are present. Of special im- has been suggested that treatment begin in
portance is careful assessment of language, early adolescence and continue lifelong, in
motor skills, and social-emotional function- order to prevent osteoporosis, obesity, the
ing (Wodrich, 2008). A detailed neuropsy- metabolic syndrome, and diabetes (Bojesen
chological evaluation may also prove useful & Gravholt, 2007). It is important to recall
in documenting a profile of abilities and as- that most patients with KS have only low-
sisting in ongoing treatment planning. normal levels of testosterone, but that virtu-
However, a child may not carry a diag- ally all have increased gonadotropin levels.
nosis, since many of the features most typi- For this reason, testosterone replacement
cal of KS (e.g., delayed puberty, diminished has been recommended if gonadotropin lev-
testes, absent secondary sex characteristics) els are elevated, even if testosterone levels are
do not appear until the beginning of ado- in the low end of the normal range. The aim
lescence. Therefore, child care professionals of testosterone supplementation is normal-
should be familiar with the characteristic ization of LH and testosterone levels to the
learning, behavioral, and physical presenta- middle of the normal range, rather than just
tion of KS in order to recognize affected in- the low-normal range (Bojesen & Gravholt,
dividuals, refer them for genetic evaluation 2007). Interestingly, a small imaging study
and appropriate psychoeducational testing, of 10 individuals with KS also found relative
and then implement interventions as early preservation of the gray matter in the left
as possible. Again, such testing should in- temporal region associated with exposure to
clude an evaluation of verbal abilities with exogenous androgen, and a subsequent asso-
an emphasis on expressive versus receptive ciation with increased verbal fluency scores
language functioning, verbal memory, and (Patwardhan et al., 2000).
auditory–verbal processing, as children with
KS are at risk for reading and spelling dis-
Psychosocial Problems
abilities.
Reviewing several studies of psychosocial
adjustment in boys with KS, Robinson,
Options for Treatment Bender, Linden, and Salbenblatt (1990)
provided common personality descriptors
Physiological Issues
from these studies, which included “shy,”
In infants born with hypospadias, cryp- “immature,” “restrained,” “reserved,” and
torchidism, or a significantly small phallus, “poor peer relationships.” The presence
appropriate and timely treatment and/or of a supportive and stable family environ-
surgical correction should be sought. Again, ment was noted to have positive effects on
however, a majority of individuals with KS psychosocial adjustment for these children.
are not diagnosed until adolescence, when Other studies have described this population
as cautious in new situations, low in motor (El-Badri & Lewis, 1991; Hindler & Nor-
activity, and possessing an easy disposition ris, 1986). There are also accounts of schizo-
(Walzer et al., 1990). Walzer and colleagues phrenia in KS, with the hypothesis that the
(1990) commented that these characteristics presence of an extra X chromosome and/or
predisposed children with KS to present as the abnormal hormonal levels during prena-
“low-key” children who were well liked by tal development may be the cause of this as-
their teachers and who had few behavioral sociation (Pomeroy, 1980; Roy, 1981). Other
management problems. One problem with types of psychopathology, such as bipolar
this study, and a characteristic that plagues disorders, have been linked to KS, but there
much research with the sex chromosome is less of a consensus regarding this relation-
disorders, is that the study examined both ship (Everman & Stoudemire, 1994). When
XXY and XYY boys. bipolar disorders are present, however, most
Bender, Linden, and Robinson (1990) de- accounts trace the etiology of these disorders
scribed a high-risk profile for children with to the presence of the extra X chromosome.
sex chromosome disorders, based on the re- In an older study examining the sexual
sults of a prospective study. These high-risk development of individuals with KS, these
children tended to be those who had prob- males were found to date and become sexu-
lems communicating with peers; academic ally involved at a later age than their peers
problems marked by low achievement; few (Raboch, Mellan, & Starka, 1979). In view
hobbies or little participation in extracurric- of the KS-related tendencies toward with-
ular activities; behavioral immaturity; and drawal and negative peer interactions, this
social isolation. This profile was viewed as relative delay is understandable. A survey of
a risk for poor psychosocial functioning as men seen at an infertility clinic who were de-
well as adult psychopathology. The authors termined to have KS reported below-average
also recognized the importance of environ- school performance, little energy, poor re-
mental factors in determining outcome. lations with parents or siblings, and more
mental illness than seen in a control group
(Kessler & Moos, 1973); however, it should
Emotional Problems
be noted that many individuals with KS do
The abnormal sexual characteristics as well marry and have successful relationships as
as the academic difficulties associated with adults.
KS often result in low self-esteem and poor As noted earlier, no current research sup-
self-concept in later adolescence or young ports the older contention that these indi-
adulthood. A follow-up study indicated that viduals have higher rates of criminality or
adult males with KS are often lonely, imma- mental health problems. Although earlier
ture, and passive, and that they may have studies asserted this possibility (Murken,
few friends (Nielsen, Johnsen, & Sorensen, 1973; Zuppinger et al., 1967), these studies
1980). Testosterone treatment’s therapeu- had significant methodological flaws (e.g.,
tic effects on sexual development have also problems with sample size and selection
been found to improve problems stemming bias), which more recent work has attempted
from low self-esteem (Nielsen et al., 1988; to correct. In fact, more recent studies have
Schwartz & Root, 1991). Mazur and Clop- reported results showing no increased rates
per (1991) reviewed clinic cases they had of mental health problems, and indeed a rar-
seen with gynecomastia and determined that ity of psychiatric problems, among men with
one of the greatest related concerns was the KS (Geschwind et al., 2000). Other studies,
impact on psychosocial functioning. They however, continue to demonstrate a signifi-
reported that their patients had a history of cantly increased risk of discharge from hos-
being teased by peers regarding their breast pitals with a psychiatric diagnosis (Bojesen
development, which in turn resulted in social et al., 2006). Still, the consensus is that there
isolation and withdrawal in approximately appears to be a significant increase in psy-
70% of these children. Cases of anorexia chosocial problems due to impulsivity and
nervosa have been described in conjunction social inappropriateness in this subpopula-
with KS, with poor body image and prob- tion, as well as introversion, unassertive-
lems with puberty implicated in the etiology ness, and lack of ambition (Geschwind &
Dykens, 2004). There is no evidence indicat- Adolescence and Adulthood

ing increased sociopathy or criminal intent Outcomes
in this population.
Onset of adolescence is typically not delayed,
but it is during this period that the major
Educational Problems
implications of this disorder become mani-
Given the difficulty identifying infants with fest. As discussed above, among the chief
KS who may not display any abnormal fea- signs are the smaller testes. An androgen
tures (e.g., congenital abnormalities), teach- deficiency may also be determined by test-
ers may come across these undiagnosed ing blood levels, with typical treatments in-
children later once they enter the regular volving testosterone replacement. Although
classroom setting. For example, Mandoki some literature recommends that this treat-
and Sumner (1991) described the case of a ment begin at age 12 for all children with
14-year-old male who was diagnosed with KS, this policy remains debated (Gardner &
KS only after suffering from years of aca- Sutherland, 1996). The beneficial results of
demic failure, interpersonal problems, and this treatment have been described earlier.
emotional disturbance. Some physical fea- A small study examining both physiologi-
tures that may indicate KS include a small cal and psychological changes as a result of
head circumference, greater-than-average testosterone treatments found that the males
height, small genitals, and proportionate- with KS not only began to develop a more
ly long legs (Mandoki et al., 1991). When masculine physique and secondary sex char-
these characteristics are coupled with learn- acteristics, but also had improved percep-
ing difficulties specific to reading and spell- tions of body image, increased assertiveness
ing, a referral for diagnostic testing (i.e., by and goal-directed behavior, and heightened
karyotype) may be in order. The most com- sexual drive (Johnson, Myhre, Ruvalcaba,
mon presenting problems of undiagnosed Thuline, & Kelley, 1970). Approximately
boys with KS are school underachievement, 50% of adolescents with KS will display gy-
poor peer relationships, impulsivity, aggres- necomastia, which can be treated surgically.
siveness, withdrawal, apathy, and immatu- Although infertility has been found to
rity. Some treatment with medication and be the general rule in individuals with KS,
hormones is available to address the abnor- and a cause of social-emotional strain, some
mal sexual development and aggressive be- exceptions have been reported in the litera-
haviors in these males (see above). Although ture. Gardner and Sutherland (1996) hy-
the learning disability will not be “cured” by pothesized that these reports were probably
this treatment, both medical and academic attributable to cases of mosaicism. A more
interventions are important for preventing important point made by these authors is
these features from developing. that there is a lack of information regarding
Some specific implications for the class- the risk of having children with sex chromo-
room have been offered by Rovet and col- some anomalies for individuals with KS who
leagues (1996). Generally, they feel that may produce children.
intervention efforts should center on the Genetic counseling for the family and the
language-based learning disorder. Speech– individual with KS can play an important
language therapy is recommended, with a role in ameliorating fears and improving
special emphasis on vocabulary building, outcomes. If KS is detected in utero through
improving sentence understanding, compre- amniocentesis or chorionic villus sampling,
hension skills, and word finding. Additional counseling should emphasize the expected
training to enhance memory functioning can phenotype and its wide variability, as well as
be provided by presenting advance organiz- a 10% increase in the risk of pregnancy loss.
ers for reading comprehension tasks, struc- Recurrence risk also should be discussed. Al-
turing lessons into smaller chunks to learn, though little empirical evidence exists in this
and providing drilling on math facts. Obvi- relatively small subpopulation to show any
ously, a detailed assessment of reading and recurrence risk at all, some have suggested
spelling skills will provide specific, targeted that the recurrence risk is probably close
areas for educational intervention. to that of trisomy 21 and trisomy 18—syn-
dromes resulting from similar age-related there will be additional gains in the treat-
meiotic nondisjunction errors (Simpson, ment outcomes for individuals with KS.
2003). The issue of sterility should be dis-
cussed with the parents and the male with
KS. Robinson and colleagues (1986) found References
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C h a p t e r 21
Phenylketonuria
Susan E. Waisbren
Historical and Theoretical able for this disorder is liver transplantation

Background (Vajro et al., 1993). Given the risks inherent
in liver transplantation, this “cure” is gen-
Religion, politics, geography, and genetics erally not considered. Moreover, treatments
all pertain to the study of phenylketonuria exist that prevent mental retardation, the
(PKU). An isolated community in San’a, most severe consequence of PKU.
the capital of Yemen more than 300 years In 1934, Asbjorn Følling, a Norwegian
ago, was probably home to the bearer of an physician, discovered PKU. A mother of
unusual gene for PKU. The Jews of Yemen two children with intellectual disabilities
were forbidden to marry persons of other came to see him after consulting many other
faiths, and others were punished by death doctors. She insisted that both her children
if they converted to Judaism. Consequently, had a similar degree of mental retardation
the gene spread only within this community, and patterns of behavior; in addition, she
and it has been possible to trace cases of PKU pointed out that both excreted urine with a
among Israelis of Yemenite Jewish origin to unique odor. Følling, who had also trained
the one family in San’a (Wright, 1990). Dif- in chemistry, studied the children’s urine
ferent mutations for PKU have been traced using a wide variety of agents until he dis-
to the Vikings and to gene bearers in Japan, covered that it contained a large amount
Italy, Denmark, Scotland, Ireland, Kuwait, of phenylpyruvic acid. He knew that phe-
South America, and South Africa. Each of nylpyruvic acid is a metabolite of phenylala-
these mutations leads to an obstruction in nine, and he suspected that the defect in this
the metabolism of phenylalanine, an essen- disorder involves phenylalanine metabolism
tial amino acid abundant in protein. As an (Følling, 1934). Others demonstrated that
autosomal recessive disorder, PKU is inher- the disorder is inherited and that excess phe-
ited from each parent and affects males and nylalanine is present in blood.
females at an equal rate. The mutant gene It was not until 1954, however, that a
produces a defect in the liver enzyme phe- treatment was discovered. Again a persistent
nylalanine hydroxylase (PAH), resulting in mother, this time in England, provided the
a block in the conversion of phenylalanine impetus for the discovery (see Koch, 1997).
to tyrosine. The only cure presently avail- She brought to a physician named Hørst
398
Phenylketonuria 399
Bickel her 17-month-old daughter, who Despite the straightforward results, the
had the typical features of PKU: intellec- simplicity of the method, and the clear ra-
tual disability, eczema, awkward gait, spas- tionale for newborn screening, its accep-
tic reflexes, and no language abilities. The tance was far from easy. With persistence
child took no interest in her surroundings, equal to that of the mothers from Norway
moaned incessantly, and banged her head. and England, Guthrie and MacCready lob-
The young doctor reasoned that perhaps if bied in Washington and traveled throughout
the child’s phenylalanine intake were limit- the United States arguing for mandatory,
ed, the buildup of the toxic amino acid could government-supported newborn screening
be prevented. Along with Louis Woolf, in (Koch, 1997). By 1964 they had succeeded
London, he created an amino acid mixture in Massachusetts, and 11 years later 43
containing all the necessary parts of protein states had enacted a newborn screening law
except for phenylalanine (Bickel, Gerrard, & (Paul, 1999). Today laws mandating new-
Hickmans, 1954). He advised the mother to born screening for PKU exist throughout
feed her daughter the special formula and to North America and most of Europe.
avoid all other protein foods or drinks. Two The reasons why PKU causes neurologi-
weeks later, the mother returned, claiming a cal problems remain unproven. Pathology
miracle. The little girl had learned to crawl reports, neuroimaging, research into bio-
and pull herself to a stand, and was bright chemical pathways, and studies using ani-
and cheerful instead of dull and irritable. mal models suggest that the accumulation
Bickel prescribed continuation of the treat- of phenylalanine metabolites in blood is not
ment, but this time added phenylalanine to directly related to neuropsychological defi-
the formula. The mother returned 2 days cits in PKU, but rather indirectly linked to
later to report that her daughter had revert- aberrations in myelin, competition across
ed to the previous state and that the formula the blood–brain barrier, and reductions in
no longer worked (Gerrard, 1994). Through neurotransmitters (Surtees & Blau, 2000).
this experiment, Bickel proved that phenyla- These hypotheses are described below.
lanine caused the neurological problems and
that dietary treatment was beneficial. He •• Myelin synthesis and turnover. Pheny-
also realized that the sooner the special diet lalanine or its metabolites in large quanti-
could be started, the greater the benefit. ties may be toxic to the brain by inhibiting
The scene then shifted to the United myelin development (Scriver & Kaufman,
States, where Robert Guthrie met Robert 2001). Magnetic resonance imaging (MRI)
MacCready at a meeting of the National As- studies suggest that when phenylalanine lev-
sociation for Retarded Children. Each was els are high, myelination in the brain is re-
a father of a child with intellectual disabili- duced (Scarabino et al., 2009). In untreated
ties. MacCready was also the director of the or poorly treated children with PKU, my-
Diagnostic Division of the Massachusetts elination is delayed; in adults who discon-
Public Health Laboratories in Boston, and tinue the diet, dysmyelination occurs. Since,
Guthrie was a physician and microbiolo- however, the degree of myelin in the brain
gist from Buffalo, New York. Guthrie told has not been clearly associated with IQ or
MacCready about a test he had invented, clinical symptoms in PKU, the precise mech-
the now famous Guthrie bacterial assay for anism of phenylalanine toxicity has eluded
the filter paper blood test (Guthrie & Susi, investigators (Jones et al., 1995).
1963). From a drop of blood obtained from •• Competition for transport. Phenylala-
the heel of a newborn infant, PKU could be nine competes with several other essential
identified within the first few days of life. amino acids (large neutral amino acids, or
Treatment started at this early age prevented LNAAs) for transport across the blood–
intellectual disabilities. MacCready was so brain barrier. Since the transport across the
impressed by this new technology that he blood–brain barrier tends to have a higher
spent a week in Buffalo learning the test. affinity for phenylalanine than for the other
He brought it back to Boston, installed it in LNAAs in the presence of a high level of
the Bacteriology Laboratory, and started the blood phenylalanine, the usual amounts
first newborn screening program for PKU of other amino acids, such as tyrosine and
(MacCready, 1963). tryptophan, fail to reach the brain (Miller,
Braun, Pardridge, & Oldendorf, 1985). Ty- sufficiently to prevent some increase in the
rosine and tryptophan are precursors of the tyrosine level; hence these experimental ani-
neurotransmitters dopamine and serotonin, mals were never very similar to humans with
respectively, which are consequently reduced PKU, who had chronically low levels of ty-
in the brain (Güttler & Lou, 1986; Krause et rosine. Using classical mutagenesis and selec-
al., 1985). Moreover, reduction of important tive breeding, researchers began to “create”
amino acids is likely to inhibit protein syn- the PKU mouse. When a known mutagen
thesis in the brain, which is critical for cog- was fed to hundreds of pregnant mice, and
nitive functioning (Hoeksma et al., 2009). when a phenylalanine-loaded diet was then
•• Dopamine reduction. Since phenylala- fed to the offspring, mice suspected of being
nine cannot be metabolized to tyrosine in carriers of the mutant PAH gene could be
PKU, tyrosine is reduced, and the metabo- identified. After cross-breeding carriers for
lites of tyrosine are also reduced. One of three generations, the researchers eventually
these metabolites is the neurotransmitter created a strain of mice with PKU. These
dopamine, and, as expected, dopamine lev- mice, when fed a normal-protein diet, had
els are reduced in the cerebrospinal fluid of elevated phenylalanine levels and appeared
people with PKU. Moreover, certain parts of to have intellectual disabilities; for instance,
the brain, specifically the prefrontal cortex, they could not swim, while their littermates
are highly sensitive to even modest reduc- without PKU did so easily. Moreover, these
tions in dopamine; this explains why specific mice had lighter-colored coats and were
functions related to these brain areas are se- smaller in size—features corresponding
lectively impaired in patients with PKU (Di- to the lighter hair and smaller stature of
amond, Ciaramitaro, Donner, Djali, & Rob- children with untreated PKU. When fed a
inson, 1994). Treatment with large doses of phenylalanine- restricted but otherwise nu-
tyrosine, however, do not prevent the neuro- tritionally balanced diet, the mice began to
logical effects of PKU. Years ago, a child was look more like their siblings without PKU.
not treated with the phenylalanine-restricted Some probably even learned to swim (Mc-
diet, but instead was treated only with high Donald, Bode, Dove, & Shedlovsky, 1990;
doses of tyrosine. Unfortunately, the treat- Shedlovsky, McDonald, Symula, & Dove,
ment was unsuccessful, and the child devel- 1993).
oped severe intellectual disability (Batshaw, With these mice, researchers have begun
Valle, & Bessman, 1981). In a more recent to study more closely the parts of the brain
study, adults with PKU who had discontin- affected by PKU. Myelin abnormalities were
ued or relaxed treatment were administered found to be a result of increased myelin
high doses of tyrosine or a placebo in a dou- turnover and decreased myelin production
ble-blind crossover study. Despite increases (Surtees & Blau, 2000). Moyle, Fox, Arthur,
in plasma tyrosine (and presumed increases Bynevelt, and Burnett (2007) found that in
in brain dopamine) during tyrosine supple- mice with PKU there is significant hypomy-
mentation, no beneficial effects were noted elination, as well as decreased activity of an
(Pietz, Landwehr, Schmidt, de Sonneville, & enzyme that contributes to cholesterol bio-
Trefz, 1995). Thus high phenylalanine levels synthesis regulation. Regions of the brain
are still considered the most likely patholog- that are known to myelinate before birth do
ical agent in PKU. not show this decreased activity, whereas re-
gions that develop after birth do.
Questions about neuropathology in PKU Cabib, Pascucci, Ventura, Romano, and
led investigators to search for animal mod- Puglisi-A llegra (2003) found that mice with
els, where brain chemistry could be studied untreated PKU had an impaired ability to
directly. Until the 1990s, no monkeys, mice, encode spatial and nonspatial information,
rabbits, or any other animals with PKU could whereas healthy mice showed no impair-
be found. It was possible to raise the blood ments, suggesting a profile of learning dis-
phenylalanine levels of normal animals by abilities similar to that found in children
loading the diet with phenylalanine, often with PKU. Pascucci, Andolina, Ventura,
in conjunction with an inhibitor of the PAH Puglisi-A llegra, and Cabib (2008) later ex-
enzyme. However, the conversion of phe- plained these deficits as potentially related to
nylalanine to tyrosine could not be blocked reduced availability of brain amines during
Phenylketonuria 401
postnatal development. Mihalick, Langlois, peared to have a milder form of PKU than
Krienke, and Dube (2000) reported on a people in Ireland: They could tolerate more
study in which mice searched for a treat hid- protein, they had lower blood phenylalanine
den in one of two different scented areas of levels, and they seemed to be less affected
sand. The task required learning where the by their PKU. In the 1980s, the answer to
treat was most likely to be hidden, based on this puzzling picture appeared. Woo and
previous trials. Although healthy mice were colleagues (1983) cloned the gene for PAH,
able to complete this task without difficul- the enzyme responsible for the conversion of
ties, mice with untreated PKU were slower phenylalanine to tyrosine. When this gene is
to find the hidden treat, suggesting slower defective, the enzyme does not function or
mental processing abilities. does not function completely; as a conse-
Although devastating effects usually occur quence, a rise in phenylalanine occurs. The
when PKU is untreated, and close-to-normal investigators eventually realized that many
development is attained when PKU is treated mutations exist in the PAH gene. Mapped
within the first weeks of life, there are excep- to chromosome 12, the PAH gene is 90 kb
tions. A few individuals with untreated PKU in length (12q22–24.2; 13 exons). Most chil-
and high phenylalanine levels have average dren inherit two different mutations, result-
intelligence, and some individuals with well- ing in substantial genetic heterogeneity in
treated PKU suffer neurological effects and those with PKU (Scriver, Kaufman, Eisen-
have lower IQs than their siblings. Two indi- smith, & Woo, 1995). By 1996, there were
viduals in the same family occasionally have over 250 known mutations linked to PKU
dramatically different outcomes. None of (Guldberg et al., 1996); by 2009, 560 dif-
the theories regarding the pathology in PKU ferent mutations had been identified (www.
can yet explain these exceptional cases. PAHdb.mcgill.ca).
Does genotype make a difference? The an-
swer is yes and no. Studies (e.g., Trefz et al.,
Genetics 1993) suggest that patients with classic PKU,
who have blood phenylalanine levels greater
The small warning label on diet soda cans than 20 mg/dl on a normal diet and no ac-
containing the artificial sweetener aspar- tivity of the PAH enzyme, have genotypes
tame reads, “Phenylketonurics: Contains differing from those patients with mild PKU
phenylalanine.” This warning has greatly (with blood phenylalanine levels of 10–20
increased the public awareness of PKU. In mg/dl and 5–15% residual activity of the
reality, PKU is one of the most common ge- enzyme) and of patients with non-PKU hy-
netic disorders known. In the United States, perphenylalaninemia (with blood phenylala-
1 out of 50 people are carriers. Results of nine levels of 2–10 mg/dl and an estimated
newborn screening of over 5 million neonates 25% residual activity of PAH).
from throughout the world indicate varying The phenotype, however, depends pri-
rates. PKU is almost unknown among indi- marily on the particular combination of
viduals of African descent, but fairly com- genes inherited from the mother and father.
mon among those of European descent, with For example, a patient with the genotype of
prevalence rates ranging from 1 in 5,400 in R408W/IVS-12 will have a more severe bio-
Ireland to 1 in 11,000 in the United States chemical defect (and probably a lower IQ)
and 1 in 16,000 in Switzerland (Woo, Lid- than a patient with the genotype R408W/
sky, Guttler, Chandra, & Robson, 1983). Y414C, even though the two patients share
As an autosomal recessive disorder, PKU is the R408W gene. The reason is that although
inherited from both parents. When both the the R408W mutation confers no PAH en-
mother and father are carriers, the chance of zyme activity, the Y414C allows for enough
each child’s inheriting PKU is 1 in 4. of the enzyme activity to produce mild PKU,
Soon after PKU was discovered, physi- whereas the IVS-12 mutation also confers no
cians and parents noted that not all children PAH activity and thus results in severe PKU.
with PKU were the same in their phenyla- In addition to the genetic factors related to
lanine levels when off diet, or in their tol- the PAH genotype, however, other physi-
erance for phenylalanine before their blood ological and genetic factors affect the pheno-
levels rose. People in Italy, for example, ap- typic outcome in PKU (Ozalp et al., 1994).
An intriguing question is that of the per- children are eventually diagnosed in early
sistence of PKU in the population. Some childhood. Treatment at this stage often re-
people have argued that the disease should sults in improvement, with some children
have “died out,” since before the era of new- who neither walked nor talked at age 3 or
born screening, amost all individuals with 4 years reaching these developmental mile-
PKU had severe intellectual disabilities, and stones shortly after restriction of their phe-
few reproduced. One explanation is that nylalanine intake. Eventual developmental
new mutations occur frequently enough to outcome in these children is variable, with
replace mutations that have disappeared some attaining an IQ within the average
through lack of reproduction (Levy, 1989). range, but most others performing within
Others believe that there must be a selective the range of mild to moderate intellectual
advantage to carrier status for PKU (Kidd, disability. Late treatment such as this, how-
1987), possibly including a lower spontane- ever, is almost always associated with sig-
ous abortion rate (Woolf, 1976). Most likely, nificant learning disabilities, even when IQ
carrier status is sufficiently high to remain is within the average range.
constant, despite the rates at which affected
individuals reproduce (Kirkman, 1982). Pre-
Dietary Treatment
natal diagnosis is available for PKU (Scriver
et al., 1995), but is not commonly request- Dietary treatment for PKU consists of a
ed. phenylalanine-restricted diet, including a
special formula and foods low in phenylala-
nine. Until recently, the only formula options
Developmental Course have been amino-acid-based formulas that
under Various Conditions contain all of the necessary nutrients (amino
acids) in protein, apart from phenylalanine.
No Treatment or Late Treatment
Unfortunately, amino acids in this form have
Children with classic PKU, if untreated, a distinctive, strong taste and odor. Almost
have severe intellectual disabilities, eczema, all infants accept the formula without dif-
seizures, ataxia, motor deficits, and behav- ficulties; however, some children find it dis-
ioral problems. Autism is often prominent. tasteful as they grow older, and many adults
Although they appear normal until about returning to the diet deem it unpalatable.
age 6 months, infants with untreated PKU The diet permits sugars and fats; measured
gradually exhibit developmental problems amounts of fruits and vegetables; and spe-
and can display self-mutilation, aggression, cial low-protein pastas, grains, and breads.
impulsivity, and psychosis (Penrose, 1972). Meats, fish, eggs, dairy products, nuts, soy
Parents and caretakers today now intro- products, regular grains, and corn are not
duce the special phenylalanine-restricted allowed. When children or adults “cheat” or
diet to adults with untreated PKU when consume more than the allocated amount of
medications and behavioral programs fail protein, they do not immediately feel ill, al-
to control psychotic symptoms, aggression, though a few individuals report feeling tired
or self-abuse. Follow-up studies document or distracted. Most experience no immedi-
little or no improvement in cognitive per- ate side effects. It is only the cumulative ef-
formance. However, case reports suggest fect of increased phenylalanine intake that
moderate and sometimes even dramatic im- is noticeable. Dietary control is monitored
provement in behavior if metabolic control through frequent sampling of blood pheny-
is achieved and maintained on a long-term lalanine levels.
basis (Adams, 2009; Baumeister & Baumeis- Until the 1980s, most clinics in North
ter, 1998; Harper & Reid, 1987; Yannicelli America and Europe recommended diet
& Ryan, 1995). discontinuation during middle childhood
Even today, an infant with PKU is occa- (Schuett & Brown, 1984). At about age 5 or
sionally missed in newborn screening be- 6 years, most children with PKU were sud-
cause of laboratory or hospital error. Not denly allowed to eat as much protein as they
receiving the benefit of early dietary therapy, desired. Although it was known that their
the child soon exhibits early signs of de- blood phenylalanine levels would rise, it was
velopmental delay. Most of these “missed” thought that their cognitive abilities would
Phenylketonuria 403
be unaffected. The fact that high phenyla- occur even in early and continuously treated
lanine levels are known to affect myelin in individuals with PKU (von Spronsen & Bur-
the brain, and that myelination is essentially gard, 2008).
complete after infancy, provided the ratio-
nale for this approach to treatment of PKU.
New and Emerging Treatments
Moreover, children who did not adhere to
the diet despite medical recommendations Oral administration of sapropterin dihy-
did not develop intellectual disabilities. drochloride (BH4), commercially known
Thus the policy of diet discontinuation was as Kuvan, recently received approval from
adopted. the U.S. Food and Drug Administration for
Despite the early enthusiasm for con- the treatment of PKU. BH4 is a cofactor of
sidering PKU a disease of early childhood, PAH, the enzyme responsible for converting
evidence gradually mounted demonstrating phenylalanine to tyrosine. BH4 boosts the
that diet discontinuation resulted in dimin- activity of this enzyme in individuals with
ished IQ in a sizable proportion of these chil- PKU who have residual enzyme activity.
dren (Waisbren, Schnell, & Levy, 1980). A Approximately 80% of patients with mild
North American PKU Collaborative Study PKU and about 10% of patients with classic
was established to determine the effects of PKU who take BH4 respond with lowered
diet discontinuation in early-treated chil- phenylalanine levels and increased tolerance
dren with PKU (Koch, Azen, Friedman, & of phenylalanine (protein), without negative
Williamson, 1982). The results of the fol- physical or neurological effects (Blau et al.,
low-up study indicated that the age at which 2009; Levy et al., 2007). Increased dietary
blood phenylalanine levels consistently ex- flexibility may lead to increased metabolic
ceeded 15 mg/dl was the best predictor of control in noncompliant patients with PKU
IQ and school achievement at ages 8 and and in women with PKU who are pregnant
10 years (Holtzman, Kronmal, van Doorn- (Fiege & Blau, 2007). Some clinicians en-
inck, Azen, & Koch, 1986). A retrospective courage a trial of BH4 therapy in all patients
study of 46 patients in Pennsylvania fol- with PKU, since it appears to have results in-
lowed beyond age 12 years reported similar dependent of patients’ genotype, phenotype,
results (Legido et al., 1993). On the other or age (Bóveda et al., 2007), although some
hand, a policy of diet discontinuation at age genotypes may be associated with BH4 re-
10 years was instituted in Scotland, and no sponsiveness (Blau et al., 2009).
declines in cognitive and motor functioning LNAA therapy is another supplemental
were noted after diet discontinuation in ado- therapy, known commercially as Lanoflex,
lescents and young adults at a median age PreKUnil, or Neophe. In large quantities,
of 20 years. However, the individuals with LNAAs can compete with phenylalanine at
PKU performed less well on all tests than the blood–brain barrier, so that less phenyla-
age-matched subjects without PKU (Grif- lanine and more LNAAs cross into the brain
fiths, Paterson, & Harvie, 1995). (Matalon et al., 2003, 2007; Schindeler et
A National Institutes of Health (NIH) al., 2007). Unlike BH4, LNAA therapy does
Consensus Conference with a multidisci- not reduce the blood phenylalanine level,
plinary panel convened in 2000 in Washing- although it may lower brain phenylalanine
ton, DC, to prepare guidelines for the treat- concentrations (Matalon et al., 2007).
ment of PKU. Lifelong diet continuation was Recently a new phenylalanine-free source
recommended, with the understanding that of protein has been identified. This protein,
the diet may be relaxed in older patients, de- called glycomacropeptide (GMP), is pro-
pending on individual needs. Patients being duced during cheese making; when isolated
treated for maternal PKU were advised to from cheese whey, it contains virtually no
maintain blood phenylalanine levels at 2–6 phenylalanine (Ney et al., 2009). GMP for-
mg/dl beginning 3 months before pregnancy mulas and foods are an alternative to the
and continuing throughout pregnancy (NIH current amino acid formulas (LaClaire et
Consensus Development Panel, 2001). These al., 2009). GMP has been noted to improve
guidelines are currently being reconsidered, protein retention and phenylalanine utiliza-
as more has become known since 2000 about tion, as well as to lower phenylalanine levels
the specific neuropsychological deficits that in the brain (van Calcar et al., 2009). GMP
foods increase satiety and have a more palat- dren and adults with PKU confirmed the
able taste and odor than the amino acid for- relationship between blood phenylalanine
mulas do, and may thus increase adherence levels and IQ. The combined results of 40
to dietary recommendations (Mcleod, Clay- studies showed that in children with PKU,
ton, van Calcar, & Ney, in press; Ney et al., mean lifetime blood phenylalanine levels
2009; van Calcar et al., 2009; van Spronsen were significantly correlated with Full Scale
& Enns, 2010). IQ (r = –.34). A similar correlation (r = –.35)
Pegylated recombinant phenylalanine am- was noted between IQ and blood phenylala-
monia lyase is an investigational enzyme nine levels during the “critical period” (0–12
substitution therapy for the treatment of years of age), and with the concurrent blood
PKU that would theoretically reduce blood phenylalanine level (r = –.31) (Waisbren et
phenylalanine levels in all individuals with al., 2007).
PKU. Studies in mice suggest that pheny- In addition to lowered IQ, visual–motor
lalanine levels could be controlled without deficits (Koff, Boyle, & Pueschel, 1977),
diet (Sarkissian et al., 2008). Known com- global processing problems (Waisbren,
mercially as Peg-Pal, this potential therapy Brown, de Sonneville, & Levy, 1994), and
involving weekly subcutaneous injections is executive functioning deficits (Pennington,
currently undergoing clinical trials in hu- van Doorninck, McCabe, & McCabe, 1985;
mans. van Zutphen et al., 2007) have been report-
Gene therapy for PKU has not been ig- ed. Even early-treated children tend to have
nored. To date, researchers have successfully awkward pencil grips and poor handwrit-
introduced into the liver of a PKU mouse a ing. Fine motor speed is diminished, copying
recombinant adenoviral vector containing a letters or figures is a laborious process, and
normal gene for PAH. Within a week, the work takes longer to complete. When asked
mouse was “cured” of PKU, but the effect to copy geometric designs, many children
did not persist. Moreover, mice once treated with PKU have notable difficulties, particu-
did not respond to repeated injections of larly when they are required to integrate fig-
the adenovirus vector (Eisensmith & Woo, ures. Visual demonstrations, diagrams, and
1994; Fang et al., 1994; Jung et al., 2008). models are less effective than verbal explana-
In another study, PAH-based fusion pro- tions. The children have difficulties remem-
teins and fragments of human hepatocyte bering the location of objects in space. The
growth factor were put together to induce “number line” may be incomprehensible for
PAH in the liver. Not only did this result in years after it has been taught in arithmetic
lowering phenylalanine levels in mice, but class.
the new proteins remained active, unlike
the recombinant adenoviral vector (Eavri &
The Prefrontal Cortex Hypothesis
Lorberboum-Galski, 2007).
and Dopamine
The pattern of deficits noted in treated PKU
Neuropsychological Effects
led to a suspicion that the prefrontal cortex
despite Treatment
is involved (Welsh, Pennington, Ozonoff,
Early diagnosis and treatment for PKU un- Rouse, & McCabe, 1990). Projections of
questionably prevent the severe neurological dopaminergic neurons in the neocortex are
complications from PKU; however, subtle found primarily in the frontal lobes (Porrino
psychological consequences have been ex- & Goldman-Rakic, 1982), and the prefron-
posed. Early studies from a clinical perspec- tal cortex has one of the highest levels of
tive focused on IQ, since it was documented dopamine turnover in the brain (Diamond
that children with PKU usually attained IQ et al., 1994; Diamond, Prevor, Callender,
scores 6–9 points lower than those of their & Druin, 1997; Tam, Elsworth, Bradber-
siblings and parents (Fishler, Azen, Hender- ry, & Roth, 1990). Diamond and her col-
son, Friedman, & Koch, 1987), and that leagues (1997) demonstrated that subjects
IQ diminished when diet was discontinued with blood phenylalanine levels greater than
(Seashore, Friedman, Novelly, & Bapat, 360 µmol/L (6 mg/dl) performed less well on
1985). A recent meta-analysis of studies tasks of executive functions (working mem-
that focused on overall intelligence in chil- ory and inhibitory abilities dependent on
Phenylketonuria 405
the dorsalateral prefrontal cortex) than on motor areas that represent less advanced
non-executive-function tasks. Other investi- functions.
gations supported these findings (Weglage, Although recent studies have generally
Pietsch, Fünders, Koch, & Ullrich, 1996; supported Diamond’s work, they also sug-
Welsh et al., 1990). In early and continuously gest a more complex neuropsychological
treated children (ages 7–14 years) compared profile in PKU. Channon, German, Cassina,
to age-matched peers, the ability to inhibit a and Lee (2004) noted impairments in atten-
“prepotent” (or expected) response was sig- tion, working memory, and fluency, but per-
nificantly poorer (Huijbregts, de Sonneville, formance did not decline with increased cog-
Licht, Sergeant, & von Spronsen, 2002). nitive load. In a study focusing on inhibitory
Children with early-treated PKU compared control in well-treated children with PKU,
to control samples have also shown lessened Christ, Steiner, Grange, Abrams, and White
attention, impaired problem-solving abilities, (2006) found only subtle differences be-
hyperactivity, impulsivity, poor planning, tween subjects and matched controls. These
and disorganization (DeRoche et al., 2008; authors suggested that discrepant results
Gassio et al., 2008; Moyle, Fox, Arthur, et could be attributed to the age at which test-
al., 2007). Stemerdink (1996) found that in ing was performed, since there is evidence
36 older patients (ages 8–19 years) treated that some executive abilities are more appar-
early and continuously, neuropsychological ent in older than in younger children with
performance on three out of four prefrontal PKU (White, Nortz, Mandernach, Hunting-
tasks was impaired. The same pattern has ton, & Steiner, 2002).
been found in another study of adults with
early-treated PKU (Ris, Williams, Hunt,
The White Matter Abnormalities Hypothesis
Berry, & Leslie, 1994).
Researchers have also found evidence Inconsistent results from tests of executive
for impairment in visual contrast sensitiv- functioning have prompted research on
ity when blood phenylalanine levels are el- white matter abnormalities and slow pro-
evated. This is relevant, since it is hypoth- cessing speed as probable causes of cognitive
esized that the retina is also highly sensitive deficits in PKU (Channon, Mockler, & Lee,
to moderate reductions in brain dopamine 2005). Some studies have used MRI to in-
(Diamond, 1994; Stemerdink, 1996). vestigate the relevance of myelin abnormali-
Not all studies, however, support the ties in PKU. Reports conclude that the sever-
dopamine–prefrontal dysfunction hypoth- ity of the MRI changes is significantly and
esis. Mazzocco and colleagues (1994), using independently associated with the phenyla-
the Tower of Hanoi and visual search tests, lanine concentration at the time of the inves-
found that children ages 6–13 years who tigation. When metabolic control improves,
were treated early and continuously showed the MRI picture also improves. The area of
no deficits on the neuropsychological tests, the brain in which white matter abnormali-
despite a range of blood phenylalanine lev- ties are most commonly noted is the parieto-
els. occipital region. Despite the provocative na-
Variations of the dopamine hypothesis ture of these results, MRI findings have not
have also been proposed. Krause and col- always been found to correlate with IQ, neu-
leagues (1985) reported a correlation be- ropsychological functioning, or neurological
tween increased reaction time and decreased symptoms (Jones et al., 1995; Thompson et
urinary dopamine in patients with PKU. al., 1993).
Since brain dopamine is concentrated in In a meta-analytic review of past research
the corpus striatum, and since choice reac- (Moyle, Fox, Bynevelt, et al., 2007) and
tion time tests require a motor response as in recent studies (Huijbregts et al., 2003;
well as integration of stimuli, they specu- Moyle, Fox, Bynevelt, Arthur, & Burnett,
lated that the nigrostriatal and corticostri- 2007), the largest effect sizes derived from
atal pathways are affected. Faust, Libon, tests of processing speed. White matter ab-
and Pueschel (1986–1987) obtained similar normalities detected on MRI were found in
results; they suspected that the deficits are association with high blood phenylalanine
associated with complex areas of the brain, levels and slow processing speed (Anderson
such as the anterior frontal regions, and in et al., 2007).
Elevated blood phenylalanine levels phenylalanine levels (Griffiths, Ward, Har-

clearly compromise neuropsychological per- vie, & Cockburn, 1998). In a study of adults
formance in individuals with PKU. Early- both on and off diet, most neuropsychologi-
treated children who maintain treatment cal test results correlated with phenylalanine
beyond early childhood and have controlled levels during childhood and not with con-
blood phenylalanine levels function better current levels (Brumm et al., 2004).
on cognitive tests (Schmidt, Rupp, Burgard, One novel approach to explaining vari-
& Pietz, 1992; Antshel & Waisbren, 2003a, ability in neurocognitive functioning among
2003b; Moyle, Fox, Bynevelt, et al., 2007). individuals with PKU posits an association
IQ loss occurs in early-treated adolescents between stability of blood phenylalanine
with elevated phenylalanine levels (Beasley, levels and functioning. In a retrospective
Costello, & Smith, 1994). Recommenda- study of 45 early and well-treated children
tions from the various PKU clinics vary with with PKU, stability of blood phenylalanine
regard to what constitutes metabolic control level was a better predictor of IQ (r = –.37,
in children over 6 years of age. The target p = .06) than lifetime mean blood phenyla-
for most clinics is now 2–6 mg/dl. However, lanine level (r = –.18, p = .34) (Anastasoaie,
due to the restrictiveness of the diet, few Kurzias, Forbes, & Waisbren, 2008).
teenagers are able to maintain levels within
this range (Walter et al., 2002). In a follow-
Developmental Domains Usually
up study of children in the United Kingdom,
Unaffected in PKU
only 12% of the children were following a
strict diet by age 14 years, and only 4% were Infants with early-treated PKU generally at-
following a strict diet by age 18 years (Beas- tain developmental milestones at the appro-
ley et al., 1994). One research group suggests priate ages. Most sit up at about 6 months
that levels as high as 15 mg/dl may be benign of age, walk at a year, and begin talking at
in teenagers and young adults (Griffiths et 18–24 months. Although some do not want
al., 1995). Other investigators contend that to give up the bottle, most graduate to a cup
any elevation above 6 mg/dl may have ad- and demonstrate appropriate table manners.
verse effects (Diamond, 1994). They learn to tie their shoes in kindergarten,
Concurrent blood phenylalanine levels in and can ride a two-wheeler, count by twos,
individuals with PKU have been correlated and recite the alphabet at the same times as
with reaction time (Clarke, Gates, Hogan, most of their peers. Most do not have dif-
Barrett, & McDonald, 1987; Schmidt et al., ficulties learning to read. They interact well
1994) and were once thought to reflect the with peers, try to please their teachers, and
level of brain phenylalanine (Jordan, Brun- spend hours on the computer as teenagers.
ner, Hunt, & Berry, 1985). In one study, And many children treated early and con-
short-term dietary intervention and reduc- tinuously show no impairments on a wide
tions in blood phenylalanine led to improved variety of tests of information processing
performance on tasks assessing speed of in- (Stemerdink et al., 1995). Thus, in many re-
formation processing in adults (Huijbregts, spects, children with early-treated PKU are
de Sonneville, Licht, von Spronsen, & Ser- indistinguishable from other children their
geant, 2002). However, not all investiga- age.
tors reported clear-cut associations between
blood phenylalanine levels and neuropsy-
chological outcomes. In a study of children Behavioral, Academic,
at approximately age 11 years, blood phe- and Emotional Presentation
nylalanine correlated with performance on
Attention-Deficit/
tests of attention, fine motor coordination,
Hyperactivity Disorder
and IQ, but blood phenylalanine was no
longer related to performance on any test 3 Often linked to the underlying neuropsycho-
years later (Weglage et al., 1999). Similarly, logical deficits in PKU is attention-deficit/hy-
in a study in which phenylalanine intake was peractity disorder (ADHD). Researchers and
manipulated to increase phenylalanine lev- clinicians have alluded to an increased prev-
els, no change was found in performance for alence of attentional problems in PKU (Bur-
individual children under lower or higher gard, Rey, Rupp, Avadie, & Rey, 1997; Lou,
Phenylketonuria 407
1994). More recent studies have supported and less than, equal distances between num-
the idea that elevated phenylalanine levels bers, and fixed sequences are not secure
are toxic to neurological systems, resulting ideas. One-to-one correspondence between
in symptoms of ADHD, with exposure earli- numbers and objects comes slowly. Addition
er in life leading to increased risk for ADHD and subtraction can be drilled, but an intui-
(Antshel & Waisbren, 2003a). An estimated tive sense of sums and differences may be
26% of children with early-treated PKU forever lacking. Multiplication facts can be
received medication for ADHD, compared learned with considerable effort, but with-
to 7% of children with diabetes (Arnold, out frequent use, they are easily lost. Frac-
Vladutin, Orlowski, Blakely, & DeLuca, tions present almost insurmountable obsta-
2004). This is significantly higher than the cles, as do geometric shapes and formulas.
rate of 4.3% of children who received medi- A good sense of spatial arrangement is also
cation for ADHD in the general population needed to line up numbers for performing
(Visser & Lesesne, 2003). Methylphenidate calculations with paper and pencil. Chil-
(Ritalin) and other medications do not ap- dren with PKU commonly turn in disorga-
pear to result in significant improvements in nized papers, with wrong answers because
attention and school achievements, although numbers are lined up improperly. A second
some parents report that their children ex- impediment to success in arithmetic is a
hibit greater self-control when on medica- weakness in executive functioning. Because
tion. However, careful studies of the effects of their difficulties maintaining information
of medications for ADHD in children with in memory, children with PKU struggle with
PKU need to be conducted. calculations requiring more than one step.
Word problems are especially challenging
because they require a child to decide on
School Achievement
the appropriate operation and to remember
Difficulties in arithmetic typify the learn- numbers for computing the answer.
ing profile among young children with PKU As the children grow older, difficulties
(Weglage, Fünders, Wilken, Schubert, & in reading comprehension become appar-
Ullrich, 1993). Achievement spans the full ent. Decoding skills come readily to most
range, with some children placed in special children with PKU, and the first through
programs, others struggling in regular class- third grades pass uneventfully. Fourth grade
es, still others proceeding at the same rate as brings new demands for reading comprehen-
peers, and a few gaining honors in law school. sion and application of rote skills; suddenly
Nonetheless, when children with PKU con- many children with PKU fall behind their
front problems in school, they invariably fal- classmates and are referred for psychologi-
ter in math class. The North American PKU cal evaluations. In actuality, the underly-
Collaborative Study documents a steady ing weaknesses have always been there, but
decline in arithmetic scores in both diet- simple compensatory strategies have sufficed
continued and diet-discontinued children to keep the children at grade level. By fourth
from ages 6 to 10 years (Fishler et al., 1987). grade, problems in executive functioning
By age 12 years, achievement scores in arith- and sustaining attention interfere with the
metic fall again in 90% of children, regard- acquisition of new knowledge and the abil-
less of dietary control (Azen et al., 1991). A ity to master new skills. Science and social
study by Gassio and colleagues (2008) found studies, as well as arithmetic and reading,
that children with PKU were twice as likely become difficult subjects.
as their peers to experience school problems. Spelling continues to be a strength for
Thirty-nine percent required special tutor- most of these children, although for some
ing, and 12% repeated grades. In patients the sequencing issue hinders visualization of
whose phenylalanine levels were elevated, the correct order of letters. In fourth grade,
these issues were amplified. homework increases, as does the amount of
With arithmetic, the underlying cause for written work required. Again, the problem
difficulties seems to be twofold. First is the in visual–motor coordination that could
issue of spatial perception. Simply put, the once be overcome by hard work now over-
children fail to perceive the number line in whelms the children’s coping mechanisms.
their “mind’s eye.” The concepts more than Occupational therapy is sometimes recom-
mended for children with poor visual–motor parents’ homes (Waisbren, Hamilton, St.
skills. If teachers do not recognize such a James, Shiloh, & Levy, 1995). Other studies
child’s underlying learning difficulties, they of adolescents with PKU have indicated that
may deem the child lazy, dull, inattentive, they are less independent, less achievement-
or obstinate. Even if teachers do suspect a oriented, lower in self-esteem, and more
learning disability, they may assume that frustrated than peers (Weglage et al., 1992).
the child has a typical form of dyslexia or Off-diet individuals with PKU function
ADHD. However, this may not be the case. poorly in social situations (Schuett 1997),
Careful evaluation of the child is important but those who remain on diet experience a
to identify the specific pattern of deficits positive quality of life (Bosch et al., 2007;
and the particular factors related to PKU Koch et al., 2002).
that may have an impact on the child’s be- Agoraphobia has been identified as a com-
havior in the classroom. The child’s level of plication of elevated phenylalanine levels.
PKU, treatment history, and current degree Among five adults who experienced panic at-
of metabolic control need to be considered, tacks and were unable to venture more than
along with the psychosocial stresses the child a short distance from their homes, the two
may be experiencing. who returned to the phenylalanine-restricted
diet experienced dramatic improvement in
symptoms (Waisbren & Levy, 1991).
Emotional Disturbances
Adolescents and young women with PKU
The effects of PKU on personality and tem- who either were late-treated (i.e., treatment
perament were noted by early researchers was initiated after 90 days of age) or had
(Fisch, Sines, & Chang, 1981). Measures terminated the diet for a period of at least
of “persistence,” “intensity,” and “rhyth- 5 years were compared to women who were
micity” were observed to be lower in chil- early-treated and had remained continuously
dren with PKU (Schor, 1983). Early-treated on the diet. The women who had extended
school children were rated as more clumsy, exposure to elevated phenylalanine levels
talkative, and hypersensitive than their peers evidenced significantly greater psychopa-
(Siegel, Balow, Risch, & Anderson, 1968). thology as measured by the Minnesota Mul-
On the other hand, patience, sociability, and tiphasic Personality Inventory. The pattern
obedience to the law were also attributed of scores was remarkably consistent, with a
to the genetic defect. In untreated and late- tendency toward elevations on scales related
treated PKU, bizarre behaviors were noted, to thought disorder and mood. Although
including obsessive–compulsive rituals, self- they were not actively psychotic, the women
abuse, and extreme tactile sensitivity. Al- who had experienced extended exposure to
though such attributions are rare today, they high blood phenylalanine levels were poor
presaged interest in the effects of metabolic assessors of the emotions or expectations of
disequilibrium on personality and emotion. others. They were also prone to feelings of
Today parents note that their children some- alienation, depression, and social isolation,
times undergo personality changes when and had difficulties thinking and communi-
their phenylalanine levels rise (Schuett, cating (Waisbren & Zaff, 1994). For patients
1997). who remain on the diet, the future appears
The long-term consequences of early- brighter (Weglage et al., 1992).
treated PKU are relatively unknown. Woolf Researchers from the German Collab-
(1979) speculated that if diet was discontin- orative Study (Pietz et al., 1997) reported
ued in middle childhood an insidious pro- that the rate of psychiatric disorders in the
cess would begin, culminating in loss of IQ, adults with PKU was 35.7%, compared
antisocial behavior, and severe emotional to 16.1% in controls. Patients with PKU
disturbance (including frank psychosis). Al- showed exclusively “internalizing” distur-
though such consequences are rare, effects bances (especially depression and anxiety),
of a less serious nature are common. One whereas control subjects demonstrated both
study of young women with PKU revealed internalizing and externalizing (antisocial)
that they were less mature than their peers: symptoms. Females with PKU were more
They obtained a driver’s license at a later likely than males to experience depression.
age and tended to remain longer in their No correlation has been found between the
Phenylketonuria 409
severity or pattern of psychopathology and ment, & Pimentel, 1981), diabetes (Webster
biochemical control (Weglage et al., 2000). & Wallace, 1995), Down syndrome (Bleho-
Moreover, no correlations between psychi- va, Pazoutova, & Subrt, 1970; Fisch & Hor-
atric symptoms and MRI abnormalities have robin, 1968), Duchenne muscular dystrophy
been observed. However, a restrictive, con- (Roth, Cohn, Berman, & Segal, 1976), Hart-
trolling style of parenting is a risk factor for nup disease (Jonxis, 1957), hereditary fruc-
the development of psychiatric symptoms, tose intolerance (Celiker, Dural, & Erdem,
prompting the German researchers to con- 1993), histidinemia (Walker et al., 1981),
clude that psychiatric disturbances in adults and lymphoblastic leukemia (Wang et al.,
with PKU may be related to psychological 2007). Genetic linkages have been sought,
factors rather than to biochemical or neuro- but not found, between PKU and these dis-
logical sources. Researchers also report high orders.
rates of depression and anxiety in adults
with PKU in association with elevated blood
phenylalanine levels (Brumm et al, 2004; Maternal PKU
Smith & Knowles, 2000).
In a single generation, the benefits of new-
born screening for PKU in terms of prevent-
Medical Comorbidity ing intellectual disability could be erased
by the effects of maternal PKU (Kirkman,
In the past, children with untreated PKU 1982). Maternal PKU refers to the risks to
were often diagnosed with autism, and in- the fetus when the mother has PKU. The
deed presented with the hallmark features of damage to the fetus occurs because of the in-
this disorder (Koch, Acosta, Fishler, Schaef- trauterine environment, since the fetus relies
fler, & Wohlers, 1967). Even today, the few on the mother to metabolize phenylalanine.
children in the United States missed by new- There are no particular risks inherent in pa-
born screening and therefore not treated are ternal PKU, apart from the possibility of the
often diagnosed with autism, as well as de- child’s having PKU if the mother is a car-
velopmental delays. rier (Fisch, Matalon, Weisberg, & Michals,
If “overtreated,” with extreme limitation 1991). On the other hand, when the mother
of protein intake resulting in phenylalanine has PKU and does not receive treatment, her
depletion, a child with PKU can experience fetus is exposed to toxic levels of phenyla-
significant growth retardation, lethargy, and lanine. Among the birth defects that result
even death. Fortunately, the need to moni- from phenylalanine exposure in untreated
tor metabolic status carefully to avoid over- maternal PKU are intellectual disability
restriction was recognized early in the his- (95%), microcephaly (90%), and congenital
tory of treatment for PKU (Hanley, Linsao, heart disease (17%) (Lenke & Levy, 1980).
Davidson, & Moes, 1970). The precise mechanism of fetal damange in
Some individuals who discontinue treat- maternal PKU is still unknown, although it
ment experience dramatic consequences, is clear that the fetus is harmed by the abnor-
including seizures, problems with balance, mal intrauterine environment produced by
hallucinations, and paralysis of the legs. the genetically abnormal mother (Ghavami
These reports, though quite alarming, do & Levy, 1986; Levy & Ghavami, 1996).
not represent the usual course of PKU in The risks in maternal PKU are significantly
diet-discontinued individuals. Nonetheless, reduced if the mother initiates strict dietary
when they do occur, there is little doubt treatment prior to pregnancy and maintains
that phenylalanine toxicity is a contributing metabolic control throughout pregnancy
factor, since returning to treatment allevi- (Hanley, Clarke, & Schoonheyt, 1987; Koch
ates (though it may not cure) the problems et al., 1990, 1994; Lynch, Pitt, Maddison,
(Schuett, 1997). Wraith, & Danks, 1988). Women with non-
Single-case reports of distinct medical PKU mild hyperphenylalaninemia, whose
conditions in association with PKU have natural blood phenylalanine levels are much
also been published. These include anorexia less elevated than those in women with PKU,
nervosa (Clarke & Yapa, 1991), congenital incur little or no risk for adverse pregnancy
hypothyroidism (Schmidt, Solberg, Dia- outcomes (Levy & Waisbren, 1983; Levy et
al., 1994). This finding underscores the im- weeks’ gestation was within the average
portance of metabolic control in maternal range, whereas the DQ of offspring whose
PKU. mothers were not in metabolic control until
Given the known benefits of dietary after 20 weeks’ gestation was below 85. As-
therapy, delivery of treatment for maternal sessments at age 4 years confirmed the as-
PKU should be a straightforward process. sociation between offspring outcome and
However, this is not the case. Since many timing of maternal metabolic control. A
young women with PKU deviate from medi- total of 253 children of women with PKU
cal recommendations in adolescence, they (n = 149) were assessed with the McCarthy
must significantly modify their diet for preg- Scales of Children’s Abilities. The General
nancy. Many have difficulties resuming the Cognitive Index (similar to an IQ) decreased
highly restricted diet and tolerating the spe- as weeks to metabolic control increased (r
cial formula. Many have not been followed = –.58; p < .001). The mean IQ was 93 for
by a metabolic clinic since childhood, and offspring whose mothers attained metabolic
some may not even remember that they have control by 10 weeks, 88 for those whose
PKU. Despite tracking and educational ef- mothers attained metabolic control between
forts, metabolic control is often not achieved 10 and 20 weeks, and 73 for those whose
adequately or in time to prevent damage to mothers were not in control until after 20
the fetus. weeks (Hanley et al., 1996; Waisbren et al.,
The International Collaborative Study of 2000). Among all children born to mothers
Maternal Phenylketonuria was a longitudi- with PKU, 30% had social and behavioral
nal, prospective study of the effects of di- problems (Waisbren et al., 2000).
etary treatment during pregnancy in women In a study that included some offspring
with PKU in the United States, Canada, through 10 years of age, 44% were noted
and Germany (Koch et al., 1993, 1994). to exhibit significant behavioral problems
The pregnant women received ultrasound (Ng, Rae, Wright, Gurry, & Wray, 2003).
examinations, nutrition consultation, and The most recent large-scale study of mater-
metabolic monitoring as part of the study nal PKU (Maillot, Lilburn, Baudin, Morley,
protocol. Offspring received developmen- & Lee, 2008) included 105 children born
tal evaluations in the neonatal period and to 67 mothers with PKU, the majority of
at 12 and 24 months; thereafter, they were whom were in relatively good metabolic
evaluated every 2 or 3 years through age 10 control during pregnancy. The sample was
years. Results indicated that the number of divided into two groups: offspring of moth-
gestational weeks until a mother reduced her ers who received a low-phenylalanine diet
blood phenylalanine level predicted a child’s prior to pregnancy, and offspring of moth-
neonatal course, developmental quotient ers who initiated the diet after they became
(DQ), and IQ. Birth head circumference was pregnant (usually within the first trimester).
significantly related to maternal phenylala- Although birth head circumference did not
nine levels during weeks 8–12 of gestation differ between the two groups of offspring,
(Rouse et al., 1997). Examiner ratings of in- DQ at 1 year of age was 107 for offspring
fants on the Dubowitz Neurological Assess- of mothers treated prior to pregnancy and
ment of the Preterm and Full-Term Newborn 99 for offspring whose mothers were treated
Infant suggested that 29% evidenced signs of after pregnancy began. At 8 years of age, the
abnormalities in muscle tone, head control, difference in IQ between the two groups was
reflexes, and responsiveness. Those who at- more than 15 points (111 vs. 91). Variabil-
tained abnormal ratings had poor responses ity in the blood phenylalanine level during
on measures of axial tone: posterior head pregnancy also correlated negatively with
control, anterior head control, head lag, and IQ scores, even when the blood phenyla-
ventral suspension. Scores on the Dubowitz lanine level was within the recommended
Neurological Assessment were significantly range, with correlations as high as –.71 at
influenced by the gestational age at which a age 14 years.
mother with PKU attained metabolic control The neurodevelopmental picture of mater-
(Waisbren et al., 1998). The DQ at age 6–12 nal PKU offspring is not yet complete. How-
months in maternal PKU offspring whose ever, there are indications that it is similar
mothers attained metabolic control by 20 to that found in fetal alcohol syndrome. Not
Phenylketonuria 411
only are there similarities in facial dysmor- Assessment

phology (Levy & Ghavami, 1996), but the
neuropsychological profile may be similar, Children with PKU require careful monitor-
with increased rates of language deficits, hy- ing, especially during infancy and school
peractivity, and deficient motor skills (Jan- years. As described earlier, even those chil-
zen, Nanson, & Block, 1995). dren who maintain excellent metabolic con-
Thus, despite treatment, offspring from trol are at risk for learning disabilities. An-
maternal PKU pregnancies often function nual testing in the preschool years should
developmentally and cognitively below nor- be followed with biennial testing during
mal levels (Koch et al., 1990). One reason elementary school, preferably by a psy-
for this is that more than 60% of women chologist familiar with metabolic disorders.
with PKU who become pregnant do so un- Thereafter, testing is recommended when a
intentionally and are not in metabolic con- child experiences difficulties or when meta-
trol (Waisbren et al., 1995). Although this bolic control changes. The frequency with
rate of unplanned pregnancies is similar to which problems in executive functioning
that in the general population in the United and attention occur suggests that neuropsy-
States (Harrison & Rosenfield, 1996), it has chological testing should also be performed.
serious consequences for women with PKU Assessments are critical for prevention of
(Hanley et al., 1987; Koch et al., 1994; Levy future learning disabilities, since it is now
& Ghavami, 1996). clear that early intervention can lead to im-
The factors found to be most highly corre- proved neuronal structures, even in babies
lated with adherence to medical recommen- with disrupted brain development—and, by
dations in maternal PKU are social support extrapolation, in infants and children at risk
and positive attitudes about the efficacy and for frontal lobe or white matter abnormali-
acceptability of treatment. Programs to en- ties (Shonkoff, 2003). Assessments are also
hance social support and positive attitudes important for determining treatment effi-
have had promising results (Levy & Wais- cacy and the need for modifications in diet
bren, 1994; Waisbren, Shiloh, St. James, & or supplementation with medications to re-
Levy, 1991; Waisbren et al., 1995, 1997). In duce phenylalanine exposure or variability.
addition, compliance can sometimes be im- In addition, neuropsychological evaluations
proved through changes in the type of for- identify the types of remedial educational
mula prescribed, the use of gelatin capsules services that may be needed.
containing the formula (Kecskemethy, Lob- It is critical for the psychologist to com-
bregt, & Levy, 1993), or supplementation municate with the parents and schools about
with BH4 (Cunningham, Pridjian, Smith, & the specific learning profiles of students with
Anderson, 2009; Koch, Moseley, & Güttler, PKU. Their difficulties in arithmetic may not
2005). Use of a gastrostomy tube led to good be the same as the deficits noted in children
metabolic control in a pregnant woman suf- without PKU. A recurring theme in the treat-
fering from severe nausea and poor tolerance ment of PKU is the importance of metabolic
of formula (Schwoerer, Bingen, van Calcar, control. In almost all situations, the test re-
Heighway, & Rice, 2009). sults must be interpreted in association with
The deficits in offspring from treated ma- the current blood phenylalanine level and
ternal PKU pregnancies may also be caused the degree of metabolic control in previous
in part by suboptimal home environments. years. Early history must also be taken into
Of concern are the limited intellectual abili- account.
ties, reduced social resources, and emotional Table 21.1 presents instruments that have
difficulties of women with PKU. In a study been used to identify deficits common in PKU.
of adolescents and young adult women with After the preschool years, a full Wechsler
PKU, the mean IQ was 85, and a substantial Intelligence Scale for Children should be
proportion of the women were of low so- administered to establish a baseline. There-
cioeconomic status (Waisbren et al., 1995). after, the Wechsler Abbreviated Scales of
These discouraging demographics persist Intelligence may be used, since IQ tends to
today in the subgroup of individuals who remain stable for those who maintain meta-
have discontinued treatment (Brumm et al., bolic control (Waisbren et al., 2007). Em-
2004). phasis shoud be placed on tests of executive
TABLE 21.1. Instruments for Assessment of Various Domains Affected by PKU

Domain Age group Instrument
Infant development 6 months to 36 months Bayley Scales of Infant and Child Development, Third
Edition; Adaptive Behavior Assessment System—Second
Edition
Preschool intelligence > 30 months to 6 years, Wechsler Preschool and Primary Scale of Intelligence—
11 months Third Edition
Child intelligence 7 years to 16 years, Wechsler Intelligence Scale for Children—Fourth
11 months Edition; Wechsler Abbreviated Scales of Intelligence
Adult intelligence > 17 years Wechsler Adult Intelligence Scale—Third Edition;
Wechsler Abbreviated Scales of Intelligence
Achievement 5 years to adult Wechsler Individual Achievement Test—Second Edition
Language > 5 years Boston Naming Test
Executive 4 years to adult Behavior Rating Index of Executive Function; California
functioning Verbal Learning Test
Visual–motor skills 3 years to adult Beery–Buktenica Developmental Test of Visual–Motor
Integration; Rey–Osterreith Complex Figure
Attention 3 years to 17 years Conners 3rd Edition
Adaptive behavior 2 years to adult Adaptive Behavior Assessment System, Second Edition
Emotional well-being 4 years to adult Behavior Assessment System for Children, Second
Edition; Beck Depression Inventory, Second Edition;
Beck Anxiety Inventory
functioning, processing speed, behavior (in- et al., 1994; Johannik et al., 1994; Jones et
cluding attention) and emotional well-being, al., 1995; Peng et al., 2004), have been used
since these areas present challenges for most primarily for research purposes. White mat-
children and adults with PKU. ter abnormalities (reflecting reduced myelin)
Current efforts are underway to develop have consistently appeared, but not in asso-
a uniform assessment method for PKU and ciation with reduced IQ (Peng et al., 2004).
other metabolic/genetic disorders (Waisbren The MRI examinations indicate that myelin
& White, 2010). A Genetics and Metabolism reduction in PKU results from a reversible
Psychology Network has recently been orga- condition of reduced myelin synthesis rather
nized to accomplish this task and will post than from excessive myelin loss. The term
the recommended test battery on its website dysmyelination is more appropriate than
(www.GMPsych.org). demyelination for describing what occurs
In addition to neuropsychological testing, in PKU (Pearsen, Gean-Martin, Levy, &
assessment techniques aimed at uncovering Davis, 1990).
physiological correlates of functioning have In a recent study using T2-weighted and
been employed. Electroencephalographic fluid-attenuated inversion recovery scans,
examinations traditionally identified slow- white matter in the parietal region was con-
wave abnormalities, but only in late-treated sistently affected. Myelin reduction in the
or off-diet children. Evoked potentials ap- occipital region ranked second in frequency,
peared promising in the 1980s (Pueschel, followed by frontal and temporal regions.
Fogelson-Doyle, Kammerer, & Matsumiya, The authors concluded that MRI abnormal-
1983), but other studies using evoked po- ities in PKU reflect intracellular accumula-
tentials revealed no correlations between tion of a hydrophilic metabolite, but do not
these and current clinical, biochemical, indicate abnormalities in white matter archi-
and neurophysiological parameters (Leuzzi, tecture and structure (Leuzzi et al., 2007).
Cardona, Antonozzi, & Loizzo, 1994). MRI Another study using more advanced imag-
and other brain imaging techniques (Cleary ing techniques have contributed additional
Phenylketonuria 413
information about white matter changes in can help their children regain equanimity,
32 subjects with classic PKU. Using MRI, but sometimes psychological counseling is
plus proton magnetic resonance spectros- needed. The rebellious children who refuse
copy and diffusion MRI with a 3.0-tesla formula, cheat on the diet, fuss, and com-
scanner, investigators detected periventricu- plain are well known to every clinic. These
lar and subcortical white matter changes in children frighten their parents and siblings
all subjects. In 29 patients, proton magnetic by their nonchalant attitude about the con-
resonance spectroscopy documented pro- sequences of elevated phenylalanine levels.
nounced abnormal signal elevation at 7.36 Parents try rewards, punishments, and pleas.
ppm, corresponding to phenylalanine, de- They ask doctors, nutritionists, and other
spite its low concentration. Diffusion MRI professionals to talk to their children. They
revealed hyperintensity in the areas exhib- may drink the formula themselves to show
iting MRI changes. The investigators con- that it is not distasteful. They may involve
cluded that the 3.0-tesla diffusion MRI was the children’s friends to encourage dietary
the most suitable imaging technique in PKU compliance. Nothing seems to alter the situ-
(Scarabino et al., 2009). ation.
One interpretation of the time of rebellion
is that it represents a struggle for identity—
Treatment Implementation a sense of oneself apart from one’s parents.
This struggle can occur at many different
Treatment Adherence: Emotional
ages. Some 2-year-olds go through this stage.
and Developmental Issues
Some 10-year-olds or teenagers suddenly ap-
The biggest challenge in PKU is adherence pear incorrigible with regard to the diet. The
to treatment. Maintaining metabolic control best strategy at this time is to validate the
necessitates massive adjustments in daily life struggle for independence. The topic should
once a child is beyond infancy. Every social be discussed in age-appropriate terms, and
gathering, school lunch period, travel plan, the need for greater autonomy should be ac-
summer activity, and nightly meal must be knowledged. Greater independence should
planned. Adolescents with PKU describe then be granted in areas that are unrelated
their social lives and emotional development to food. For young children, this may mean
as much more restricted than those of their later bedtimes or more choices about activi-
peers (Weglage et al., 1992). Despite the best ties, friends, or clothing. In older children,
efforts of parents, most children and adoles- encouragement to attend camp or to pursue
cents reject the formula or deviate from the a new hobby or skill may satisfy the need for
diet at some periods. At different ages, the independence without placing the children
emotional issues vary, but the result is simi- at risk. In every case, when the struggle for
lar: a rise in blood phenylalanine levels and independence is at its height, there is a need
an increase in the risk for attentional, cogni- to engage the child. This can be in the form
tive, and emotional problems. of more special time with parents and extra
The impact of PKU on neuropsychologi- support from professionals. A direct focus
cal functioning may lead to behaviors or on the diet will be of little benefit, since the
personality styles in children that, in turn, underlying issue is elsewhere.
elicit certain types of responses from parents For children who have generally been rea-
or teachers. These responses may exacerbate sonable about the treatment but suddenly
the problem. For example, the hyperactive reject the diet, a cognitive approach may
or impulsive behavior common in children be best. A trip to the laboratory to see how
with PKU may lead to poor self-control with blood specimens are analyzed, participation
the diet. This produces an anxious or overly in PKU conferences, exposure to articles in
controlling response from the parents, which newsletters or scientific journals, or discus-
may lead to an increase in poor dietary com- sions about the genetics and consequences of
pliance and oppositional behavior in the PKU may be helpful. Some children benefit
children (Hendrikx, van der Schot, Slijper, from writing reports on their disorder or
Huisman, & Kalverboer, 1994). from learning to cook low-protein foods,
When resistance to the diet occurs, various prepare the recipes, and maintain food re-
strategies may be employed. Usually parents cords. A change in formula, a trial of using
capsules, or a new schedule for drinking the •• Understands basic number concepts nec-
formula can renew the commitment to the essary for measuring foods
diet. •• Is knowledgeable about the daily phenyla-
In adults, difficulties in executive function- lanine allowance
ing (planning abilities, organization, memo- •• Identifies and serves proper portions of al-
ry, and impulse control) increase the chal- lowed food
lenges of adherence to diet. A vicious cycle
ensues, with poor metabolic control leading School age (7–11 years)
to increased executive functioning deficits,
•• Prepares formula (with parents’ supervi-
which in turn make it even more difficult
sion)
to plan meals, organize schedules to include
•• Is beginning to list foods on food record
drinking the formula, remember protein al-
•• Understands untreated versus poorly
lowance, and resist disallowed foods.
treated versus treated PKU
•• Acknowledges having PKU to peers
Suggestions for Developing •• Has knowledge of PKU and PKU diet
Treatment Plans •• Follows a low-phenylalanine recipe
•• Performs blood sampling with parental
An achievement protocol for knowledge and
support
skills can serve as a guide for parents, pa-
•• Monitors own blood levels and under-
tients and professionals. Below is an outline
stands recommended range
of one such protocol. This protocol can be
•• Understands basic genetics of PKU
referred to whenever a child or adolescent
•• Can determine phenylalanine content of
attends a clinic, in order to assess the level
foods from manual or label
of knowledge and self-management that the
young person has achieved.
Adolescence (12–18 years)
Infants and toddlers (2–3 years) •• Prepares formula independently
•• Prepares low-protein recipe
•• Eats with rest of the family at dinner
•• Performs blood sampling independently
•• Names foods (in general)
•• Explains the genetics of PKU
•• Asks before eating uncertain foods
•• Explains the rationale of dietary therapy
•• Shows awareness of difference between his
•• Understands whom to consult about PKU
or her diet and that of family and friends
or the PKU diet
•• Has knowledge of “yes” and “no” foods
•• Demonstrates ability to cope with social
•• Has knowledge of procedural methods for
pressures
blood sampling
•• Maintains diet record independently
•• Drinks formula out of a cup
•• (For a girl) Demonstrates knowledge of
•• Helps prepare formula—child can pour
maternal PKU
and stir/shake/blend
•• Begins to count food items
Some clinics now offer a “PKU school,”
•• Reports foods consumed that day
in which several children of similar age at-
•• Has basic knowledge of reasons for PKU
tend a clinic together and participate in
diet
a group learning activity, such as prepar-
ing a low-protein recipe or taking a finger
Preschool (4–6 years) stick blood specimen (Heffernan & Trahms,
•• Handles social situations concerning 1981). This provides social support, as well
food as practical experience with some aspects of
•• Prepares formula (with assistance) self-monitoring.
•• Can explain PKU and PKU diet in simple
terms
Making the Transition
•• Is knowledgeable about the daily schedule
to Adult Health Care
for formula intake
•• Takes blood sample with help Making a smooth transition from pediat-
•• Has knowledge of basic reasons for his or ric to adult health care is important for any
her clinic visits adolescent or adult with a chronic health
Phenylketonuria 415
condition (Lotstein, McPherson, Strick- iel, & Minniti, 2009; Rubin, 2008; Tuch-
land, & Newacheck, 2005; McManus, Fox, man, Slap, & Britto, 2008). Psychologists
O’Connor, Chapman, & MacKinnon, 2008; can contribute to this process by supporting
Reiss et al., 2005). Moreover, there are spe- patients in considering their feelings about
cial issues for adults with PKU, including taking on greater responsibilities and over-
vitamin deficiencies, osteoporosis, and the coming barriers to continued treatment.
maternal PKU syndrome (Hoeks, den Hei-
jer, & Janssen, 2009). In order to make
sure patients have a successful transition to Summary and Conclusions
adult health care, six critical steps have been
identified for patients and health care pro- PKU exemplifies the challenges inherent in
viders to follow: (1) Patients should have an the study of neurodevelopment in genetic
identified health care professional to oversee disorders. In one of nature’s best-designed
their individual transition; (2) patients and experiments (Roth, 1986), a defect in a
providers should identify the knowledge and single gene leads to disruptions in brain de-
skills required for developmentally appro- velopment that affect behavior, cognition,
priate care; (3) an up-to-date and portable personality, social relationships, and even
medical record (personal health summary) the health of the next generation. PKU is a
should be kept by patients; (4) health care disorder that has bred controversy since its
providers should assist patients in writing a discovery. Følling (1934), the doctor who
health care transition plan by the time a pa- first discovered the disorder, worked hard
tient is 14 years of age; (5) all patients should to convince colleagues that the musty smell
receive the necessary care to protect and op- noted in the urine of some children with
timize their health; and (6) continuous and intellectual disabilities represented a meta-
affordable health insurance should be guar- bolic disorder. Bickel and colleagues (1954),
anteed, so that all costs of the transition who discovered a treatment for PKU, fought
planning and care are covered (American skeptics who discounted their contention
Academy of Pediatrics, American Academy that high phenylalanine levels were harm-
of Family Physicians, & American College ful and that a low-phenylalanine diet could
of Physicians–A merican Society of Internal prevent brain damage in children with PKU.
Medicine, 2002). These steps are reason- Guthrie, who discovered the simple bacte-
able, but many patients and their families rial assay to measure phenylalanine in fil-
are not prepared to make the transition to ter paper blood specimens (Guthrie & Susi,
adult health care (Reiss, Gibson, & Walker, 1963), and MacCready (1963), who worked
2005). In addition, many physicians do not for the Massachusetts Public Health Labo-
discuss the steps of this transition. The ma- ratories, at first faced ridicule for insisting
jority of pediatric practices do not employ on mandatory newborn screening. The re-
designated transition staff; offer transition placement of the Guthrie test with tandem
services, referrals for adult health care physi- mass spectrometry for newborn screening
cians, or transition plans; or create portable sparked controversy as well (Tarini, 2007).
medical records (McManus et al., 2008). Later arguments arose over the safety of diet
Reasons behind this failure to implement a discontinuation, the value of dietary therapy
transition procedure include a lack of com- for untreated adults with intellectual dis-
munication between physicians and patients abilities, and the benefits of a return to diet
regarding the transition, adult health care for apparently well-functioning adults on a
providers who are unequipped for dealing regular diet. Current debate surrounds the
with pediatric-onset conditions, and lack of introduction of nondietary treatments for
funds for transition teams in pediatric clin- PKU, such as BH4 (sapropterin) (Schuett,
ics. Many patients and families also express 2008). Much still needs to be discussed about
anxiety about leaving their familiar pediatric the theory that attributes deficits in frontal
care providers (McManus et al., 2008; Reiss lobe functioning to moderate reductions of
et al., 2005). To address these problems, brain dopamine in children with PKU who
some programs provide an identified transi- are treated early and continuously. Investi-
tion “navigator,” educational materials, and gations continue to clarify the meaning of
a written transition plan (McPherson, Than- abnormal MRI findings, the relevance of
genotype, and the feasibility of gene therapy cephaly, congenital heart disease, low birth-
and enzyme replacement therapy. weight, and intellectual disability in the
Research on neuropsychological outcomes offspring. Treatment largely prevents these
in early-treated PKU over the past 25 years adverse outcomes. However, the majority of
has identified a typical profile of learning maternal PKU pregnancies continue to be
deficits and behavioral problems, despite inadequately treated because of psychoso-
considerable inconsistency in results. Failure cial factors.
to replicate some findings reflects diversity •• Assessment of children with PKU per-
in study designs and limitations due to lack mits the early identification of learning diffi-
of control populations, disparities in instru- culties and indicates directions for alternative
ments used, small sample sizes, and reliance interventions or supplemental treatments.
on cross-sectional rather than longitudinal Particular attention needs to be give to ex-
studies (DeRoche & Welsh, 2008). Never- ecutive functioning, information-processing
theless, despite uncertainty in some areas, speed, visual–motor skills, arithmetic, and
much is now known about PKU. The fol- reading comprehension.
lowing list summarizes the key information •• The degree of metabolic control is usu-
useful to psychologists: ally correlated with neuropsychological out-
come. Stability of blood phenylalanine levels
•• PKU is an inherited disorder of phe- may also be critical.
nylalanine metabolism, which inhibits the •• Neuropsychological testing, along with
conversion of phenylalanine to tyrosine. In neuroimaging, can provide information
PKU, the gene controlling PAH (the enzyme about the brain effects associated with PKU.
responsible for this conversion) is defective. Neuropsychological testing suggests specific
•• Treatment with a diet low in phenyla- deficits in the prefrontal cortex, an area of
lanine (and a synthetic protein supplement) the brain selectively sensitive to diminished
prevents the most severe consequences of levels of brain dopamine. MRI studies sug-
PKU if started within the first few weeks of gest myelin abnormalities that do not appear
life. Newborn screening provides the best to be related to IQ but may affect processing
means for identifying babies with PKU, so speed.
that the diet can be initiated before signifi- •• Dietary compliance remains the critical
cant brain damage occurs. factor in PKU treatment. Different strategies
•• Despite treatment, learning disabilities for maintaining metabolic control need to
and deficits in neuropsychological function- be employed, depending on the child’s age
ing are common in children with PKU. and psychological issues.
•• Some adolescents and adults with PKU •• Treatment plans for PKU must address
experience agoraphobia, anxiety, depres- biochemical, nutritional, and psychosocial
sion, social withdrawal, and other emo- issues. Social support and positive attitude
tional disturbances as a consequence of diet toward treatment appear to be the most im-
discontinuation. portant factors associated with adherence to
•• Treatment for PKU must not be too medical recommendations in PKU and ma-
strict or too lax. Since different individu- ternal PKU.
als appear to have different tolerances for •• This field is rapidly changing as innova-
phenylalanine and varying responses to el- tive therapies, more sophisticated neuropsy-
evated levels, predictions about future com- chological testing, and advanced neuroim-
plications are impossible. Some individuals aging become available.
experience dramatic consequences after diet
discontinuation, while others appear to be Three key conclusions emerge:
relatively unaffected.
•• Occasionally other disorders coexist 1. The first 3–5 years of life represent the
with PKU, but no genetic linkages have been most critical period to maintain blood phe-
discovered. nylalanine levels within the recommended
•• Damage to the fetus from untreated range with as little variability as possible.
maternal PKU is caused by the intrauterine 2. Current treatments do not prevent
environment and is associated with micro- deficits in mental processing speed and ex-
Phenylketonuria 417
ecutive functioning, which affect nearly all of stimulant use for attentional dysfunction in
aspects of life and inhibit adherence to diet children with phenylketonuria. Journal of Inher-
for PKU. ited Metabolic Disease, 27, 137–143.
3. Lifelong treatment for PKU leads to Azen, C. G., Koch, R., Friedman, E. G., Berlow, S.,
Caldwell, J., Krause, W., et al. (1991). Intellectual
more positive outcomes in intellectual func-
development in 12-year-old children treated for
tioning, emotional well-being, and quality phenylketonuria. American Journal of Diseases
of life. of Children, 145, 35–39.
Batshaw, M. L., Valle, D., & Bessman, S. P. (1981).
The field remains open for research. With Unsuccessful treatment of phenylketonuria with
technological advances in genotyping, bio- tyrosine. Journal of Pediatrics, 99, 159–162.
chemical analysis, neuroimaging, treatment Baumeister, A. A., & Baumeister, A. A. (1998).
alternatives, and neuropsychological testing, Dietary treatment of destructive behavior associ-
answers should be forthcoming to some of ated with hyperphenylalanineuria. Clinical Neu-
the basic questions regarding the underlying ropharmacology, 21, 18–27.
pathology in PKU and the nature of optimal Beasley, M. G., Costello, P. M., & Smith, I. (1994).
Outcome of treatment in young adults with phe-
therapies for this disorder. nylketonuria detected by routine neonatal screen-
ing between 1964 and 1971. Quarterly Journal
of Medicine, 87, 155–160.
Acknowledgment
Bickel, H., Gerrard, J., & Hickmans, E. M. (1954).
The influence of phenylalanine intake on the
Rebecca Owens and Lydia Carr are acknowledged
for their help in revising and editing this chapter. chemistry and behavior of a phenylketonuric
child. Acta Paediatrica, 43, 64–73.
Blau, N., Bélanger-Quintana, A., Demirkol, M.,
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Chapter 22
Rett Syndrome
A Truly Pervasive Developmental Disorder
Robert T. Brown
Kathleen K. McMillan
Rett syndrome (abbreviated RTT in the tion. Although RTT is a rare disorder, with
present chapter, but also often as RS) is a ge- a prevalence of approximately 1 in 15,000
netically based neurodevelopmental disorder females, it may be the second most com-
that presents in infancy or early childhood mon form (after Down syndrome) of severe
as a striking deterioration after apparently mental retardation (Hagberg, 1995b), and
normal initial development. The Diagnostic the most common cause of profound mental
and Statistical Manual of Mental Disorders, retardation (Percy, 2002), in females. The
fourth edition, text revision (DSM-IV-TR; many thousand known cases occur appar-
American Psychiatric Association, 2000) ently equally in all parts of the world and
terms it Rett’s disorder and classifies it as all ethnic groups. Over 4,400 cases have
a pervasive developmental disorder (PDD). been diagnosed in the United States (Percy,
Classic RTT is the most severe and the most 2009); many older cases may be undiag-
truly pervasive PDD, affecting virtually all nosed (Smeets et al., 2003). Major increas-
domains of functioning. Although it has es in our understanding of RTT’s genetic
been the subject of hundreds of original basis, genotype–phenotype relations, cases
articles and reviews, RTT is little known in males, and potential treatments have oc-
to many professionals (Percy, 2008a). This curred since the chapters on it in the first
situation is unfortunate, as RTT is in some edition of this handbook (Brown & Hoad-
ways unique among PDDs, and those work- ley, 1999) and the more recent Handbook
ing with clinical populations should have a of Neurodevelopmental and Genetic Disor-
basic knowledge of its characteristics. ders in Adults (Brown, McMillan, & Her-
Classic RTT involves dramatic slow- schthal, 2005) were published.
downs in normal development, deceleration RTT is unique in several ways:
of growth, lack of interest in the environ-
ment, deterioration of motor functioning, 1. Apparently normal initial development is
hand stereotypies, loss of expressive lan- only apparent; it is frequently marked by
guage, abnormal sleep and breathing, sei- growth retardation from birth and pas-
zure disorders, abnormal social interac- sivity in early infancy.
tions, self-injurious behaviors, orthopedic 2. Rapid mental and physical deterioration
abnormalities (particularly scoliosis), and is often followed by stabilization or re-
eventual severe/profound mental retarda- duction of some symptoms.
425
3. Classic RTT develops through a series of [IRSF], 2008). These criteria were devel-
four stages. oped by an expert panel sponsored by the
4. Initially thought to affect only females, International Rett Syndrome Association,
RTT and RTT-like disorders occur in the IRSF’s predecessor (Hagberg, Hanefeld,
males. Percy, & Skjeldal, 2002). Particularly im-
5. At least 95% of female cases have a mu- portant is criterion 6: “The almost continu-
tation in the MECP2 gene; however, such ous repetitive wringing, twisting or clapping
mutations are involved in other condi- hand automatisms during wakefulness con-
tions. stitute the hallmark of the condition,” ac-
6. RTT occurs in both classic and specific cording to Hagberg (1995b, p. 973). Overall
variant forms. growth retardation is also generally seen:
7. Although classic RTT symptoms are se- 95% of girls with RTT are below the 5th
vere, variability is higher than was first
realized.
8. Physical appearance in childhood and TABLE 22.1. Classic RTT: Necessary,
life expectancy are generally nearly nor- Supportive, and Exclusionary
mal. Diagnostic Criteria
Necessary criteria (must occur)

History and Background 1. Apparently normal prenatal/perinatal history
2. Psychomotor development delayed from birth
In the early 1960s, in his pediatric clinic at or apparently normal to about age 6 months
3. Normal head circumference at birth
the University of Vienna, Andreas Rett by
4. Postnatal deceleration of head growth in most
chance saw two unrelated thin girls who cases
were wringing their hands in an unusual 5. Loss of purposeful hand skills between 6 and
manner and rocking in autistic-like move- 30 months of age
ments. In 1966, he published descriptions of 6. Persistent stereotypic hand wringing/squeezing,
several girls with similar symptoms and de- clapping/tapping, mouthing, and/or washing/
velopmental histories in an obscure German rubbing
7. Progressive social withdrawal, verbal/nonverbal
journal. Although Rett (1977) subsequently communication loss and/or dysfunction, and
published a chapter in English, his findings cognitive impairment
were largely overlooked. Hagberg (1995b) 8. Impaired locomotion or loss of locomotion
has summarized Rett’s work.
Also in the early 1960s, Bengt Hagberg in Supportive criteria (may occur)
Sweden was independently studying similar 1. Disturbed breathing (hyperventilation, breath-
cases. Rett and Hagberg met by chance at holding, forced expulsion of air/saliva, air
a conference in Canada and discussed their gulping) while awake
common observations (Percy, 2009). That 2. Bruxism
3. Impaired sleep patterns from early infancy
discussion led to the first widely circulated 4. Abnormal muscle tone resulting in muscle
description of RTT in English (Hagberg, wasting and dystonia
Aicardi, Dias, & Ramos, 1983). In a sense, 5. Peripheral vasomotor disturbances (cold, blue
two chance events—Rett’s initial observa- hands and feet)
tions, and Rett and Hagberg’s meeting—led 6. Progressive scoliosis/kyphosis
to RTT’s becoming widely known. The story 7. Overall growth retardation
8. Hypotrophic (small) feet; small, thin hands
supports Louis Pasteur’s classic statement
that in fields of observation, chance favors Exclusionary criteria (must not occur)
the prepared mind.
1. Enlarged organs or other signs of storage
disease
2. Retinopathy, optic atrophy, or cataract
Diagnosis of Classic RTT 3. Pre-, peri-, and/or postnatal brain damage
and RTT Variants 4. Identified metabolic or other progressive
neurological disorder
Classic RTT 5. Neurological disorder owing to severe infection
or head trauma
Necessary, supportive, and exclusionary cri-
teria for classic RTT are given in Table 22.1 Note. Adapted from IRSF (2008). Copyright 2008 by the
(International Rett Syndrome Foundation International Rett Syndrome Foundation.
Rett Syndrome 427
percentile in height and weight by 2 years of some girls retain language, although it tends
age (Percy & Lane, 2005). to be atypical and telegraphic. Several spe-
Diagnosis of RTT is based on clinical cific variants have been identified, including
signs, not genetic analysis (e.g., Hagberg et early-onset seizure, congenital with abnor-
al., 2002; Percy, 2008a). The relationship mal early development, delayed, and Zap-
between RTT and MECP2 gene mutations pella variant/preserved speech (e.g., Percy,
is not perfect, as described in more detail in 2008a). Since girls with the last-mentioned
a later section. Some individuals diagnosed variant show actual, although slow, motor
with RTT do not have a known mutation, and language development in childhood and
and some with a mutation do not show can draw and speak in sentences, the term
RTT. Zappella variant may be preferable to pre-
served speech (e.g., Renieri et al., 2009).
Atypical RTT
Diagnostic Concerns
The realization that females diagnosed with
RTT were more heterogeneous than was Of importance for parents and therapists is
originally thought led to the category of accurate diagnosis as early as possible. Some
atypical RTT or RTT variants (Hagberg, professionals may be reluctant to diagnose
1995a, 1995b). Main and supportive crite- RTT early because of its eventual severity,
ria for atypical RTT are given in Table 22.2. but many parents are frustrated by the lack
Atypical RTT should be diagnosed only in of a diagnosis that fits their children’s behav-
girls of 10 years or older, although criterion iors or has implications for treatment and
behaviors may appear throughout child- care. A parent checklist and video technique
hood. Girls with atypical RTT generally may be useful in making a detailed diagnosis
show less severe symptoms than those with (Fyfe et al., 2007), and a symptom checklist
classic RTT. Gross and fine motor control may help determine whether a girl should be
and mental retardation may be less severe; referred for testing for a MECP2 mutation
(Huppke, Köhler, Laccone, & Hanefeld,
2003). Classification and diagnosis are still
controversial issues (e.g., Matson, Fodstad,
TABLE 22.2. Atypical RTT: Main
and Supportive Diagnostic Criteria
& Boisjoli, 2008).
Main criteria (must meet at least three)

1. Absence or reduction of hand skills Developmental Trend of Classic RTT
2. Reduction or loss of babble speech
3. Monotonous pattern of hand stereotypies Classic RTT develops through a four-stage
4. Reduction or loss of communication skills sequence of behavioral and physical changes
5. Deceleraton of head growth from first years of first described by Hagberg and Witt Enger-
life
6. RTT disease profile: a regression stage
ström (1986). Kerr and Witt Engerström
followed by a recovery of interaction (2001) provide a useful table of the stages.
contrasting with slow neuromotor regression Age of onset, transition time from one stage
to the next, manifestation of features, and du-
Supportive criteria (must meet at least five) ration of all stages are variable. This section
1. Breathing irregularities draws on Budden (1997), Hagberg (1995b),
2. Bloating/air swallowing Hagberg and Witt Engerström (1986), Kerr
3. Teeth grinding (harsh-sounding type) (1995), Moser and Naidu (1996), and Naidu
4. Abnormal locomotion (1997) to describe major characteristics of
5. Scoliosis/kyphosis
6. Lower-limb muscle atrophy
early development prior to onset of symp-
7. Cold, purplish feet, usually growth-impaired toms and at each stage, along with disorders
8. Sleep disturbances, including night screaming from which RTT should be differentiated.
outbursts
9. Laughing/screaming spells
10. Diminished response to pain Pre-Stage 1: Early Development
11. Intense eye contact/eye pointing
Development appears largely normal until
Note. Adapted from IRSF (2008). Copyright 2008 by the at least 5–6 months of age. Early motor
International Rett Syndrome Foundation. skills, including reaching for objects, usu-
ally appear. Infants commonly develop self- Cognitive functioning, purposeful hand use,
feeding and can be weaned onto solid foods. and expressive language deteriorate further.
Many babble and walk, although their gait Hand stereotypies typically appear and may
is often unusual. However, subtle signs of be continuous during waking hours. Walk-
RTT appear early. Newborns who later ing may deteriorate or not develop. Girls
manifest RTT generally have below-normal who do walk generally show gait abnormali-
occipital frontal circumference, length, ties, particularly a spread-legged stance. Hy-
and weight, suggesting prenatal effects of perventilation, bruxism, and breath holding
MECP2 mutations (Huppke, Held, Lacco- are common, as are behaviors characteristic
ne, & Hanefeld, 2003). Many developmen- of autism. Seizures and vacant spells resem-
tal milestones are delayed. Feeding difficul- bling seizures may occur, and virtually all
ties, floppiness, jerkiness, delays in babbling girls with RTT have abnormal electroen-
and motor development, poor mobility, re- cephalograms (EEGs) by the end of stage
petitive limb movement, failure to recognize 2. Sleep patterns may become erratic and
familiar adults, limited play, repeated facial accompanied by bouts of screaming and
and mouth twitching, and repeated open- inappropriate laughter (Kerr & Witt Enger-
ing/closing of hands when trying to grasp ström, 2001). Differential diagnoses include
an object may appear in early infancy (e.g., autism, encephalitis, metabolic disorders
Kerr, 1995). (including inborn errors of metabolism), and
Many girls use single words, and a few use neurodegenerative disorders.
short phrases (Tams-Little & Holdgrafer,
1996). Of interest for potential early aware-
Stage 3: Plateau
ness of the disorder, these authors also found
that parents of only 1 of 17 girls with RTT Stage 3 generally lasts until about 10 years
reported use of three nonverbal communica- of age. Hand stereotypies continue, and
tion gestures (giving, pointing, and showing) mobility may further deteriorate. Measured
that typically develop at about 9–10 months mental retardation is generally in the severe/
of age. profound range, but assessment is difficult
because of communication and motor im-
pairments. Tremulousness, ataxia, brux-
Stage 1: Early-Onset Stagnation
ism, hyperventilation or breath holding,
The first stage begins at 6–18 months of age seizures, overall rigidity (hypertonia), and
and lasts for months. Overall, an infant ap- scoliosis may appear or increase. However,
pears to hit a developmental wall, although autistic symptoms may diminish, and so-
some advances (particularly in gross motor cial interactions, hand use, communication,
control) may occur. Much cognitive devel- alertness, and self-initiated behavior may in-
opment ceases. Deceleration of head growth crease. Nonverbal communication through
leads to below-normal head circumference eye pointing is claimed to improve, but
by the end of the second year (Kerr, 1995). this claim is controversial. Using a “blind”
Although no obvious pattern of abnormali- procedure, Meyer, Kennedy, Shulka, and
ties is apparent, hypotonia, loss of interest in Cushing (1999) found that caretakers of an
play and the environment, loss of acquired adolescent with RTT did not accurately in-
hand functions, and random hand move- terpret her eye pointing, but made inferences
ments are typical. Differential diagnoses in- based on their familiarity with her. Unfor-
clude benign congenital hypotonia, cerebral tunately, many studies that claim to have
palsy, Prader–Willi syndrome, and metabol- demonstrated choice behavior through eye
ic disorders. pointing have not controlled for potential
confounding effects. In one study (Baptis-
ta, Mercadante, Macedo, & Schwartzman,
Stage 2: Rapid Destructive
2006) claiming that girls with classic RTT
At about 18 months of age (range = 1–4 answered correctly on cognitive tasks via
years), affected children’s general function- eye pointing and looking time, the girls sat
ing deteriorates so rapidly that onset “may on their mothers’ laps, allowing for subtle
be so acute that parents can sometimes give cueing. Researchers measuring eye pointing
a specific date after which their child was or gazing need to control for confounding
no longer ‘normal’ ” (Budden, 1997, p. 2). sources of cueing and experimenter effects.
Rett Syndrome 429
Differential diagnoses include cerebral palsy The breakthrough occurred in 1999,

and other motor disorders, Angelman and when Amir and colleagues reported muta-
Lennox–Gastaut syndromes, and spinocer- tions in several cases of RTT of MECP2, a
ebellar degeneration. large gene at the tip of the long arm of the X
chromosome. MECP2 (pronounced meck-
pea-two [National Institute of Neurologi-
Stage 4: Late Motor Deterioration
cal Diseases and Stroke, 2003]) encodes a
Final phenotypes of classic RTT vary widely protein, MeCP2, a transcriptional repres-
(e.g., Hagberg, 1995b), but virtually all older sor that controls expression of other genes.
patients will be dependent on others for Most mutations reduce or eliminate func-
meeting basic needs. Physical size, includ- tion of MeCP2. Impaired MeCP2 in turn
ing brain size, is dramatically below nor- may disrupt normal developmental path-
mal (e.g., Cass et al., 2003). Motor function ways by leading other genes to turn and/
decreases further, with increased rigidity, or stay on at inappropriate times, resulting
muscle wasting, and scoliosis. Mobility also in uncontrolled gene expression (Johnston,
decreases further; many girls will need to 2004). Given MeCP2’s broad role in regulat-
use wheelchairs, although others will walk ing gene action, one should not be surprised
with altered gait throughout life. Repetitive that MECP2 mutations may have severe ef-
hand stereotypies, drooling, feeding/sleep- fects. As Armstrong (2005, p. 751) stated:
ing problems, skeletal deformities, seizures, “The abnormalities in the anatomy, chemis-
joint problems, gastrointestinal problems try, and clinical manifestations of Rett syn-
(including constipation), and breathing ab- drome all suggest that MECP2 is essential
normalities are almost universal (e.g., Percy, for neuronal maturation.”
2008a). Puberty is often delayed, but other- More than 200 mutations have been iden-
wise normal. Girls may be unable to convey tified on the four MECP2 exons. About
pain from menstrual discomfort or vaginal 95% of females with RTT have a MECP2
infection. Remaining expressive language mutation. However, some with RTT have no
generally disappears, and receptive language known mutation, and some with mutations
decreases. Eye pointing as communication do not show RTT. About 39% of all cases
is claimed to continue, and girls often seek are associated with four missense MECP2
social interaction. Chewing and swallow- mutations (T158M, R306C, R133C, and
ing problems may necessitate artificial feed- R106W); 35% with four nonsense muta-
ing (e.g., Lava, Slotte, Jochym-Nygren, van tions (R168X, R255X, R294X, and R270X);
Doorn, & Witt Engerstrom, 2006; Leon- 8.8% with C-terminal deletions; and 6.4%
ard, Fyfe, Leonard, & Msall, 2001). The with large deletions (e.g., Percy, 2008a;
girls have likes and dislikes, and can indi- Percy & Lane, 2009).
cate likes through such behaviors as facial Severity of RTT symptomatology varies
expressions and laughter (Cass et al., 2003; with type of MECP2 mutation (e.g., Naidu
Kerr & Witt Engerström, 2001). Survival et al., 2003). Relatively mild symptoms are
rate is essentially normal to 10 years of age, associated with R133C, R294X, R306C,
but then begins to drop. Survival at ages 20, and C-terminal deletion mutations. Girls
35, and 50 years is 80%, 70%, and 50%, with the T158M mutation may show only
respectively (Percy, 2008a). RTT behavioral symptoms in infancy and
childhood, but slowly deteriorate into clas-
sic RTT in adolescence. The R306X muta-
Genetics tion appears largely to impair only language.
On the other hand, R168X mutations are
For many years, RTT was assumed to be associated with more severe outcomes, par-
a single-gene X-linked dominant disorder, ticularly in walking, hand use, and language
for many reasons: (1) Concordance is close (Neul et al., 2008; Smeets, Chenaul, Curfs,
to 100% in monozygotic twins and 0% in Schrander-Stumpel, & Frijns, 2009). Con-
dizygotic twins; (2) only about 0.5% of RTT siderable variability in severity occurs in girls
cases are familial; and (3) early findings in- with the same mutation, suggesting that ad-
dicated that RTT fully appeared only in fe- ditional factors, such as skewed X chromo-
males, with a few cases of males with Rett- some inactivation or action of other mutated
like symptoms. genes, influence severity (e.g., Naidu et al.,
2003). About 2 weeks after conception, one developed tremors, motor impairments, low
of the two X chromosomes in female zygotes general activity, apparent anxiety, seizures,
is inactivated. In some cases, the inactivation curvature of the spine, and stereotypic fore-
may be skewed or partial, leading to over- or limb movements (Shahbazian et al., 2002).
underrepresentation of some genes. Jaenisch mutant mice developed apparently
Several nonclassic RTT phenotypes are normally initially and were fertile, but at
associated with MECP2 mutations in both about age 5 weeks began to show progressive
males and females. Female phenotypes in- RTT-like symptoms such as nervousness,
clude the preserved speech/Zappella variant, tremors, cold limbs, and breathing problems.
the delayed-onset variant, mild learning dis- Brain size and neuronal cell size were both
ability, Angelman syndrome, and unaffected reduced. Death occurred at about 10 weeks
carriers. Male phenotypes include fatal en- of age. Females heterozygous for MECP2
cephalopathy (most cases), Rett/Klinefelter developed normally for about 4 months, but
syndrome (47,XXY genotype), Angelman then showed reduced activity, gait abnor-
syndrome, X-linked mental retardation/pro- malities, and weight gain (Chen, Akbarian,
gressive spasticity, and somatic mosaicism/ Tudor, & Jaenisch, 2001). Bird MECP2-null
neurodevelopmental delay (Hagberg et al., male and female mice developed an unnatu-
2002; Online Mendelian Inheritance in Man ral gait and reduced movement at ages 3–8
[OMIM], 2004). However, detailed analysis weeks, followed by hindlimb clasping, irreg-
of the DNA sequence of the MECP2 gene in ular breathing, and teeth/jaw abnormalities.
28 males with Rett-like characteristics, 13 of Increasingly severe symptoms led to death at
whom met criteria for a RTT variant, failed about 54 days. Bird female mice heterozygot-
to find any MECP2 mutations (Santos et al., ic for MECP2 behaved normally until about
2009). If other mutated genes are found to be age 12 weeks, when they began to show
responsible for cases such as those of Santos hindlimb clasping and reduced movement.
and colleagues (2009), efforts should be made By age 9 months, about half showed addi-
to determine whether they exacerbate symp- tional symptoms, but then largely stabilized
toms in those who also have a MECP2 muta- (Guy, Hendrich, Holmes, Martin, & Bird,
tion. For example, the congenital RTT vari- 2001). Tam mice have virtually no MECP2
ant has recently been attributed to a mutation and show severe early motor deficits, stereo-
on the FOXG1 gene (Ariani et al., 2008). typed hindlimb clasping, impaired motor
learning, fear conditioning, and memory.
Analyses revealed impaired amygdaloid and
Mouse Models hippocampal formation, as well as impaired
activity of several specific genes involved in
Basic Aspects
nervous system development and function-
Research using mouse models of RTT, de- ing (Pelka et al., 2006). Another Rett mouse
veloped through several means of reducing model (Stearns et al., 2007) showed similar
levels of MECP2, has advanced our under- patterns: Males without MECP2 showed low
standing of the effects of MECP2 mutations activity, abnormal gait, paw stereotypies,
on development of Rett-like symptoms that relatively high fear, and deficits in learning.
complement many findings on human cases Brain volumes overall and in the amygdala,
(for summaries of earlier models, see Arm- hippocampus, and striatum were smaller
strong, 2005; Percy, 2008b). Increasing num- than those of controls. Females with one nor-
bers and types of models are being reported, mal and one mutant MECP2 gene showed
to the extent that only summaries can be pro- similar, but less severe, abnormalities
vided here. Because the different models have In mice, MeCP2 regulates brain-derived
been formed by using different techniques of neurotrophic factor (BDNF). BDNF encodes
reducing MECP2, each has its specific char- a protein essential for adult neuronal plas-
acteristics. In general, they develop appar- ticity, which in turn is essential for learning
ently normally until about 3–8 weeks of age, and memory. MECP2 mutations deregulate
but then develop various RTT symptoms. this protein in mice, and this deregulation,
Following Armstrong (2005), we describe through action on BDNF, may be at least
mutants in terms of the laboratories in which partly responsible for RTT (e.g., Chen et al.,
they were developed. Zoghbi mutant mice 2003; Gabellini, Green, & Tupler, 2004).
Rett Syndrome 431
Implications for Potential Therapy ed two possible cases in males. Subsequent

research has confirmed both classic and
Various manipulations reduce the effects of
atypical RTT in males, but at extremely low
MECP2 mutations in mouse models. Gia-
rates.
cometti, Luikenhuis, Beard, and Jaenisch
As might be expected, classic RTT has been
(2007) provided Jaenisch mice with a “res-
reported in boys with the 47,XXY karyotype
cue transgene” that postnatally activated of Klinefelter syndrome or 47,XXY/46,XY
MeCP2 in the mice’s brains. Rescued mice mosaicism. One boy with Klinefelter syn-
showed delayed development of RTT-like drome initially developed normal sitting,
symptoms and lived longer than untreated grasping, playing, and feeding, and had
ones. Furthermore, the brains of rescued begun to say a few words appropriately. By
Jaenisch mice were similar to those of typi- a year of age, he was losing hand, language,
cal nonmutant mice. Thus postnatal reme- and social skills, and was developing ste-
diation of MeCP2 deficiency may reduce reotyped hand movements, bruxism, and
severity of subsequent brain damage and constipation. By age 3, he had severe mental
RTT. retardation, had lost purposeful hand move-
At least two studies support Giacometti ments, and exhibited general hypotonia—all
and colleagues’ (2007) suggestion. In the characteristic of RTT, but not Klinefelter. Ge-
first study, rearing heterozygous female Tam netic tests indicated that the second X chro-
MECP2-deleted mutant mice in enriched mosome came from the father through non-
environments improved their performance disjunction (Schwartzman et al., 1999). In a
on several behavioral tests and showed in- highly unusual case (Maiwald et al., 2002),
creased cerebellar levels of BDNF, relative to a boy who was identified as male by prenatal
those of such mice reared in standard cages. sonogram and postnatal phenotype, but who
Male mice with no MECP2 gene raised in had a female 46,XX genotype, showed RTT-
enriched environments showed no improve- like symptoms (delayed motor development,
ments in behavioral tests or brain measures lack of language, hypotonia, microcephaly,
over such mice raised in standard cages. The and loss of purposeful hand movements) by
authors (Kondo et al., 2008) infer from these age 24 months.
findings that a normal MECP2 gene is need- RTT-like symptoms, including growth
ed for the enriched environment to have a and mental retardation, hypotonia, absent
positive effect. or lost language, microcephaly, seizures,
In the second study, injections of a sub- scoliosis, abnormal EEG patterns, and re-
stance reactivating the MECP2 gene in spiratory irregularities, have been reported
Bird mutant male and female mice that in boys from families with recurrent RTT in
were several weeks old and manifesting their daughters (Schanen et al., 1998) and
Rett-like symptoms considerably reduced boys with somatic MECP2 mutations (Clay-
the symptoms, prolonged life, and reversed ton-Smith, Watson, Ramsden, & Black,
hippocampal long-term potentiation defi- 2000; Topcu et al., 2002). One of Schanen
cits present in untreated mutant mice (Guy, and colleagues’ (1998) cases died at age 18
Gan, Selfridge, Cobb, & Bird. 2007). These months, apparently from respiratory failure;
findings indicate considerable malleability the other showed motor and other delays
in the structure of the nervous system even and a head circumference below the 5th per-
in adult mutant mice. Obviously these find- centile at 9 months of age. Clayton-Smith
ings have implications for, if not direct ap- and colleagues’ (2000) case developed hand
plicability to, human RTT (see, e.g., Percy, stereotypies, whereas Topcu and colleagues’
2008a, 2008b). (2002) did not. 46,XY males with nonmo-
saic MECP2 mutations may manifest a va-
riety of disorders: classic and atypical RTT,
RTT in Males congenital encephalopathy and early death,
mild to severe mental retardation, neuro-
Basic Aspects
logical disorders (e.g., ataxia, seizures, and
RTT for many years was thought to occur hypotonia), and PPM-X syndrome (mental
only in females, but then Coleman (1990) retardation, pyramidal signs, psychosis, and
and Philippart (1990) independently report- macro-orchidism) (Moog et al., 2003).
Why Is RTT Rare in Males? neurophysiological effects. Areas involved in

motor control are greatly affected. As would
Two explanations have been offered for the
be expected from the fact that seizures and
very low prevalence of RTT in males. The
sleep disorders are common in RTT, EEG
more generally supported is that males’
patterns tend to be abnormal (e.g., Jellinger,
shorter Y chromosome lacks a normal gene
2003). Perhaps the most striking effect is
to moderate the effects of an MECP2 mu- small brain size, which appears to be about
tation on the X chromosome. 46,XY males that of a normal 12-month infant virtually
would be nonviable, dying either prenatally throughout life.
or early postnatally. The other explanation On initial inspection, many parts of the
(Thomas, 1996) was based on evidence that brains of those with RTT appear normal
RTT is a dominant X chromosome disorder (Armstrong & Kinney, 2001), and the brains
largely caused by spontaneous mutations show no abnormal neuronal migration or ob-
that are more frequent in sperm than in vious cell loss or atrophy (Neul & Zoghbi,
eggs. Since chromosomally normal women 2004). However, numerous abnormalities
(46,XX) get one X chromosome from their have been documented. The cerebral hemi-
fathers, and chromosomally normal males spheres progressively atrophy, with overall
(46,XY) always get their X chromosome reduction of gray and white matter, particu-
from their mothers, more affected females larly in the frontal and temporal lobes (e.g.,
than males would be expected, owing to Kaufmann, 2001). The corpus callosum
normal patterns of inheritance. may be 30% below normal size. The brains
Evidence supports both explanations. of those with RTT also have small dendritic
Akesson, Hagberg, and Wahlström (1997) trees in pyramidal neurons of layers III and
reported significantly fewer male siblings V in the frontal, motor, and temporal lobes;
among girls with RTT than would be expect- small neurons with increased neuronal pack-
ed. Since males’ X chromosome is received ing density in the cerebral cortex, thalamus,
from the mother, maternal transmission basal ganglia, amygdala, and hippocam-
was indicated in these cases. Furthermore, pus; and reduced numbers of synapses in
early postnatal death of males with MECP2 many areas (e.g., Armstrong, 2005; Jell-
mutations suggests more prenatal deaths. inger, 2003; Neul & Zoghbi, 2004). Blood
Finally, a knockout MECP2 mouse model flow is reduced throughout the cortex (e.g.,
produced no surviving male offspring (see Armstrong & Kinney, 2001), particularly in
Trappe et al., 2001, for details and referenc- prefrontal and temporoparietal areas (e.g.,
es). Trappe and colleagues’ (2001) research Jellinger, 2003). The midbrain, cerebellum,
also provides support for Thomas’s (1996) and basal ganglia, particularly the caudate
explanation. Of 27 females with RTT owing nucleus and thalami, are smaller (e.g., Dunn
to spontaneous MECP2 mutations, 26 had et al., 2002; Jellinger, 2003). Cerebellar ab-
the mutation on the X chromosome from normalities suggest prenatally arrested de-
the father. Given that most male and female velopment (Jellinger, 2003). Positron emis-
cases of familial RTT and RTT-like condi- sion tomography scans show reduced uptake
tions arise from maternal MECP2 muta- of fluorodopa and increased dopamine D2
tions, most of the 99.5% of cases of RTT receptor binding in the caudate and putamen
that are nonfamilial probably originate from of girls with RTT relative to those of normal
a spontaneous MECP2 mutation on the pa- controls (Dunn et al., 2002). Dunn and col-
ternal X chromosome. The rarity of familial leagues (2002) suggest that RTT involves a
cases also supports Thomas. Since they are presynaptic deficit of nigrostriatal activity.
not mutually exclusive, both explanations Substance P, a neuromodulator, is sub-
could be involved in the low prevalence of stantially reduced in girls with RTT. Its
RTT in males. reduction in spinal cord areas involved in
transmission of pain stimuli could be in-
volved in these girls’ often reported reduced
Neuropathology pain perception. It is also involved in control
of many other functions affecting those with
RTT is associated with dramatic global and RTT, including respiration, transmission of
localized neurological, neurochemical, and visual and olfactory information, heart rate
Rett Syndrome 433
and rhythm, growth, and sleep (e.g., Arm- occurs in a caudal-to-rostral direction. This
strong & Kinney, 2001). directionality in turn may underlie the de-
Levels of many neurotransmitters are also velopmental course of RTT symptoms. This
reduced in those with RTT (e.g., Armstrong, “monoamine hypothesis” seems in keeping
2005; Neul & Zoghbi, 2004). Dysfunction with Naidu and colleagues’ (2003) proposal
of the cholinergic forebrain system, which that MECP2 mutations lead to failure of ap-
causes reduced choline acetyltransferase ac- propriate timing of MeCP2 in developing
tivity, is often found (e.g., Jellinger, 2003). cerebellar neurons and increased glutamate
The brains of those with RTT generally have and N-methyl- D -aspartate (NMDA) recep-
low levels of dopamine, norepinephrine, tors. High levels of glutamate and NMDA
serotonin, and their metabolites. Consis- receptors in turn lead to hyperexcitability of
tently found is reduced pigmentation in the neurons in the brain, contributing to many
substantia nigra (Jellinger, 2003). Some of RTT symptoms.
these abnormalities may owe to the reduced
concentrations of nerve growth factor found
in the cerebrospinal fluid of girls with RTT Treatment and Management
(Riikonen, 2001). As reported by Percy
(2008a), abnormal development of brain- Although no completely and generally effec-
stem serotonin transporter binding has been tive treatment regimen for RTT is available,
observed in brainstem tissue of human cases intense intervention may delay the appear-
of RTT, which may lead to characteristic ance of some symptoms and alleviate oth-
dysregulation of gastrointestinal and respi- ers (e.g., Glaze, 1995). Given RTT’s multi-
ratory systems. Percy suggests that clinical dimensional and generally severe effects, a
trials of serotonin and/or norepinephrine multidisciplinary treatment team of profes-
inhibitors are warranted in an attempt to re- sionals should be available either directly
mediate this dysregulation. or through connection with a regional RTT
The variety of respiratory and cardiovas- center to develop a fully accurate diagnosis,
cular conditions led Julu (2001) to suggest including identification of specific MECP2
that RTT is a “congenital dysautonomia” mutations, and course of treatment. This
and that “early brainstem dysfunction un- team is likely to include a pediatrician,
derlies the respiratory disturbance and may neurologist, neuropsychologist, geneticist,
contribute to sudden deaths” (p. 132). Levels orthopedic surgeon, gastroenterologist, en-
of cardiac sensitivity to baroflex and cardiac docrinologist, physical therapist, speech–
vagal tone in girls with RTT are almost 50% language therapist, and family therapist.
lower than normal, indicating a lack of inte- Several factors need to be considered in
gration in the brainstem, particularly in the planning interventions:
nucleus tractus solitarius (Julu, 2001).
Of interest, brainstem neural systems that 1. Those with RTT typically have very
develop between 36 weeks’ gestational age long latencies, as long as a minute, to re-
and 2–3 months postnatally appear to be spond to directions. Therapists and parents
abnormal, whereas those developing earlier must allow time for response.
appear normal. Thus RTT onset may occur 2. Accurate diagnosis is important to en-
in late fetal or early postnatal development sure effective, and avoid ineffective, treat-
and may involve early lesions of monoam- ment. For example, three girls with RTT,
ine neurons (Nomura & Segawa, 2001). initially diagnosed with autism, were inad-
According to Nomura and Segawa (2001), vertent participants in Lovaas’s intensive
low functioning of the noradrenergic and behavior modification program (Smith,
serotonergic neurons that develop during Klevstrand, & Lovaas, 1995). The program,
that period may be responsible for RTT- although demonstrably effective with autis-
associated sleep disorders, and deficiencies tic children, had few positive effects on these
in dopaminergic neurons may follow. They girls, and gains tended to be offset by losses.
propose that early lesions of monoamine More targeted behavioral treatment may be
neurons in brainstem and midbrain may lead effective, however, as described below.
to arrested or inadequate synaptogenesis at 3. Individual differences in degree and
all brain levels (including the cortex) that type of impairments, and in responsiveness
to (as well as tolerance of) various interven- ambulation, and use of an adaptive switch
tions, necessitate individualized treatment in an adult woman who had been completely
programs (e.g., Van Acker, 1991). dependent on staff members.
4. Most reports of successful interven- Of interest is a program (Roane, Pi-
tions have had few participants, making azza, Sgro, Volkert, & Anderson, 2001)
generality of findings uncertain. that successfully reduced stereotyped hand
5. Most behavioral interventions involve movements in an adolescent and an adult
extensive training. Much effort, persistence, who engaged in chronic stereotyped hand
and tolerance for frustration are required, movements—behaviors thought to be inher-
since the changes reported in some studies ent to RTT. Initial observations indicated
have been slow and even difficult to see. In- that the stereotyped behaviors occurred
deed, Piazza, Anderson, and Fisher (1993) almost continuously across situations and
suggest that parents be warned about the ef- regardless of external contingencies, sug-
fort involved and the need to keep careful gesting that they were under “automatic
response records in order to see progress. reinforcement” (Roane et al., 2001, p. 142)
6. Generally, those with RTT appear to that produced or alleviated stimulation. The
respond strongly to music (e.g., Kerr, Beli- most successful treatment involved response
chenkob, Woodcock, & Woodcock, 2001). interruption: Whenever one of the girls en-
It facilitates learning and development of gaged in a stereotyped hand movement, a
skills to such an extent that “music therapy therapist said, “Hands down, [girl’s name],”
should now be regarded as an essential part while moving her hands away from her face
of communication assessment and therapy” and holding them for 20 seconds. During
(Kerr, 2002, p. 283). Preferred music may be treatment sessions, both girls’ stereotyped
a reinforcer (e.g., Merker & Wallin, 2001). hand movements declined to near zero levels.
7. Some with RTT show hearing loss, par- However, treatment involved some 65–100
ticularly with increasing age (e.g., Pillion, 10-minute sessions given 8–10 times daily,
Rawool, Bibat, & Naidu, 2003). They may 5 days a week, and the effects showed little
benefit from hearing aids, but caretakers generalization to other settings.
need to attend carefully to their use. Parents, Mechanical and computer-based devices
therapists, and teachers may need to adjust have been used to modify girls’ behavior.
oral communication and music therapy to Using a computer fitted with a touch-sensitive
the auditory functioning of those with RTT. screen and voice synthesizer, Van Acker and
8. Claims that girls with RTT can com- Grant (1995) presented combined visual–
municate through eye pointing must be in- auditory representations of favored (and, in a
terpreted with caution, as discussed above. subsequent phase, nonfavored) foods to three
girls. In the first phase of training, a picture
In the studies described here, all partici- of a favored food item appeared on the com-
pants had been formally diagnosed with puter screen as the voice synthesizer asked,
RTT. Specialized behaviorally based pro- “Would you like some ?” To
grams have successfully modified various varying extents, the girls learned, with ini-
behaviors in persons of different ages with tial guidance, to touch the screen to receive
RTT, often in institutional settings. Using a small amount of a favored food. Acquisi-
verbal and physical prompts and reinforce- tion took weeks at two sessions a day. In
ment (praise), Piazza and colleagues (1993) the later phase, two of the girls clearly dis-
attempted to teach five girls who initially criminated between favored and nonfavored
had very limited self-feeding skills to scoop foods, learning relatively quickly to respond
food onto a spoon, bring the spoon to their at a high rate for favored foods and at a low
mouths, and put the spoon in their mouths. rate for nonpreferred foods. In subsequent
The girls’ self-feeding improved to varying generalization testing, the same two girls
degrees both during the 8-week program and responded appropriately in lunchroom and
in later follow-up. One girl was almost com- home settings.
pletely feeding herself 18 months after the Working with a 3-year-old, Sullivan, La-
end of the program. Through use of shap- verick, and Lewis (1995) tried to increase
ing, graduated guidance, and hand regula- contingent responding for music and mu-
tion, Bat-Haee (1994) increased self-feeding, sical toys. They fitted the girl’s orthopedic
Rett Syndrome 435
chair with two pad switches, one behind her (4) movement in water, teaching the client
head and one between her hands. Pressing elementary swimming (e.g., Starfish Club,
on either pad led to presentation of a toy 2004). An 11-year-old girl with RTT was
for as long as the switch was depressed. The given weekly treatment sessions of unspeci-
child rapidly acquired the head-pressing re- fied length. Her stereotypical hand move-
sponse, keeping the switch closed for min- ments declined after the first session and
utes at a time. Hand responses also occurred continued to decline across sessions. After
at a lower frequency. Subsequent introduc- 8 weeks, she showed improved hand use
tion of novel toys increased responding. in feeding, holding objects, and transfer-
After 6 months of training, the girl showed ring objects from hand to hand; improved
positive anticipatory emotions at the outset balance; increased interaction with the en-
of sessions and smiling, laughter, and vo- vironment; and reduced hyperactivity and
calizations during sessions; after 9 months, anxiety. This technique obviously warrants
she began to show similar responses in an- evaluation with more subjects over a longer
ticipation of a session. Other (and more period of time.
easily implemented) procedures may reduce As apraxia and other distortions of motor
stereotyped hand clasping and other move- movements are virtually universal in RTT,
ments. These include physical restraints that physical therapy is critical (e.g., Hanks,
prevent hand-to-mouth movements, simply 1990). It helps girls to maintain or reacquire
holding a girl’s hand, or allowing the girl to ambulation, an obviously important skill
hold a favored toy. Giving one girl a set of (Van Acker, 1991), and to develop or main-
baby keys, which she manipulated for long tain transitional behaviors needed to stand up
periods of time, reduced her hand wringing from sitting or lying positions. Such therapy
(Hanks, 1990). may involve use of a therapy ball and activi-
Adaptive technology may help to overcome ties to stimulate balance, weight shifting and
some RTT-associated motor and language bearing, and gait. Gait is further impaired
impairments. For example, Skotko, Kop- by rigidity in the heels of the feet, leading to
penhaver, and Erickson (2004) successfully toe walking. Ankle–foot orthoses and physi-
increased communication between girls and cal therapy help to maintain more normal
their mothers while the mothers read story- walking (Budden, 1997). Whirlpool baths
books to the girls. The researchers restrained may be helpful. Most girls begin to develop
each girl’s nondominant hand in order to in- scoliosis before age 8, and many also show
crease functional use of the dominant hand, kyphosis (hunchback) (Huang, Lubicky, &
and gave the girls augmentative and alterna- Hammerberg, 1994). Physical therapy and
tive communication (AAC) devices with ma- careful positioning in seated positions may
terial related to their storybooks. Mothers slow the development of scoliosis, but cor-
began asking their daughters more questions, rective surgery is often required.
which the daughters could answer with the RTT is often characterized by abnor-
AAC devices. Communication between each mal sleep patterns. Two quite different ap-
mother and daughter subsequently became proaches have successfully helped to increase
synchronized into actual dialogue. Moth- normal sleep. Using a behavioral approach
ers also increased their responses to their with three cases, Piazza, Fisher, and Moser
daughters’ AAC communications. (1991) woke the girls from daytime sleep
The Halliwick method of hydrotherapy that occurred outside of their usual nap-
has shown promising results in reducing times, removed them from bed for 1 hour
stereotyped behaviors and increasing motor if they showed delayed sleep (response cost),
skills (Bumin, Uyanik, Yilmaz, Kayihan, & and gradually advanced bedtimes (fading).
Topçu, 2003). In the Halliwick method, a Treatment increased regular sleep patterns
therapist guides an individual client through and nighttime sleep, and decreased daytime
a structured four-phase sequence: (1) men- sleep and nighttime waking. Using a 4-week
tal and physical adjustment to water; (2) melatonin treatment for nine girls with RTT,
rotation control, designed to increase con- McArthur and Budden (1998) reported that
trol over balance; (3) controlled movement during baseline, subjects had long sleep
in water, teaching the client to float and lie onset and short, interrupted total sleep time.
flat in both still and turbulent water; and Overall, melatonin decreased sleep onset
and increased total sleep time and efficiency no other signal. Gastrointestinal problems
in girls whose baseline sleep was most im- are a potential cause of such agitation (e.g.,
paired, but their response to melatonin was Percy, 2008a). After the girls go through pu-
highly variable. berty, caretakers need to be sensitive to their
Mobility and feeding generally require the menstrual cycles; agitation in older individu-
most day-to-day intervention by caregivers. als may reflect premenstrual discomfort or
According to Percy (2008a), gastrointestinal a gynecological disorder that may be easily
problems may be the most difficult medical treatable (Budden, 1997). Behavior modifi-
issue. In extreme cases, tube feeding may cation may be helpful; one of us (Kathleen
be necessary. Owing to feeding difficulties, K. McMillan) successfully used behavior
many with RTT will be underweight. Those modification to reduce her daughter’s tan-
who can feed themselves, on the other hand, trums, as described later. Other suggested
may become overweight. A detailed food treatments include medication (particularly
intake record may help identify foods that at night), music, quiet settings, massage, and
are consistently accepted or refused. Chew- hydrotherapy (particularly warm baths) (see,
ing and swallowing problems, as well as gas- e.g., Van Acker, 1991).
troesophageal reflux and digestive problems, Clinical trials of various treatments are
can contribute to growth retardation. Speech underway.
therapy may be helpful not so much for re-
taining language as for facilitating chew-
ing and swallowing. Supplementary tube Effects on Parents and Siblings
feedings may be necessary to help increase
growth (Glaze & Schultz, 1997), and some Descriptions relying predominantly on medi-
older girls may need to be fitted with gastric cal terminology barely convey the extent to
tubes, as in the case history near the end of which families are challenged. After a fairly
normal period of development, parents . . . wit-
this chapter. Further complicating feeding is-
ness their infant suddenly lose hand skills, not
sues is frequent constipation, which may be progress, lose words she had already learned,
difficult to correct through diet or additional and start to withdraw. The search for a diag-
fluids (e.g., Kerr & Witt Engerström, 2001). nosis and for therapeutic help can be time con-
Laxatives or enemas may be necessary. suming and emotionally challenging. Because
Seizures occur in most cases, particularly Rett syndrome is usually the result of a spon-
in stage 3 (Glaze & Schultz, 1997). Unfor- taneous mutation, the diagnosis of a genetic
tunately, parents may overestimate daytime disorder is totally unexpected. In the middle
seizure activity, some of which may be be- phase of adjustment, families have to deal with
haviorally based, but may miss actual sei- extremely distressing behaviors associated
zures, many of which occur during sleep with the disorder. . . . For parents, this means
that they have to rearrange their life to make
(e.g., Budden, 1997; Glaze & Schultz, 1997). space for a child with many cognitive, physi-
Most seizures can be controlled with anti- cal, and communicative impairments. Having
seizure medication, most frequently carbam- a child with Rett syndrome requires multiple
azepine and/or valproic acid. Occasionally, medical and educational visits that limit par-
in otherwise intractable cases, a ketogenic ents’ abilities to hold jobs or advance in their
diet may be used (Budden, 1997; Liebhaber, careers. (Retzlaff, 2007, p. 249)
Riemann, & Baumeister, 2003), although it
presents management problems. Retzlaff’s (2007) description trenchantly
Agitation, screaming, and tantrums are captures the difficulties facing those who
frequently reported. The rapid neurologi- deal with an individual with RTT. He might
cal and physical changes associated with the only have added that siblings are affected as
onset of the disease may understandably pro- well. Daily caretaking tasks may both call
voke emotional outbursts. Girls with RTT for the assistance of siblings (and other rela-
frequently respond negatively to stimulus or tives) and lead to parents’ having limited in-
routine change, so transitions from one set- teractions with those siblings. As in the case
ting or pattern to another should be gradual history described below, aggressive behav-
and accompanied by a parent if possible. Ag- iors may not only produce immediate pain,
itation or screaming may also reflect physi- but leave permanent physical scars. Many of
cal pain or irritation for which the girls have the effects of RTT can be ameliorated only
Rett Syndrome 437
with use of well-focused behavioral therapy, routinely updated, should be consulted for
which requires extensive parental involve- current research findings.
ment, and multiple medications, delivery of
which may be difficult owing to the affected
girls’ swallowing problems. Sleep problems Maggie : From Infancy
are common—and, as Percy (2009) so tell- to Adulthood
ingly stated, if a child does not sleep, nei-
ther do the parents. The stressors suffered Coauthor of this chapter and mother of Mag-
by families of an individual with RTT all too gie, a 36-year-old woman with RTT, I (Kath-
often lead to fatigue and burnout. leen K. McMillan) have lived through much
In an interview study, Retzlaff (2007) de- of what is described in this chapter. Maggie
scribed six categories of stress reported by was our first child, born when my husband
parents of children with RTT: emotional, was in military service in 1974, years before
symptom-related (e.g., seizures, screaming RTT became known. My pregnancy was
bouts), uncertainty about RTT’s effects, re- uncomplicated, and she weighed 7 pounds,
jection by others, incompetent or unavail- 9 ounces after a normal birth. She reached
able professionals, and comparisons with milestones at the following months of age:
healthy children and families. Not surpris- She sat at 4, wound up toys by 7, said her
ingly, parents differed in their success in first word at 10, had a vocabulary of about
dealing with the stresses. Those who had 16 words and showed interest in books at
other family members with serious medical 16, and somersaulted independently at 21.
problems, had strong social supports, spoke But her behavior had started to deteriorate
positively about the child with RTT and the at 12 months, when she began having vio-
family as a whole, and took charge of work- lent temper tantrums. At 16 months, her lan-
ing with the child coped well. In particular, guage skills started to regress. She learned no
they described their daughter with RTT as new words and used old ones less and less.
having enriched the family. On the other At 20 months, Maggie said only “mama,”
hand, those who viewed the child from the “papa,” and “baby.” She also aggressively
outset as a burden, were rejected by others threw toys and ate everything from cigarette
(including extended family and friends), had butts to dirt and plants. Maggie pushed, hit,
negative experiences with professionals, and and scratched her younger sister, born when
focused almost exclusively on the negative Maggie was 20 months old, severely enough
impact of dealing with their child took far to scar her face. She not only lost the ability
longer and were less successful overall in ad- to wind up toys, but by 24 months could not
justing to their situation. even pick them up. Her pediatrician told me
Owing to the lifelong impact of RTT on that Maggie was showing “normal regres-
parents and other family members, counsel- sion” owing to the birth of her sister, but
ing for them will be particularly important months later said he felt she showed some
(Lieb-Lundell, 1988). Of importance, given autistic characteristics.
the degree of care that adults with RTT re- Growth retardation became prominent
quire and their relative longevity, parents and persistent. Maggie entered an apparent-
are likely to face issues of lifelong care and ly autistic phase, smearing feces on herself
financial arrangements for their adult child and her surroundings. At 28 months, if I did
after they can no longer care for her. not attend to her, she often defecated in her
The IRSF makes available numerous re- hands and threw the feces at me. If I left
sources for professionals and families deal- her bed at night, she screamed and vomited.
ing with those affected by RTT, and its Her eating behaviors became bizarre: She
website (www.rettsyndrome.org) should be chewed ice, bit and chewed glass, and put
routinely consulted. It publishes the Rett everything in her mouth, including a dead
Syndrome Handbook (Hunter, 2007), a de- animal she found in the yard. One of her
tailed presentation of virtually all aspects grandmothers urged me to spank her. But
of RTT; provides a Regional Representative when spanked, Maggie laughed, suggesting
Program, made up of individuals who serve insensitivity to pain. At one point, when I
as human resources to families; and lists was afraid of becoming abusive, a physician
diagnostic clinics. OMIM (2004), which is recommended a course in behavior modifi-
cation. My use of behavioral principles led however, she was still totally dependent on
Maggie to stop vomiting and reduce other others for basic needs.
attention-getting behaviors, helping me deal Near the end of Maggie’s last year in pub-
with her for the first time since her infancy. lic school, my husband and I began to worry
At age 7 years, she was placed in a class about her long-term future in light of her
for autistic children. A year later, although need for care and our own ages. At home,
on medication, she began to have about 20 we could provide Maggie with love and sup-
tonic–clonic seizures daily. Tests indicated port, but residential care provided many ser-
multiple allergies, but changes in diet had vices that we could not: frequent bed checks
little effect. At about age 9 years, she began at night; full-time nursing; physical, speech,
again behaving aggressively toward herself occupational, and aquatic therapy; and a de-
and others. Once she slapped her face so gree of both independence and inclusion. At
hard that she deformed her jaw and began age 19, while still in public school, Maggie
to cry hysterically. When I tried to soothe moved into her own room in a residential
her, Maggie bit me so hard that I had to pry home. The timing was important because
her off. she was used to being away from the family.
Physicians proposed various diagnoses, in- If she had become accustomed to living full-
cluding schizophrenia, autism, mental retar- time at home, adjustment to the residential
dation, childhood aphasia, and hyperactivity. home would have been more difficult. The
Because Maggie was small and not gaining residential home provides many activities.
weight even though she ate a lot, malnutri- Her favorite was going out to eat, and she
tion was also suggested, and I felt accused of gained 17 pounds in her first year. Unfortu-
being a neglectful mother. At about the time nately, she later developed a serious swallow-
my husband and I were considering residen- ing problem; her weight began to plummet,
tial treatment, Maggie had a severe seizure, and a gastric tube was implanted in 1998.
fell down a flight of stairs, and was admit- Maggie now participates in the adult day
ted to a hospital. Having read about RTT, program at the residential home, which cre-
I shortly thereafter described it to some of ates jobs to meet residents’ individual needs
her physicians. Fortunately, her neurologist and abilities. Maggie helps make pet biscuits
had recently attended an RTT conference and beds that are sold to local pet stores. For
and diagnosed her correctly. She was among example, she stuffs pet beds, which are held
the first 250 girls diagnosed worldwide with in place with an adaptive frame. The pro-
RTT. Depakote, which had been found ef- gram also has pet therapy, computer learn-
fective for girls with RTT, reduced her sei- ing, horticulture, and aquatics.
zures and aggressive behavior. We dropped At this writing, Maggie can see and hear,
plans for residential treatment, although she but not talk. Unlike many adults with RTT,
still showed severe mood swings. Speech she can walk, but with gait problems. Her
therapy was not effective, but Maggie’s con- hands are often clasped at her mouth, lead-
tinued walking may owe a great deal to the ing to balance problems. She drools, leaving
physical therapy she received. her hands wet and subject to fungal infec-
Maggie met virtually all diagnostic cri- tions; she gulps air and has H-pyloris, both
teria for RTT and went through the four of which lead to gastric distress; she has
developmental stages described earlier. Her gastroesophageal reflux, eating difficulties,
cognitive development became largely ar- and swallowing problems; and she still has
rested, and her hands became infected from occasional tonic–clonic seizures, only par-
stereotyped hand mouthing. Bruxism, air tially controlled by medication. Because she
swallowing, and breath holding were com- also continues to fall during seizures, she
mon. She still walked, but had gait apraxia now wears a staff-designed vest to reduce
and jerky body movements. She had surgery injury. She appears to communicate through
for scoliosis at age 15 years. Growth retar- eye gaze and finger pointing, but with long
dation continued. Compared to her earlier response latency. Generally loving and ap-
“Jekyll–Hyde” behavior, her temperament preciative, she occasionally lashes out, ap-
became calmer, and by her late teens, she parently to communicate pain from gastric
was easygoing most of the time, had fewer distress. Recent genetic analysis has revealed
seizures, and had regained some lost skills; that she has a MECP2 C-terminal deletion.
FIGURE 22.2
FIGURE 22.1
FIGURE 22.3
FIGURE 22.4
FIGURES 22.1–22.4. Photographs of Maggie at ages 22 months, 15 years, 26 years, and 30 years,
respectively. Note (1) stereotyped hand clasping even at 22 months; (2) change in relative height (in
Figure 22.2, Maggie is taller than her 10-year-old sister, but in Figure 22.3, 11 years later at the same
sister’s wedding, she is far shorter); (3) diminished growth and the still common hand clasping near her
mouth—both apparent in Figure 22.4 (in 2005), where she is between her two younger sisters.
439
Is RTT a PDD, an Autism Spectrum generally more severe than ASDs, and usu-
Disorder, Both, or Neither? ally has an identified genetic basis. In short,
it does not fall on the same spectrum (i.e.,
An unfortunate current tendency is to use continuum or range) as do ASDs.
the term autism spectrum disorders (ASDs)
interchangeably with, or even use it to re-
place, the DSM-IV-TR (American Psychiat- Concluding Remarks
ric Association, 2000) category of PDDs. A
brief summary of current terminology prob- In recent years, much progress has been
lems follows. made in understanding RTT’s genetic basis,
Two U.S. National Institutes of Health phenotypic variability, and neurological cor-
agencies have taken contradictory positions. relates. Unfortunately, similar progress has
The National Institute of Mental Health not occurred in treatment. Indeed, those
(NIMH) “Autism Spectrum Disorders (Per- involved with treatment may feel as Ignaz
vasive Developmental Disorders)” webpage Semmelweis (1861/1981) did when he was
(NIMH, 2009, p. 1) states that “ASDs [are] searching for the cause of childbed fever:
also known as PDDs. . . . These disorders . . . that their attempts are “like a drowning
range from a severe form, called autistic dis- man, who grasps at a straw.” Although sev-
order . . . to a much milder form, Asperger eral promising treatments are now available,
syndrome. They also include two rare dis- all have been used in only small numbers
orders, Rett syndrome and childhood disin- of cases, and most require extensive train-
tegrative disorder.” Thus NIMH uses ASDs ing. Greatly needed are larger-sample, well-
and PDDs interchangeably and implies that controlled evaluations with long-term fol-
autistic disorder is the most severe form—a low-up of these programs, particularly those
highly questionable implication, given clas- that can be relatively easily implemented.
sic RTT’s severity. What we can state with most confidence
On the other hand, the National Institute is that, given the rate of new findings, some
of Child Health and Human Development material in this chapter will turn out not to
(NICHD) has it both ways. Its “Autism Spec- be accurate. Indeed, it is quite likely that this
trum Disorders (ASDs)” webpage (NICHD, will be the case at publication. We wish we
2008, p. 1) states: “Health care providers knew which material this will be. We hope,
think of autism as a ‘spectrum’ disorder, a of course, that the first to be discarded will
group of disorders with similar features. . . . be what we have said about the lack of gen-
Currently, the ASD category includes: Au- erally effective treatment.
tistic disorder . . ., Asperger syndrome, and
PDD-NOS (or atypical autism). In some
cases, health care providers use a broader References
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Chapter 23
Lesch–Nyhan Syndrome
A Sex-Linked Inborn Error of Metabolism
David L. Wodrich
Lori A. Long
Lesch–Nyhan syndrome (LNS) is a rare syndrome). These same characteristics ap-

inborn error of metabolism (estimated to pear in LNS.
be present in 1 of 380,000 live births). In
LNS, mutations in the gene coding for the
enzyme hypoxanthine–guanine phosphori- History and Background
bosyltransferase (HPRT) on the X chromo-
some lead to deficient enzyme activity. This LNS has an interesting history. Its under-
results in abnormal purine metabolism, and standing has potential relevance for diverse
therefore in elevated levels of uric acid, the professional groups seeking to clarify the
end product of purine metabolism. Several causes of particular neurodevelopmental
physiological problems may ensue, including disorders (of which LNS is one), as well
chronic kidney disease and central nervous as the broader topics of genetic, biochemi-
system (CNS) impairments (Nyhan & Wong, cal, and neurological underpinnings of be-
1996). It now appears that neurotransmitter havior and development. In 1962, William
deficiencies in dopamine underlie the CNS Nyhan had completed pediatric training at
impairments, and thus the developmental, Yale and earned a PhD at the University of
behavioral, and motoric impairments, that Illinois before receiving an appointment at
characterize LNS. Anatomically, dopamin- Johns Hopkins. Michael Lesch was a medi-
ergic pathways are known to encompass cal student on his service at Johns Hopkins
basal ganglia (symmetrical masses com- when the two men encountered a 4-year-old
posed of gray matter) and connected struc- patient who presented with recurrent he-
tures (e.g., frontal lobes). Behaviorally, do- maturia (blood in the urine) and, on closer
pamine is understood to be associated with inspection, crystals in his urine (Nyhan,
movement, reward, planning, and response 2005). When the crystals were identified as
inhibition. Neuropsychiatrically, dopamine uric acid, and elevated uric acid was also
and dopaminergic pathways are central to found in the blood, a problem with me-
the expression of various movement disor- tabolism of purine was deduced. Coupling
ders (e.g., Parkinson disease) and psychiatric these unexpected findings with the patient’s
disorders in which compulsions and impulse developmental and behavioral presentation
dysregulation are hallmarks (e.g., Tourette prompted further contemplation. This boy
445
suffered from significantly delayed motor used antirejection drug, azathioprine, failed
development and, apparently, cerebral palsy. to produce its typical effect among boys with
More striking were a badly mutilated lip and LNS. Important clues included the facts that
fingertips. The detection of a brother with azathioprine was known to undergo conver-
the same phenotype, a typically develop- sation to 6-mercaptopurine via involvement
ing sister, and two phenotypically normal of HPRT, and that azathiopine was known
parents suggested to Nyhan and Lesch the to reduce uric acid levels. However, in pa-
presence of a genetic disorder, later docu- tients with LNS, azathiopine exerted none of
mented to be an X-linked recessive disorder. the expected effect on uric acid levels. This
An examination of the patient revealed ab- helped to implicate HPRT as the underlying
normal reflexes, spasticity, and involuntary metabolic error in LNS (see Figure 23.1).
movements, suggesting a syndrome that was It was soon discovered, however, that a
neurological in nature. subgroup of patients existed in whom HPRT
Michael Lesch devoted himself full-time to metabolism was disordered, but who ex-
the study of the disorder. He and Nyhan depressed none of the classic LNS symptoms.
tected extreme elevations of serum uric acid This latter group still had gout (as did all
in both brothers; their results were published boys with full LNS) and the previously men-
in 1964 (Nyhan, 2005). When patients from tioned crystals in their urine. It was found
around the world were subsequently report- that this group had 1–50% of the normal
ed, all of whom were boys, the X-linked basis HPRT activity, but no CNS involvement.
of the disorder was substantiated. Within a Males with zero HPRT activity remain the
few years, the nature of the enzymatic error rule, but other variations have been found
was understood and shared with the scien- (Nyhan, 2005). By the early 1980s, the gene
tific community (Nyhan, Sweetman, Carpe- involved in production of HPRT was un-
nier, Carter, & Hoefnagel, 1968; Seegmiller, derstood to be located on the long arm of
Rosenbloom, & Kelley, 1967). In part, the the X chromosome (Jolly et al., 1983). Later
role of HPRT was discovered when a widely research suggested dopamine abnormalities
FIGURE 23.1. Disordered metabolic pathway associated with LNS. The inborn error of metabolism
concerns the absence of HPRT (1). Because in patients with LNS the HPRT enzyme is unavailable to
accomplish its typical task of enabling hypoxanthine (2) and guanine (3) to be converted to inosinic
acid (4) and guanylic acid (5), hypoxanthine and guanine accumulate to excessive levels, which results
in excessive accumulation of uric acid when they are converted to uric acid by xanthine oxidase (an
enzyme not depicted in this figure). The accumulation of excess hypoxanthine may directly produce
adverse neurological consequences. Data from Torres and Puig (2007).
Lesch–Nyhan Syndrome 447
and basal ganglia dysfunction, and broadly Developmental Course

stimulated questions about the relationship
of biochemistry and behavior. Children with LNS develop such severe im-
LNS is unique in terms of its metabolic– pairments that extremely early detection of
behavioral links. As seen below, quite note- abnormalities is the rule; however, the dis-
worthy self-abuse behavior characterizes order presents so rarely that precise LNS
nearly all boys with LNS. LNS represents diagnosis may be at risk. For example, in
the first metabolic disease in which there ex- presenting an interesting case from Slove-
isted a clear set of behaviors. In part, this nia, Levart (2007) commented that only a
prompted Nyhan in 1971 to coin the term single case would be expected in her country
behavioral phenotype (see Nyhan, 2005). every 20 years. Consequently, children may
Crucially, Nyhan pointed out that a behav- be incorrectly diagnosed. For instance, the
ioral phenotype, “a characteristic pattern of presentation of significant motor delays may
behavior consistently associated with a bio- result in a cerebral palsy diagnosis (Nyhan,
logic disorder” (Nyhan, 2005, p. 1), some- 2005). It may not be until children present
times permits professionals to establish a with self-injurious behaviors that physicians
syndromal diagnosis, just as physical signs consider other diagnoses. The “gold stan-
(i.e., dysmorphic signs) do. dard” for diagnosis is laboratory testing that
In the end, Nyhan went on to found the determines less than 1.5% HPRT activity in
Department of Pediatrics at the University erythrocytes (Nyhan, 2005). Research sug-
of California–San Diego. He remains there, gests that analysis of erythrocytes, or red
actively studying LNS and many other in- blood cells, permits detection of minute lev-
herited diseases of metabolism. Lesch’s later els of HPRT that may be missed if other cells
career path led to internal medicine and car- alone are studied. To date, no known stud-
diology; he never returned to the disorder ies are available to offer descriptive statistics
that bears his name (Nyhan, 2005). about diagnosis.
Diverse research efforts have continued to The hallmark features of LNS are quite
reveal the makeup of LNS. By the 1990s, the striking, and they encompass both biologi-
location and extent of dopamine anomalies cal and behavioral–developmental dimen-
were documented. For example, Wong and sions. During the first 6–8 months, however,
colleagues (1996) used positron emission to- developmental milestones may appear to be
mography (PET) and MRI to study a small grossly normal (Nyhan, 1973). Typically, the
group of men (ages 19–35 years) with LNS. first indication of abnormality may occur
PET results, established by using a ligand that when orange crystals appear in diapers,
binds to dopamine, showed between 50% indicating the presence of urate crystals in
and 63% reduced dopamine-binding poten- the urine. Later, children will present with
tial in the caudate and between 64% and motor and cognitive developmental delays,
75% reduction in the putamen (both basal as well as begin engaging in self-injurious
ganglia structures) compared to controls. behaviors. The developmental course of each
MRI results failed to detect differences in of these phenomena is reviewed.
putamen volume, but detected a 30% reduc- Essentially every patient with full LNS
tion in caudate volume compared to controls. expresses the following set of neurological
This information fits with small-scale au- signs and impairments: increased muscle
topsy findings, in which documented anoma- tone, associated with a scissor position of the
lies in the dopamine system were associated lower extremities; extremely delayed motor
with caudate and putamen. It also appears development; spasticity with deep tendon
to match animal studies in which the HPRT reflexes and Babinski signs; and involuntary
system was altered (producing a reduction in movements (Nyhan, 1997). Thus a particu-
striatal dopamine transporters) or in neona- lar motor phenotype appears evident in in-
tal rats that underwent intentional dopamine dividuals with LNS and is distinguishable
depletion procedures (producing LNS-like from the phenotypes of other motor disor-
self-abusive behavior; see Wong et al., 1996, ders. Jinnah and colleagues (2006) stud-
for details). Cumulative information like this ied a group of 44 patients with LNS (ages
suggests that the dopamine system is central 2–38) who expressed the full syndrome (i.e.,
to producing LNS signs and symptoms. mental retardation, self-injurious behaviors,
motor disability, and overproduction of uric six individuals (ages 14–23 years) with fol-
acid). Examinations included a complete low-up scores earned at 2 and 4 years later.
medical history, standardized written proto- Overall, scores on the SB-IV declined. Initial
cols focusing on motor features, and assess- scores averaged 61.3 (range = 40–81); scores
ments of muscle tone. A scale was also used at the 2-year follow-up averaged 59.2 (range
to index the severity of motor deficits (1 = = 39–77); and scores at the 4-year follow-
motor abnormality absent; 2 = motor abnor- up averaged 54.7 (range = 36–75). Though
mality mild; 3 = motor abnormality severe the decline in scores from initial testing to
enough to preclude meaningful function). the 2-year follow-up was not statistically sig-
The developmental progression of motor nificant, the scores at the 4-year follow-up
impairments began at 3–6 months with hy- were statistically significantly different from
potonia and failure to sit upright. Typically those at both the initial (p < .02) and the
by 6–12 months, involuntary movements 2-year follow-up (p < .02) assessments. Men-
appeared (although some parents reported tal age of the sample did not meaningfully
this to be delayed up to 4 years). No signifi- increase over 4 years (i.e., it rose from 7.0
cant progression of motor impairments was to just 7.9). The greatest gains were seen in
noted beyond ages 5–6 years. The primary children under the age of 13, with a plateau
feature of the motor disorder in all patients apparently reached between ages 13 and
was dystonia (i.e., a disabling movement dis- 17 years concerning abstract visual reason-
order characterized by sustained contraction ing and aspects of short-term memory. The
of muscles, leading to twisting, distorted plateau may occur because older boys suf-
postures). Mild to moderate forms of chore- fer decreases in attentiveness and flexibility
oathetosis (50%) and ballismus (30%) were of thinking with age. However, many of the
also found. teenage boys in this study enjoyed continued
As motor deficits intensify, most babies ei- growth in some areas (e.g., vocabulary and
ther lose the ability to sit or fail to master sit- memory for objects). Quite variable mental
ting at all. No patients with full LNS walk or abilities are reported by parents, and some
sit independently (Nyhan, 1997). Gout may boys appear to maintain surprisingly well-
also appear when uric acid is deposited on preserved skills and assorted interests (An-
the articular cartilage of joints, tendons, and derson, Ernst, & Davis, 1992).
surrounding tissues. Wheelchair use (usually LNS’s most troubling aspect is extreme
a narrow chair, with supports at the chest) self-injurious behavior. Nyhan (1973) has
is then nearly universal, and it follows that long argued that this behavioral feature itself
executing activities of daily living depends helps suggest LNS, and is often implied quite
on assistance from others. quickly by observation of missing tissue.
LNS is also associated with speech and Nyhan points out that although self-abusive
eating problems. For example, Jinnah and behavior is common among individuals with
colleagues (2006) found that speech was developmental delay, patients with LNS are
delayed in all 44 of their patients with LNS unique in their tendency to cause loss of
(first words by age 2–4 years). All speech their own tissue. Virtually all patients have
was dysarthric, resulting in slowed expres- bitten their lips destructively upon eruption
sion and constrained intelligibility. Chew- of their primary teeth. These are well docu-
ing and swallowing were difficult for most mented photographically in numerous case
patients; 20% of the sample required a gas- reports appearing in the literature. Para-
trostomy tube. Eating problems may also doxically, these children remain sensitive to
compromise caloric intake for many, and pain (e.g., screaming with pain upon biting
aspiration, accompanied by pneumonia, is a themselves). Thus one might speculate that
looming risk. a disturbance in the subjective experience of
Cognitive impairments are often present in pain or in the body’s response to pain (e.g.,
individuals with LNS; however, relatively lit- release of pain-induced endorphins) exists in
tle is known about the development of these those with LNS. This line of thinking is vis-
impairments over time. A study by Matthews, ited again in discussion of some LNS treat-
Solan, Barabas, and Robey (1999) compared ments (i.e., botulinum toxin; see below).
the initial results on the Stanford–Binet In- In an extensive study of 64 individuals
telligence Scale: Fourth Edition (SB-IV; with LNS (ages 1–40 years), parents/care-
Thorndike, Hagen, & Sattler, 1986) among givers reported on types of self-injurious
behaviors (Robey, Reck, Giacomini, Bara- Second Edition (ABS-RC2; Nihira, Leland,
bas, & Eddey, 2003). Ninety-one percent of & Lambert, 1993) to evaluate emotional
parents/caregivers reported self-mutilating and behavior status. They studied individu-
behaviors, with the age at emergence of als with full LNS, individuals with a variant
these behaviors ranging from 5 months to of LNS including no self-injurious behaviors,
10 years. Over half of the sample (53%) re- and healthy controls. Boys with full LNS
ported that the first behaviors observed in- were found to have higher levels of anxi-
cluded lip and finger biting. The behaviors ety, depression, social problems, disrupted
reported included biting fingers (78%), bit- thinking, inattention, and distraction, as
ing lips and mouth (77%), extending arms in well as stereotyped, hyperactive, attention-
doorways (66%), banging head (56%), tip- seeking, and aggressive behaviors, compared
ping wheelchair (33%), poking eyes (31%), to healthy controls (Schretlen et al., 2005).
inserting fingers in wheelchair spokes (30%), In contrast, those individuals with the vari-
rubbing head on wheelchair headrest (27%), ant of LNS free of self-injurious behavior
and rubbing arms on restraints (17%). Hi- were generally more similar to healthy con-
erarchical cluster analyses were performed trols on most behavioral dimensions, but
to examine the degree of co-occurrence they showed levels of inattention similar to
among self-injurious behaviors. The stron- those of individuals with LNS. These find-
gest association was found between inser- ings suggest the possibility of a behavioral
tion of fingers in wheelchair spokes and the phenotype that is broader and includes more
rubbing of arms on restraints. Finger biting than just self-injury.
and lip biting were also closely associated. Why changes may occur over time is not
Likewise, older patients with LNS displayed well known. Certainly accumulation of
more varied self-injurious behaviors in the frustration is one possibility. CNS changes,
past than did younger patients, indicating such as cerebral atrophy, may occur in in-
that these behaviors continue over time, but dividuals with LNS. Neuroimaging studies
may change in appearance. of 25 patients found that three experienced
For some individuals with LNS, aggres- atrophy—reduction in cerebral (17%) and
sion may also be outwardly directed, es- basal ganglia (34%) volumes (Jinnah et al.,
pecially toward caregivers. For instance, 2006). These findings are consistent with
children may vomit and spit to express inter- those of Matthews and colleagues (1999),
personal aggression (McCarthy, 2004). Both who identified declines in cognitive func-
self-mutilation and aggression, however, are tioning as these individuals moved into
compulsive in that afterward children typi- adulthood.
cally report feeling powerless to have stopped As a group, individuals experience reduced
themselves, and many communicate remorse life expectancy. Causes of death include
(Morales, 1999). A unique finding concerns pneumonia and various infectious diseases.
a phenomenon called emotional self-injury, With the use of medication (allopurinol),
which caregivers have referred to when de- kidney function can be preserved. Patients
scribing outwardly directed behaviors (i.e., often survive into the second or third decade
a child’s saying no when he actually wants (Torres & Puig, 2007).
something, caregiver-directed verbal abuse)
that appears to eventuate in negative emo-
tional consequences for the patient himself Genetics and Family Patterns
(Robey et al., 2003). This potential aspect
of self-directed aggression may be an im- Because LNS is an X-linked recessive disor-
portant component of the behavioral pheno- der, the disorder is almost exclusively evident
type; however, there is currently no research among boys and young men (five anomalous
detailing such consequences. female cases have apparently been reported,
The behavioral phenotype of LNS may however; see Torres & Puig, 2007). The gene
extend beyond self-injurious and aggressive responsible for HPRT production is located
behaviors. Schretlen and colleagues (2005) on the long arm of the X chromosome (at
used the Child Behavior Checklist (CBCL; Xq26) and consists of nine exons. Mutations
Achenbach, 1991) and the American Associ- are known to be quite heterogeneous in both
ation on Mental Retardation’s Adaptive Be- location and type, and include deletions, in-
havior Scale—Residential and Community, sertions, duplications, and point mutations
(Torres & Puig, 2007). A second X chromo- says. Patients with partial variants lack both
some (XX) in females with LNS typically the classic LNS behavioral features and the
results in a favorable outcome of adequate hallmark spasticity and choreoathetosis of
production of the enzyme HPRT. Conse- those with the neurological variants.
quently, normal brain development occurs in Hladnik, Nyhan, and Bertolli (2008) re-
most girls with the LNS genotype, although cently published an article with important
rare cases of females expressing the pheno- implications for the genotype–phenotype
type have been reported (McCarthy, 2004). correlations in LNS. Typically, families with
In 1989, Gibbs, Nguyen, McBride, Koepf, a mutation in the HPRT gene express this
and Caskey found among 15 cases the oc- in the same, or a similar, phenotype. This
currence of DNA base substitutions, small article describes a single family with an
DNA deletions, a single DNA base insertion, HPRT gene variant that permits some en-
and an error in RNA splicing. It is possible to zyme activity, and associated milder clinical
use DNA as a means of diagnosis and carrier expressions, rather than the full LNS syn-
identification; that is, mutant alleles within drome. This family, however, was character-
individual families are directly detectable. ized by three discernible phenotypes. One
Nonetheless, because nearly all families have family member expressed the classic LNS
their own mutation, there are practical limi- syndrome, whereas this patient’s brother
tations imposed on clinical diagnosis. Mo- and an uncle had a much milder disease and
lecular methods of prenatal diagnosis and associated symptom expression. These indi-
heterozygote detection are viewed as labo- viduals’ clinical presentation was difficult
rious. Thus physicians use them only when to distinguish from that of disease-free in-
working with families in which there is an dividuals. Finally, two cousins of the patient
affected individual whose mutation has been with classic LNS had an intermediate level
determined (Nyhan, 2005). of expressed disease. As a result, the authors
concluded, it is no longer possible to assume
that a given mutation in the HPRT gene will
Risk Factors predictably lead to “a reproducible pattern
for Phenotypic Expression of clinical expression.”
The range of phenotypic expression in LNS

now appears to be larger than might have Assessment
originally been anticipated. In part, this de-
rives from a more diverse underlying geno- Of special concern for psychologists is the
type. As noted above, it was recognized fair- fact that valid cognitive assessments of chil-
ly early in the course of studying LNS that a dren with LNS are difficult to accomplish.
few individuals experience HPRT deficiency Assessment techniques that can circumvent
representing more than zero activity, where- each child’s impairments—such as observa-
as the vast majority of patients with LNS tion techniques, untimed items that can be
have no HPRT activity. This means that, answered by pointing/eye gaze, or other ap-
broadly, three variations in HPRT deficiency propriate nonverbal response measure (e.g.,
can be recognized: LNS variants, so-called the Peabody Picture Vocabulary Test, Fourth
neurological variants, and partial variants Edition; Dunn & Dunn, 2007)—may rep-
(Nyhan, 2005). Those with any of the LNS resent the best hope for valid appraisal. On
variants have virtually no HPRT activity de- the other hand, Anderson and colleagues
tectable; they express the classic LNS syn- (1992) used a parent survey as an alterna-
drome described in this chapter. Those few tive to intelligence tests to identify cogni-
individuals with the neurological variants tive functioning and characteristics specific
may have essentially no HPRT in erythro- to patients with LNS (Anderson & Ernst,
cyte assay, but some activity in whole-cell 1994). The questionnaire consisted of 176
assay. These males have a phenotype char- items organized into 18 sections, including
acterized by neurological signs, but not clas- family genetics, patient health, motor abil-
sic behavioral features of LNS or frank men- ity, school achievement, verbal ability, and
tal retardation. Those with partial variants self-injury. Such a survey may be useful in
have 0–50% HPRT activity in erythrocyte obtaining baseline measures of cognitive
assay, but HPRT activity in whole-cell as- functioning that would otherwise be impos-
sible to collect via examiner-administered toms or promote development are unavail-

cognitive assessments. able. One aspect of care that professionals
Nonetheless, standard IQ tests have been often overlook is the importance of inform-
used and may provide some insight. For exam- ing and supporting parents. The salience
ple, as part of a National Institute of Mental of parents’ needs, which concern primarily
Health study that concerned neurotransmit- bottom-line issues of dealing with difficult
ter anomalies in LNS, Ernst and colleagues behavior, is eloquently summarized by Wil-
(2000) collected SB-IV (Thorndike et al., liam Nyhan (2005) himself:
1986) IQ test scores on 11 males with LNS
(ages 10–20 years). The mean IQ score was The realization that there is a biological basis
67.9 (standard deviation = 17.7). The degree of behavior could be very helpful to parents
to which these individuals were representa- in understanding their children and learning
tive of the population with LNS as a whole, ways to deal with such children. Parents want
to know what their children will be like as the
or how much their observed IQ scores were
years go on and this is particularly true for be-
influenced by motor or behavioral problems, havior that must be lived with day to day. It is
is unknown. Nonetheless, this information behavior that can destroy a family or lead to
provides some evidence to support parents’ admission to an institution, not intelligence or
speculation that many of these individuals a cytogenetic or enzymatic status. Appropriate
are often spared cognitive impairment as counseling as to what to expect and introduc-
severe as their motor dysfunction and be- tion to parent support groups and to others
havioral disturbances. Also using the SB-IV, with the same phenotype lead to realistic ways
Matthews, Solan, and Barabas (1995) found to cope with an unusual child. (p. 2)
that composite scores ranged from those in-
dicating the moderate range of mental retar- Beyond these compelling informational/sup-
dation to the low-average range (see “Devel- port needs, most treatment can be consid-
opmental Course,” above, for more details ered biological, behavioral, or preventative
of this study). Again, cognitive ability may in nature. These three classes of treatments
be variable in this patient population, and are covered below, and summarized in Table
mental retardation does not appear to be 23.1, in that order. Recommendations for
universal. educational interventions are also present-
Though self-injurious behaviors are the ed.
most characteristic of the disorder, a broader
spectrum of emotional and behavioral prob- Biological Treatments
lems may exist. Parents and other caregivers
can provide information on both adaptive Seeking to remedy LNS’s core HPRT en-
behaviors and psychosocial adjustment. For zyme deficiency would be a logical starting
instance, as noted earlier, Schretlen and col- point for any treatment. Unfortunately, this
leagues (2005) used the CBCL (Achenbach, deficit cannot be remedied. In fact, failure of
1991) and the ABS-RC2 (Nihira et al., 1993) a medication (azathioprine) that was known
to evaluate the emotional and behavioral im- to lower uric acid levels in kidney transplant
pact of the disorder. Various internalizing patients to produce an effect in the urine or
and externalizing behaviors, as well as so- blood of patients with LNS was one early
cial difficulties, were present. The findings cue to the presence of the HPRT enzyme de-
suggested the usefulness of psychosocial and ficiency (Nyhan, 2005). Still, controlling an
adaptive behavior measures in the assess- immediate consequence of HPRT deficiency,
ment of LNS. overproduction of uric acid, is possible. Al-
lopurinol is a xanthine oxidase inhibitor,
which is administered as an oral medica-
Treatment tion. Because xanthine oxidase converts the
excess of hypoxanthine and guanine found
It is understandable that those concerned in patients with LNS into uric acid, its inhi-
with the care of patients with LNS are in- bition can diminish uric acid levels in serum
tensely interested in treatment. A host of re- and urine. This has the effect of reducing the
lated questions about school, developmental development of gout-related symptoms and
therapies, and the like also routinely arise, helping to preserve kidney function. Conse-
even when direct ways to ameliorate symp- quently, allopurinol is advocated for use at
TABLE 23.1. Summary of Interventions for Patients with LNS

Patients Symptom reductions and other
Reference Intervention type studied improvements
Biological
Kirkpatrick- Serotonergic diet a , 6-year-old Decrease in lip and tongue biting,
Sanchez et al. paroxetine (SSRI), and male finger biting, kicking, scratching, and
(1998) sertraline (SSRI) rubbing face; reduced use of mouth
guard and limb restraints
McManaman and Gabapentine (antiepileptic) 3-year-old Decreases in cheek and lip biting
Tam (1999) male
Harris (2008) Deep brain stimulation Four patients Decreases in dystonia and self-
(ages not injurious behavior
reported)
Cif et al. (2007) Deep brain stimulation 16-year-old Decreases in dystonia and self-
male injurious behavior; teeth extraction
no longer under consideration;
reduced limb restraint
Dabrowski et al. Botulinum toxin A 10-year-old Decreases in self-injury to hands,
(2005) (BTX-A) male lip, and tongue; reportedly improved
speech; return to school
Gutierrez, Pellene, Botulinum toxin A 30-year-old Decreases in lip and finger biting
and Micheli (2008) male
Serrano et al. Levodopa/carbidopa 3-year-old Improved head control; able to pick
(2008) male up objects
Behavioral
Duker (1975) Extinction and DRO 9-year-old Decreases in finger biting and crying
male following self-induced biteb
Bull and Systematic desensitization, 10-year-old Decreases in coprolalia, biting,
LaVecchio (1978) extinction, and play therapy male head banging, injury to others, neck
snapping, spitting, and vomiting
Anderson et al. Punishment a , time- Males ages Decreases in finger biting, head
(1978) out, DRO, and positive 3, 5, 11, 12, banging, and use of restraints
reinforcement of self- and 13 years
injurious behaviora
Gilbert et al. Extinction and DRO 4½-year-old Decreases in leg, arm, head, face, and
(1979) male nose banging, as well as nose and face
scratching; splints removed
Buzas et al. (1981) DRI 14-year-old Decreases in lip damage, finger-
male to-mouth responses, crying, and
vocalizations of wanting to be
restrained
Wurtele et al. Extinction, self-instruction, 13-year-old Decreases in finger bitingb
(1984) and relaxation male
McGreevy and DRI and punishment 2-year-old Decreases in biting arms, forearms,
Arthur (1987) male and back of handsb
Grace et al. (1988) Self-instruction, positive 14-year-old Decreases in lip biting; freedom from
reinforcement, and time-out male restraints
Note. Interventions listed are confined to those that were the subjects of peer-reviewed journal articles (other interventions
coincidentally mentioned in the articles are not listed separately in the table). Despite our efforts to search medical and
psychological journals, some articles may have been missed.
a Denotes an intervention that failed to improve target symptoms (whereas other listed interventions produced improve-
ment).
bThis study included other variables that failed to improve, besides those noted.
the first detection of HPRT deficiency (Tor- reuptake inhibitor [SSRI]) was introduced at
res & Puig, 2007). Unfortunately, this treat- 5 mg and increased stepwise to 30 mg at the
ment does not have an effect on CNS-related end of 4 weeks. It appears that subsequently
symptoms. paroxetine was discontinued, and sertraline
When one reads the background of patients was introduced and increased eventually to
with LNS in case studies, use of psychotropic 200 mg. The authors indicate that parox-
medication is commonly noted. Summaries etine was associated with a 32% reduction
of LNS typically confirm that physician ex- in self-injurious behaviors occurring when
perts also often use medications to address the patient was unrestrained (measured by
neurological and behavioral signs/symp- rate per minute recorded by an observer).
toms. For example, Torres and Puig (2007) The more effective medication, however, ap-
confirm that medication affecting gamma- peared to be sertraline, adjusted to 200 mg.
aminobutyric acid (GABA) receptors, such No percentage of reduction was reported in
as benzodiazepines and baclofen, are used the article, however, and the authors report-
to address spasticity and dystonia as well as ed that no reliability checks were available
anxiety. Moreover, parents report that their for this portion of the data set. Remaining
children have frequently been tried on vari- on 200 mg of sertaline (and with a change of
ous medications to diminish the almost uni- residential setting), the patient appeared to
versal array of behavioral and neurological show significant overall improvement, such
symptoms (Anderson & Ernst, 1994). De- as reduced mouth guard and limb restraint
spite their apparently frequent case-by-case use.
use, little has been published regarding the Gabapentine, an antiepileptic drug affect-
efficacy of these medications in LNS. ing the GABA system, was reportedly effi-
In 1998, a U.S. group (Kirkpatrick- cacious in reducing lip and cheek biting in
Sanchez, Williams, Gualtieri, & Raichman, a 3-year-old boy with LNS (McManaman
1998) reported a case in which psychotro- & Tam, 1999). Following a gastrostomy
pic medication was augmented by behav- (i.e., surgical insertion of a feeding tube),
ioral treatment (see also “Behavioral Treat- self-injurious behavior increased in sever-
ments,” below). The patient was a 6-year-old ity and frequency. The patient was initially
African American male with LNS who pre- prescribed diazepam, which proved ineffec-
sented with unmanageable behavior in a tive. Gabapentine was then added at 400
group setting. He had been placed in this mg daily, leading to decreased biting within
setting at age 3 years because of his behav- the first week; consequently, diazepam was
ior, although he also had mild mental retar- discontinued. At 3 weeks, the gabapentine
dation. His lengthy behavioral problem list dose was increased to 800 mg daily, and the
included lip and tongue biting, finger biting, boy’s parents reported that the self-injurious
kicking, scratching, and rubbing his face behaviors ceased. When a bowel obstruction
against solid objects to the point of bleed- occurred several weeks later, gabapentine
ing. Like many boys with LNS, he required treatment was discontinued, resulting in an
restraints. During the night, these consisted immediate reappearance of self-injurious be-
of tight bedsheet wrapping, the use of arm haviors. Once the obstruction was treated,
splints, and a face mask (to prevent him gabapentine was reintroduced, resulting in
from rubbing his face on the bed); during immediate reduction of self-injurious behav-
the day, wrist restraints (on his wheelchair), iors.
arm splints, a neck roll head support, and Another medication approach involves
a mouth guard were used. After behavioral dopamine, the key neurotransmitter that is
treatments had reduced baseline aggressive anomalous. An interesting single case is re-
behavior by 71%, medication and other bio- ported by a Spanish group (Serrano et al.,
logical options were considered because the 2008). This involved a child with LNS who
boy’s aggressive behavior remained at clini- had the expected low dopamine metabolite
cally unacceptable levels. An attempt at a values in his cerebrospinal fluid. He had
serotonergic diet (e.g., accentuation of fruit, been first identified because of conspicuous
curtailment of caffeine and salt) produced no motor problems evident for four months.
discernible effect on behavior, however. Sub- With early introduction of levodopa/carbi-
sequently, paroxetine (a selective serotonin dopa (L-dopa) therapy, clinical improvement
was noted. For example, by 18 months the It was the psychosocial/behavioral presenta-
patient reportedly demonstrated improved tion, however, that proved most troubling.
head control, and he was able to pick up This involved frequent hand, tongue, and
objects, although dyskinetic movements re- lip biting; lip amputation; eye poking; spit-
mained. The authors propose that L-dopa ting; and coprolalia. He required constant
treatment begun very early in the lives of limb restraint. Efforts to treat him with
children with LNS may have the potential medications (baclofen, diazepam, clomip-
to improve neurological symptoms and con- ramine, cyamemazine) proved ineffective.
tribute to better outcome. More controlled Deep brain stimulation was accomplished
investigations of medication appear to be in via double bilateral simultaneous stimula-
order (see also Cif et al., 2007, below, for tion to limbic and motor internal pallidum.
a list of medications that apparently proved Dystonia (measured by the Burke–Fahn–
ineffective in a case ultimately treated by Marsden Dystonia Rating Scale; Burke et
other means). al., 1985) and self-injurious and aggressive
The extreme disabilities accompanying behavior (measured by the Behavior Prob-
LNS have no doubt contributed to the wide- lems Inventory; Rojahn, Matson, Lott, Es-
ranging search for viable treatments. This bensen, & Smalls, 2001) improved during
search has been extended to the realm of the first week of stimulation. The patient’s
neurosurgical procedures, which at first may caregivers were also eventually able to aban-
seem surprising or disquieting to readers don consideration of extracting his teeth (to
who associate such procedures with the un- prevent mutilation). Moreover, the patient
fortunate psychosurgical history of frontal no longer required attachment to his bed or
lobotomy. On reconsideration, however, the wheelchair and was ultimately able to drive
use of such techniques may make more sense his own wheelchair.
if one recalls that the profoundly debilitat- An alternative biological treatment, botuli-
ing symptoms characterizing LNS may be num toxin A (BTX-A), was recently reported
attributable to known brain dysfunctions, by two research groups. BTX-A is well known
and that reversible treatments involving to temporarily inhibit release of acetylcho-
neuropacemakers to accomplish deep brain line from presynaptic neurons; this ultimate-
stimulation are already approved by the U.S. ly results in muscle weakness or paralysis, as
Food and Drug Administration for essential occurs in the cosmetic use of Botox. In the
tremor and Parkinson disease (U.S. Depart- first study, Dabrowski, Smathers, Ralstrom,
ment of Health and Human Services, 1997). Nigro, and Leleszi (2005) used BTX-A injec-
James Harris at Johns Hopkins (2008) re- tion in both masseter muscles (i.e., muscles
ported a series of four patients who under- in the cheek that close the jaws during chew-
went implantation of electrodes to stimulate ing) at two sites. The subject was a 10-year-
both motor and limbic circuits in the globus old male with developmental delay from
pallidus. The procedure is accomplished in infancy and apparent cerebral palsy, but an
a consciously sedated or fully anesthetized LNS diagnosis was not confirmed until age
state and is guided by the use of MRI. The 8 years. Self-mutilation began before 8 years
implanted electrodes enable deep brain and comprised ulceration of hands, lips, and
stimulation in a process aimed to represent tongue. Within a few days of initiating treat-
“neuromodulatory treatment.” Compared ment, self-mutation diminished to the point
to baseline, at follow-up patients expressed that the wounds healed and the boy was able
reduced dystonia and complete elimina- to return to school. Speech also reportedly
tion of self-injurious behavior. One patient improved (no objective measurements were
reportedly remained free of self-injurious undertaken, however). Injections were re-
behaviors 7 years after the intervention. A quired each 12 weeks to maintain effects.
clinical trial of the procedure is reportedly Equivalent results were obtained with a
scheduled to begin. 30-year-old with LNS who was also treated
A similar approach was reported by a with BTX-A (Gutierrez, Pellene, & Micheli,
French group (Cif et al., 2007). A 16-year-old 2008). The mechanism by which injections
male with severe LNS was diagnosed at age 6 of BTX-A work is not clear. Peripheral ac-
months and expressed generalized dystonia, tion alone (production of muscle weakness
athetosis of all four limbs, and dysarthria. at the injection site) is not a plausible expla-
nation. Among the speculative possibilities of several behavioral treatments in five male
are that BTX-A exerts a CNS sensory effect patients with LNS ages 3, 5, 11, 12, and 13
via altered feedback that is somehow instru- years. The patients wore arm restraints due
mental in diminished self-abusive behavior; to frequent finger biting, lip biting, head
inhibition of substance P or glutamate is an- banging, or neck snapping. To address these
other possibility (Dabrowski et al., 2005). self-injurious behaviors, four behavioral
treatments were evaluated: aversive conse-
quences (i.e., an electric finger shock contin-
Behavioral Treatments
gent on self-injurious behavior); differential
Considering the severity of the self-injurious reinforcement of other behavior (DRO—i.e.,
behaviors exhibited in LNS, it is not surpris- smiling, talking, and playing while a child
ing that the most common form of interven- was not engaging in self-injurious behavior);
tion is mechanical restraints. In behavioral positive reinforcement of attempts at self-
terms, this practice might be viewed as an injurious behavior (i.e., preventing the self-
example of response prevention. A study injurious behavior, and then making reas-
executed over a decade ago ascertained suring statements and stroking the child—a
that nearly one-half of affected boys were common response of parents); and time-out
restrained 100% of the time (Anderson & contingent on self-injury (i.e., withdrawal of
Ernst, 1994). Such restraints are often wel- adult attention following self-injurious be-
comed by children who feel unable to inhibit havior). In all treatment conditions (with the
their self-injury (i.e., there is a compulsive exception of time-out), a response preven-
quality to their acts). Commonly used re- tion procedure was used, wherein an adult
straints include arm and elbow splints, wrist intercepted the child’s attempts at self-injury.
and leg restraints on the wheelchair, finger Though not all subjects in the study received
guards, mouth guards, face masks, helmets, all four treatments, results indicated that
and bed straps. Coverings have also been the DRO and time-out procedures resulted
used to prevent injury, including dishwash- in decreases in self-injurious behavior. The
ing gloves, biking gloves, and towels and Ace most substantive effects resulted from a com-
bandages wrapped around thumbs. The use bination of time-out and DRO: Self-injury
of restraints, however, is not a preferred in- was eliminated in all four subjects that were
tervention because they may diminish qual- evaluated. Aversive consequences (i.e., fin-
ity of life; furthermore, clinicians are legally ger shock) were unsuccessful in suppressing
and ethically obligated to provide patients self-injurious behaviors and in some cases
with the least restrictive method of control- accelerated behaviors (as measured by two
ling behavior (Olson & Houlihan, 2000). raters using frequency counts). As would be
Another form of response prevention is expected, reinforcement contingent on at-
extraction of teeth, which is often useful tempts at self-injurious behavior resulted in
in cases when children engage in lip, finger, a rapid increase in self-injury. To sustain im-
and cheek biting. Anderson and Ernst (1994) provements in self-injurious behaviors, ther-
confirmed that 24 of 40 children with LNS apists trained parents to use time-out and
had undergone teeth extraction. Parents and positive reinforcement and provided home
patients in the study overwhelmingly sup- visits to ensure proper implementation. Fol-
ported teeth extraction to manage biting and low-up at 22–24 months indicated that all
had no regrets following the procedure. Fol- children were free of restraints at school and
lowing extraction, a child’s ability to chew that three of the five children were placed in
food should be largely unaffected. Likewise, restraints at night.
because articulation in most patients with Anderson and colleagues’ (1978) find-
LNS is poor to begin with, it may not worsen ing that aversive consequences (i.e., finger
speech, although no known study provides shocks) may facilitate self-injurious behav-
objective evidence for this speculation. ior highlights the importance of developing
Wide use of restrictive practices aside, it is behavioral treatments that are responsive to
advantageous to employ alternative behav- the unique needs of patients with LNS. In
ioral treatments that do not jeopardize qual- response to these findings, Zilli and Hassel-
ity of life. In an early study, Anderson, Dan- mo (2008) developed a model of behavioral
cis, and Alpert (1978) examined the effect treatments specific to patients with LNS.
Consistent with the hypothesized dopamine distress. Two studies have evaluated the ef-
signal dysfunction in individuals with LNS, fectiveness of such interventions. Wurtele
they demonstrated that painful consequenc- and colleagues (1984) identified the ante-
es act as reinforcement. Though this model cedents of a 13-year-old boy’s self-injurious
provides an explanation for the results of behavior as muscle tension and an internal
behavioral treatments in patients with LNS, voice telling him to bite. Intervention includ-
how it can be used to improve interventions ed extinction, wearing of a mouth guard and
remains unclear. Nonetheless, this study un- gloves, relaxation training, self-instruction
derscores that painful consequences may not to refrain from self-injurious behavior, and
have the desired effect of decreasing behav- social support. In addition, the parents re-
iors in these individuals, thus emphasizing ceived training in how to use the procedures
the necessity of techniques such as differen- and ways to prompt their son. At a 6-month
tial reinforcement. follow-up, attempts at self-injury had mark-
The effectiveness of differential reinforce- edly decreased, and the boy only occasion-
ment compared to aversive procedures for ally wore the mouth guard (although he still
children with LNS was a consistent finding wore gloves). Likewise, Bull and LaVecchio
in a recent review of seven behavioral treat- (1978) used a combination of extinction,
ment studies (Olson & Houlihan, 2000). systematic desensitization (e.g., relaxation
The most common interventions, and in- exercises, exposure to a hierarchy of anxiety-
deed those shown to be most effective, were provoking situations, and removal of re-
DRO, differential reinforcement of incom- straints), and play therapy for a 10-year-old
patible behaviors (DRI), and extinction. boy with LNS. After 10 sessions, the child
Reinforcement was offered through verbal no longer engaged in self-injury. Results at
praise, attention, hugs, or dispensing cola an 18-month follow-up indicated the boy
into the mouth when a child was engaged in no longer used restraints, did not engage
either non-self-injurious or incompatible be- in coprolalia, and was learning to walk on
haviors (i.e., drawing, playing games, eating crutches. Interventions aimed at preventing
candy, learning sign language, and touch- anxiety in order to prevent self-injurious
ing toys). Extinction involved ignoring the behavior thus appear promising for patients
children (i.e., withdrawing attention) when with LNS, but more systematic, controlled
they engaged in self-injurious behaviors. research seems warranted.
Though extinction appears to be effective, One issue threatening the use of behav-
serious damage can occur during extinction ioral techniques in patients with LNS is the
bursts; therefore, that technique may be best prospect of symptom substitution (i.e., as
used in combination with response preven- one self-injurious behavior decreases, it may
tion (i.e., mouth guards, wraps) and DRI or be replaced with another; Olson & Houli-
DRO (Wurtele, King, & Drabman, 1984). han, 2000). For example, Duker (1975)
Aversive techniques (e.g., finger shocks) were found that a combination of DRO and ex-
also studied, but these procedures paradoxi- tinction resulted in decreased self-biting,
cally intensified self-injury (see discussion but concomitant increases in head banging.
above). Parents corroborated these results, Similarly, McGreevy and Arthur (1987) re-
confirming that positive reinforcement was ported that a combination of DRI and pun-
useful in controlling self-injury, whereas pu- ishment decreased biting of forearms, arms,
nitive techniques such as time-out or loss of and the backs of hands; however, finger
reinforcement were not (Anderson & Ernst, biting increased, and the boy in their study
1994). began a new self-injurious behavior of biting
Many patients and parents have reported the palms of his hands. Unfortunately, pro-
that anxiety is an antecedent to self-injury. cedures to address the problem of symptom
Moreover, many patients have reported substitution do not exist. Crucially, studies
feeling anxiety when restraints are re- that systematically used generalization pro-
moved (Gilbert, Spellacy, & Watts, 1979); cedures across both change agents and set-
when presented with new situations, tasks, tings did not report such problems, either
or people; or when ill (Anderson & Ernst, during active study phases or at follow-up
1994). The role of anxiety in triggering self- (Anderson et al., 1978; Buzas, Ayllon, &
injurious behaviors suggests a need for in- Collins, 1981). Thus it may be advantageous
terventions targeted at reducing emotional to include generalization procedures in be-
havioral treatments to help preclude the oc- do not appear to have been addressed yet (see
currence of symptom substitution. Kazdin, 2001, for discussion). The impact of
In general, the studies on behavioral any procedure or combination of procedures
modification techniques indicate short-term (e.g., pharmacotherapy and behavior tech-
decreases in self-injurious behaviors in indi- niques) that reduces the need for more inva-
viduals with LNS; however, concerns about sive practices, such as mechanical restraints,
maintenance and generalization remain. seems to be especially compelling.
Generalization procedures were used in four
of the seven studies reviewed by Olson and
Preventative Treatments
Houlihan (2000), which included training
staff and parents, and employing interven- Genetic counseling may have a role in pre-
tions across multiple settings. These studies vention of LNS. Because LNS is inherited
showed improvements at 6-week to 24-month in an X-linked fashion, fathers of boys with
follow-ups (Anderson et al., 1978; Grace, LNS will not have LNS, and they are not
Cowart, & Matson, 1988; McGreevy & carriers of a mutant HPRT allele. The risk
Arthur, 1987; Wurtele et al., 1984). In addi- to unborn siblings of a patient with LNS de-
tion to staff and parent training, procedures pends on the mother’s carrier status. If she is
to enhance generalization and maintenance documented to carry a mutant HPRT allele,
might include pairing natural reinforcers then she has a 50% chance of transmitting
with artificial ones or training individuals the HPRT mutation in each pregnancy. Sons
in self-instruction and evaluation. In this who inherit the mutation will be affected,
regard, Grace and colleagues (1988) used a whereas daughters who inherit the mutation
self-assessment procedure with a 14-year- are themselves carriers but will not express
old male with LNS who engaged in compul- the LNS phenotype (just as is true of their
sive self-biting. The youngster was taught mothers). If the nature of a family’s muta-
to point to a happy face when he engaged tion (as in an affected male family member)
in a non-self-injurious behavior and a sad is known, then a woman’s carrier status can
face for a self-injurious behavior. Correct be determined by biochemical and enzymat-
self-assessments were reinforced with hugs, ic testing procedures (Torres & Puig, 2007).
whereas incorrect ones were punished with a Interestingly, however, approximately 30%
30-second time-out from positive reinforce- of patients’ mothers do not carry a mu-
ment. Three days following the intervention, tant HPRT allele. It is presumed that such
rates of biting behaviors went from an initial patients carry a de novo mutation arising
range of 1 to 60 bites (hospital) and a range from germinal cell mutation (Torres & Puig,
of 1 to 37 bites (bedroom) per 30-minute 2007). For pregnancies at risk of LNS, pre-
session down to zero bites in each setting. natal testing is possible by amniotic cells at
At a 19-week follow-up assessment, no re- approximately 15–18 weeks of gestation or
currence of self-biting was noted. Such pro- by chorionic villus cells acquired at an ear-
cedures appear to offer patients with LNS lier point during pregnancy. Either enzyme
the skills to monitor and control their own (HPRT) analysis or molecular (DNA) analy-
self-injurious behaviors, thereby leading to sis can be conducted.
increased generalization and maintenance of
treatment effects.
Educational Interventions
In summary, behavioral treatments ap-
pear efficacious for an array of self-injurious Unfortunately, to date, no known studies
behaviors; however, this conclusion arises have been published reviewing common
from research conducted primarily in highly educational services and classroom inter-
controlled settings with considerable expert/ ventions for patients with LNS. Consider-
researcher support. Thus additional studies ing the severity of cognitive and behavioral
examining the effectiveness of standard be- symptoms often associated with the syn-
havioral techniques in diverse settings on the drome, most children with LNS are likely to
one hand, and the use of additional techniques qualify for special education services. Early
(e.g., overcorrection) on the other hand, are intervention services might focus on eating
needed. Furthermore, broader treatment and drinking, followed later by communi-
outcomes, such as the impact of documented cation skills and play. Many children with
behavior changes on overall qualify of life, LNS suffer from poor articulation; thus it is
often recommended that they attend regular Burke, R. E., Fahn, S., Marsden, C. D., Bressman,
sessions with a speech–language therapist, S. B., Moskowitz, C., & Friedman, J. (1985). Va-
especially a therapist knowledgeable about lidity and reliability of a rating scale for the pri-
related disorders (e.g., cerebral palsy; Mc- mary torsion dystonias. Neurology, 35, 73–77.
Buzas, H. P., Ayllon, T., & Collins, F. (1981). A
Carthy, 2004). Documentation of the effec- behavioral approach to eliminate self-mutilative
tiveness of these services, however, has not behavior in a Lesch–Nyhan patient. Journal of
yet appeared in the literature. Mind and Behavior, 2, 47–56.
Cif, L., Biolsi, B., Gavarini, S., Saux, A., Robles,
S. G., Tancu, C., et al. (2007). Antero-ventral in-
Conclusion ternal pallidum stimulation improves behavioral
disorders in Lesch–Nyhan disease. Movement
LNS is an X-linked inborn error of metabo- Disorders, 22, 2126–2129.
lism that is rare but causes profound impair- Dabrowski, E., Smathers, S. A., Nigro, M. A., &
Leleszi, J. P. (2005). Botulinum toxin as a novel
ments in the boys and men affected by it. Al-
treatment for self-mutilation in Lesch–Nyhan
though substantial progress has occurred in syndrome. Developmental Medicine and Child
understanding the causes and expression of Neurology, 47, 636–639.
the disorder, its treatments remain limited, Duker, P. (1975). Behavior control of self-biting in
and the efficacy of these treatments is large- a Lesch–Nyhan patient. Journal of Mental Defi-
ly undocumented in well-controlled studies. ciencies Research, 19, 11–19.
Nonetheless, if systematically applied and Dunn, L. M., & Dunn, L. M. (2007). Peabody Pic-
monitored in individual cases, behavioral ture Vocabulary Test, Fourth Edition. San Anto-
interventions may reduce symptoms. Prom- nio, TX: Pearson Assessments.
ising biological treatments may also be on Ernst, M., Zametkin, A. J., Pascualvaca, D., Mato-
chik, J. A., Eisenhofer, G., & Murphy, D. L., et
the horizon. Furthermore, LNS continues to
al. (2000). Adrenergic and noradrenergic plasma
hold promise for researchers hoping to un- levels in Lesch–Nyhan disease. Neuropsycho
derstand the relationship among biochemis- pharmacology, 22, 320–326.
try, brain function, behavior, and develop- Gibbs, R. A., Nguyen, P., McBride, L. J., Koepf,
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emy of Sciences USA, 86, 1919–1923.
Thanks to Mark Joseph, MD, Phoenix Children’s
Gilbert, S., Spellacy, E., & Watts, R. W. E. (1979).
Hospital, and Matthew D. Wodrich, PhD, Univer-
Problems in the behavioral treatment of self-
sité de Genève, for reviewing and commenting on
injury in Lesch–Nyhan syndrome. Developmen-
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Chapter 24
Seizure Disorders
Thomas L. Bennett
Deana B. Davalos
Maile Ho-Turner
Barbara C. Banz
Seizures are transient symptoms of abnor- have long been clinically observed to have
mal neuronal activity in the brain triggered some genetic or hereditary component. It
by a variety of etiologies. Although the has not been until the past two decades that
causes of seizures are poorly understood, increasing pathological and neurodevelop-
it is clear that the prevalence of seizures in mental data supporting these observations
infants, children, and adolescents is quite have been linked to clinical observations
high. It has been estimated that approxi- (Marini et al., 2004).
mately 5% of the world’s population may Furthermore, a child’s immature brain is
experience a seizure at some point in life, not simply a miniature of an adult brain; it
with nearly one-third of these individuals is both anatomically and physiologically dif-
developing epilepsy (World Health Organi- ferent. Thus one needs to look to, and spe-
zation, 2001). The global population with cifically study, the immature brain in order
epilepsy has been estimated at 50 million. to understand childhood epilepsy disorders.
Epilepsy has been defined as a brain disor- The appearance of epilepsy through different
der characterized by recurrent disturbances stages of cortical development in the fetus
in the electrical functions of the brain that and through the early childhood years has
result in seizures (Kobau et al., 2008). The differential implications and manifestations,
prevalence of epilepsy in people from Eu- as well as outcome prognoses and treatment
rope and North America across the lifespan implications.
has been reported at 5–8 per 1,000 (Fors- What we do know about childhood epi-
gren, 2004). Studies assessing a wide range lepsy is that many factors appear to contrib-
of age groups suggest that general prevalence ute to seizure thresholds. Seizure thresholds
rates presented in the literature should also have a major impact on the child’s propen-
be interpreted with the understanding that sity to develop a recurrent seizure disorder
the risk for developing epilepsy is not equal (epilepsy), which will in turn have resulting
across the lifespan. Instead, infants and chil- cognitive deficits associated with the epilep-
dren under the age of 5 may be at the great- tic syndrome. Three major factors affecting
est risk for both initial seizures and epilepsy the occurrence of seizures are (1) genetic
(Annegers, Dubinsky, Coan, Newmark, & predispositions/familial history, (2) age at
Roht, 1999). Childhood epilepsy syndromes onset, and (3) environmental stressors. The
460
Seizure Disorders 461
effect of these factors is cumulative. That is, ilepsy syndrome has its own peak incidence
a child of a particular age who has a famil- age ranges. Through childhood and adoles-
ial history of epilepsy and who is exposed cence (age 2 and beyond), the seizure thresh-
to environmental stressors (e.g., fever) has a old increases proportionally until it reaches
greater chance of developing a seizure disor- adult levels.
der than a child of the same age without the
familial history and/or the environmental
Environmental Stressors
stressors.
Environmental stressors include fever spik-
ing, fatigue, excitement, ionic concentra-
Major Precipitating Factors tions/metabolism, and other factors. Fevers
as agents precipitating seizures are especially
Genetics
notable in febrile seizures, as their name im-
As early as 1960, Lennox and Lennox noted plies. A fever’s rate of rise and amplitude are
a strong concordance rate for childhood directly related to a seizure’s onset and in-
absence epilepsy in identical twins, as well tensity.
as higher rates of electroencephalographic
(EEG) spike-and-wave patterns in families This chapter continues with a brief de-
with a family history of epilepsy. Since then, scription of the stages of neurodevelopment
both partial and generalized seizure types and associated neuropathologies that have
have been linked to genetic causes. Animal been recently linked together to provide a
studies in which genetic mutations result in better understanding of childhood epilepsy.
familial strain occurrences of epilepsy have We then describe the various classification
also contributed to the increased aware- schemes of childhood seizures and epilepsy
ness of the contribution of genetics to epi- syndromes. Finally, the manifestation of
lepsy syndromes. However, the exact effects childhood seizure syndromes and their be-
of these mutations and inheritances on the havioral, cognitive, and neuropsychological
neuroanatomical development and physiol- issues are considered.
ogy of the brain and seizure thresholds are
still unclear.
The occurrence and development of some Neurodevelopmental and
forms of epilepsy have been definitively Neuropathological Aspects
linked to genetic inheritance, while others
have a weaker connection. Febrile seizures, There are four relatively distinct stages of
childhood absence epilepsy, juvenile myo- neural development, which can each serve
clonic epilepsy, Rasmussen syndrome, gen- as a point of disruption and which have
eralized tonic–clonic epilepsy, and complex specific implications for the appearance of
partial seizures, among others, have all been seizure disorders. The first three stages of
shown to have definite genetic contributions neural development (regional determina-
in their development. That is, familial his- tion and segmentmation, cytogenesis, and
tory increases the occurrence of the seizures cell migration) are completed by the end of
types, although it is not the sole determinant the second trimester of pregnancy. The last
of its manifestation. stage of development (growth and differen-
tiation) begins late in the second trimester
and continues through the early years of
Age at Onset
postnatal development, when many epilepsy
Newborns have a very high cortical thresh- syndromes manifest themselves. Generally,
old, and elicitation of a seizure response is the earlier the pathology occurs, the graver
very difficult. However, as children progress the outcome.
into infancy and toddlerhood (up to about Deviance in the earliest stages of neural
age 2), they have a much higher suscepti- development is so grave, in fact, that the
bility to febrile and other seizures; in other fertilized egg may not even be implanted in
words, their seizure threshold has lowered. the uteral lining for development, or miscar-
This is the time period when most childhood riage may occur. Fetuses that do survive the
epilepsy syndromes begin, although each ep- first stage of regional determination and seg-
mentation with deviant neural development ogies associated with childhood epilepsy
often do not survive to term. If such a fetus syndromes, and their findings were striking-
does survive to term, the infant usually has ly parallel to findings regarding the develop-
severe malformations of the cerebrum. Any mental stages of the fetal brain (Meencke,
further neural development is also deviant 1985, 1989). Meencke’s group studied the
and probably will produce seizure disorders. brains of infants and children with a variety
Deviance in the cytogenic and migratory of childhood epilepsies, including infantile
stages of development is more survivable spasms (a.k.a. West syndrome), Lennox–
than earlier deviance, but it produces neu- Gastaut syndrome, and primary generalized
roanatomical anomalies that are grossly and seizure disorders (including childhood and
microscopically apparent. Displaced neural juvenile myoclonic epilepsies). From the pat-
tissue (heterotopia) defects such as agyria terns of pathologies he observed, Meencke
and microgyria occur in these stages. Also drew the following inferences: (1) Pathoana-
possible with deviant development in these tomical abnormality of the brain is reflec-
stages, but not grossly visible, is the clus- tive of an increased likelihood of epilepsy,
tering of neurons in the wrong areas of the and vice versa; (2) the younger a child is at
brain (microdysgenesis). the age of onset, the greater the gravity of
Generally, these heterotopic and microdys- the pathoanatomical disruption; and (3) the
genetic disorders are due to defects in the younger the child is at the age of onset, the
development of the neuronal guidance tracts more aggressive the syndrome is, and the
(also known as [a.k.a.] radial glides) or the greater the gravity of the seizure disorder
migrating neurons themselves. Microdys- and behavioral disability. Although facets
genetic patterns have been histologically of Meencke’s findings have been revised
linked to childhood epileptic disorders and throughout the years, the argument persists
to various cognitive problems in childhood that certain abnormalities in the developing
(e.g., dyslexia, mental retardation). Cell brain increase the likelihood of experiencing
transformation and interactions to produce seizures, and, conversely, experiencing sei-
a mature brain are the major activities in zures at different developmental stages can
the last stage (growth and differentiation) of alter the trajectory of the developing brain
development. Again, this stage begins only (Sanchez & Jensen, 2001).
after three stages of development are com- The conclusion that is beginning to emerge
plete and continues through infancy until is that epileptic syndromes are largely ge-
about age 2. This is the “fine-tuning” stage. netically based, and that their etiologies and
Of notable interest here is that many child- pathologies may eventually be explained in
hood epilepsy syndromes appear in infancy terms of inherited or acquired neurodevel-
and up to age 2, although recent research opmental anomalies. These genetically ac-
indicates that this stage of cortical develop- quired, anomalous developmental sequences
ment may be largely complete by the first of the brain may have long-term repercus-
year of life. sions in the form of (frequently) lifelong epi-
Cepeda and colleagues (2006) have uti- leptic syndromes.
lized clinical-pathological techniques sug-
gesting that the mechanisms involved in epi-
leptogenesis may begin as early as during the Classification Schemes
prenatal developmental period through the
first year of life. Others have utilized both In general, a seizure may be conceptualized
animal and human models supporting the as a sudden discharge of electrical activity in
argument that the factors precipitating epi- the brain that results in alterations of sensa-
leptogenesis may emerge as early as the pre- tion, behavior, or consciousness. Epilepsy,
natal period through the first weeks of life as noted earlier, is a condition of recurrent
(Velisek & Moshe, 2003). seizures. An epileptic syndrome is charac-
A number of studies during the past three terized by a recurrence of consistent symp-
decades have sought to understand the devel- toms and behavioral manifestations.
opmental neural mechanisms involved in ep- There are three major ways in which
ilepsy. In the 1980s Meencke and colleagues childhood seizures and epilepsy can be stud-
conducted a series of studies of neuropathol- ied and classified. In this section, we discuss
seizure classification by (1) the cause of the will rarely produce recognizable seizures in
seizure, (2) the seizure syndrome presenta- the fetus. And although recent advances in
tion, and (3) the epilepsy syndrome (this ultrasonographic diagnosis have been made,
type of classification is generally more age- there is still speculation that fetal seizures
and behavior-based). These methods of clas- are likely to be grossly underrepresented
sifying seizures are not mutually exclusive, (Maouris, 1987) and generally indiscernible
and terms from more than one scheme are to the mother or otherwise mistaken for nor-
frequently used concurrently to discuss a mal fetal movement unless they are general-
single epileptic syndrome. ized tonic–clonic seizures.
Classification by Cause of Seizure Neonatal Seizures

Symptomatic Seizures A neonatal seizure can occur from birth up
to about 1 month of age. Most neonatal sei-
Symptomatic seizures and epileptic syn-
zures occur over a short span of time (e.g.
dromes have a known cause, such as trau-
several days), and fewer than half of infants
ma, metabolic imbalance, developmental
experiencing neonatal seizures develop sei-
abnormality, or fever. Symptomatic seizures
zures later in life (Scher, Trucco, Beggarly,
are also called reactive or provoked seizures
Steppe, & Macpherson, 1998). These be-
when they occur in response to some irrita-
nign seizures have been categorized as a
tion (e.g., fever or trauma) to the brain. The
separate epileptic syndrome and are referred
cause of a symptomatic seizure, therefore,
to as either benign nonfamilial neonatal sei-
can be either developmental in nature or ac-
zures or benign idiopathic neonatal seizures
quired.
when there is not a family history, or benign
familial neonatal convulsions or benign fa-
Cryptogenic Seizures milial neonatal seizures (Claes et al., 2004).
Although there is speculation that benign
Cryptogenic seizures have a cause that is un-
neonatal idiopathic seizures may differ
determined, but that appears to be related
from benign familial neonatal seizures, the
in occurrence to some other neurological or
diagnostic criteria used to differentiate the
cognitive condition. The seizures are pre-
groups are mainly based on the presence of
sumed to be symptomatic, but their exact
a family history of seizures or epilepsy in the
cause is as yet hidden.
familial group (Plouin & Anderson, 2002).
Benign familial neonatal seizures usually
Idiopathic Seizures begin 2 or 3 days after birth and spontane-
ously resolve by 6 months of age. Minimal
Idiopathic seizures are those for which the
or no intellectual or cognitive sequelae are
cause is completely unknown and there is
known to result. Nonfamilial neonatal sei-
no evidence of an underlying abnormality.
zures are extremely rare after 2 months of
The child with epilepsy is essentially normal
age, and the neonatal seizure is typically
except for the occurrence of seizures. Idio-
symptomatic of some central nervous system
pathic seizures are presumed to be inherited
(CNS) disturbance (e.g., neurodevelopmen-
and are defined by age-related onsets.
tal anomalies, withdrawal from maternal
drug addiction, pyridoxine dependence,
Classification by metabolic disturbance, intracranial infec-
Seizure Syndrome Presentation tion). Diagnosis of neonatal seizures is dif-
ficult, due to both the variation in seizure
Prenatal Seizures
expression and the need for astute and care-
Prenatal seizures are extremely rare (Usta, ful behavioral observation.
Adra, & Nassar, 2007). In the past, prenatal Drawing on his observations and clinical
seizures that were readily recognized and re- studies, Volpe (1989) proposed a separate
ported (by the mother) were those induced by neonate seizure classification, based on a
pyridoxine dependence, resulting in a gener- newborn’s limited behavioral repertoire and
alized tonic–clonic seizure of the fetus. Even resulting seizure manifestation. The neonate
massive cortical damage to the fetal brain not only has a more limited behavioral rep-
ertoire than the older child, but also has a there are other symptoms present suggesting
vastly different level of cortical maturity. seizure activity (Simeonsson & Hillenbrand,
This neuronal immaturity has implications 2007). Tonic, clonic, and myoclonic neona-
for the newborn brain’s ability to propagate, tal seizures may be subclassified into focal
spread, and inhibit abnormal firing that and generalized seizures, and myoclonic sei-
could result in a seizure. Neurodevelopmen- zures may also be multifocal. There is some
tal aspects of seizures in the neonate are also limited evidence of lesional relationship to
evidenced by the differential manifestation seizure manifestations. Focal clonic seizures
of seizures in full-term versus premature in- in the neonate may occur with local cortical
fants. In general, the younger the neonate is lesions or may be due to metabolic abnor-
(neurodevelopmentally speaking), the more mality (Simeonsson & Hillenbrand, 2007).
primitive is the seizure manifestation. Widespread cortical lesions may result in
There are four major classes of neonatal generalized tonic or multifocal clonic sei-
seizures (subtle, tonic, clonic, and myoclo- zures. Myoclonic seizures are also observed
nic). Subtle seizures appear to be the most in the neonate, and generalized tonic–clonic
commonly observed type of neonatal sei- seizures are very rarely observed. The clas-
zure. Subtle seizures can be subclassified, sification of neonatal seizures proposed by
according to their manifestations, into those Volpe (1989) and diagnostic notes are pre-
with motor, oral buccal, eye, or apneic in- sented in Table 24.1.
volvement. Subtle motor seizures manifest
themselves as repetitive swimming, rowing,
International Classification of Seizures
and pedaling behaviors of the upper or lower
extremities. Subtle oral buccal seizures are The international classification scheme is the
manifested as lip-smacking, chewing, and most widely accepted and utilized format
sucking behaviors. Subtle eye seizures mani- for clinical classification of epileptic seizure
fest themselves as deviant horizontal eye disorders. Its rough division of seizure types
movements and sustained blinking or open- was first conceived by Gowers in 1885 (see
ing of eyes. Subtle seizures that are manifest- the reprinted original—Gowers, 1885/1964),
ed as apnea are very rare, and most neona- but was further developed and refined by
tal apnea is not indicative of seizures unless the International League Against Epilepsy’s
TABLE 24.1. Neonatal Seizure Classification

Seizure type Behavioral manifestation and general diagnostic notes
Subtle Stereotyped and involuntary movements; normal EEG
Motor Swimming, rowing, pedaling in upper or lower extremities
Oral Lip smacking, chewing, sucking
Eyes Horizontal deviation, blinking, sustained open eyes
Apneic Rare on their own but may occur with subtle oral seizures
Clonic Abnormal EEG associated with underlying pathology

Focal Rhythmic unilateral involvement of the limbs, face, or trunk
Generalized Bilateral or shifting involvement
Tonic More common in premature infants; normal EEG

Focal Sustained posturing of one limb
Generalized Sustained posturing of all limbs
Myoclonic
Focal Sudden flexion or extension of large muscle groups; normal EEG
Multifocal More than one muscle group involved; normal EEG
Generalized All muscle groups; may be accompanied by abnormal EEG
Note. From Volpe (1989). Copyright 1989 by Pediatrics. Adapted by permission of Pediatrics.
(ILAE’s) Commission on Classification and into simple and complex partial seizures,
Terminology in 1989. Although the ILAE is depending on whether consciousness is al-
currently working on an updated or entirely tered. When consciousness remains intact,
new classification, the guidelines set forth the seizure is termed a simple partial seizure.
in 1989 are those currently used in research The manifestations of these types of seizures
and practice. In this conceptualization, sei- can then be further subclassified into those
zures are broadly classified as being either affecting motor skills or those involving sen-
partial or generalized, and then further sory symptoms. Complex partial seizures af-
subclassified according to their behavioral fect consciousness.
manifestations. Although many variations Seizures whose onset involves both hemi-
of this classification system exist, one such spheres are termed primary generalized sei-
variation is presented here as Table 24.2. zures. These seizures can be convulsive or
Partial seizures (previously referred to as nonconvulsive and can also be subclassified
focal or local seizures) are initially limited to into absence (petit mal or staring spells),
one hemisphere. The onset of a seizure and myoclonic, and tonic–clonic (grand mal)
most of its initial manifestation are limited. seizures. Partial seizures of any type may
Partial seizures can be further subclassified become generalized seizures and are thus
TABLE 24.2. International Classification of Seizures
I. Partial/focal epilepsies
A. Symptomatic (note that as imaging technology improves, more and more epilepsies are being
reclassified as being symptomatic)
1. Rasmussen syndrome
2. Syndromes characterized by seizures with specific modes of precipitation
3. Partial epilepsies with a lobe of origin (e.g., temporal lobe epilepsy)
B. Idiopathic (including, but not limited to the following)
1. Benign childhood epilepsy with centrotemporal spike
2. Childhood epilepsy with occipital paroxysms
3. Primary reading epilepsy
C. Cryptogenic
II. Generalized epilepsies

A. Symptomatic (note that as imaging technology improves, more and more epilepsies are being
reclassified as being symptomatic)
1. Nonspecific etiologies
2. Specific etiologies
B. Idiopathic
1. Benign neonatal convulsions (familial and nonfamilial)
2. Benign myoclonic epilepsy in infancy
3. Childhood absence epilepsy
4. Juvenile absence epilepsy
5. Juvenile myoclonic epilepsy
C. Cryptogenic
1. Infantile spasms (West syndrome)
2. Lennox–Gastaut syndrome
3. Epilepsy with myoclonic–astatic seizures
4. Epilepsy with myoclonic absences
III. Epileptic syndromes with undetermined focal or generalized seizures

A. Neonatal seizures (see Table 22.1)
B. Severe myoclonic epilepsy in infancy
IV. Special syndromes

A. Febrile seizures
B. Status epilepticus
C. Seizures in reaction to specific environmental stressors
Note. Adapted from Commission on Classification and Terminology (1989). Not all syndromes addressed by the Com-
mission are included here.
termed secondary generalized seizures or tomatic of brain disorder or brain injury; the
secondary generalizations. remaining cases are considered idiopathic or
cryptogenic.
Infantile spasms are characterized by a
Classification by Specific Childhood
very specific seizure manifestation. The in-
Epilepsy Syndromes
fant experiences a sudden flexion of the en-
The third method of classification is prob- tire body, with knees flexed, arms extended,
ably the most useful when one is consider- and head tucked. This position is held for a
ing childhood epilepsy because virtually all couple of seconds and is repeated every few
of these syndromes are age-related. Table seconds. The spasms occur in definite sets
24.3 provides a quick reference of childhood of 5, 10, or 15. That is, the alternations be-
epilepsy syndromes, along with the peak tween flexion and relaxation (separated by
onset ages and hallmark features of each a few seconds) occur in sets of 5, 10, or 15.
syndrome. They most often occur in the transitional pe-
riod between sleep and wakefulness. These
seizures are most often treated with medica-
Infantile Spasms/West Syndrome
tions such as adrenocorticotropic hormone
Infantile spasms usually appear between the or traditional antiepileptic drugs (AEDs),
ages of 4 and 8 months. They rarely occur and if uncontrolled, the child’s epilepsy may
before 2 months of age or after 1 year. Eti- evolve into the Lennox–Gastaut syndrome
ology may be genetic (e.g., an inherited (at about age 3 or 4). Uncontrolled infantile
condition called tuberous sclerosis), or it spasms progressing into Lennox–Gastaut
may be attributable to a host of other eti- syndrome can result in some degree of im-
ologies, including birth injury or metabolic paired intellectual functioning, behavioral
imbalances. Approximately 60% of infantile disturbances, and developmental delays or a
spasms are generally considered to be symp- regression in developmental milestones.
TABLE 24.3. Childhood Epilepsy Syndromes, Their Peak Onset Range,

and Hallmark Features
Epilepsy syndrome Peak age at onset Hallmark features
Infantile spasms/West syndrome 4 to 8 months Definite sets (5, 10, or 15) of flexion–
extension
Infantile myoclonic epilepsy 1 to 2 years Flexion–extension in single or cluster events,
not sets
Febrile seizures 6 to 24 months Precipitated by a high fever with a fast rise
Myoclonic–astatic epilepsy/ 2 to 5 years Manifestation is complex and can include all
Doose syndrome seizure types
Lennox–Gastaut syndrome 3 to 4 years Specific triad: tonic–clonic seizures, abnormal
EEG, mental retardation
Progressive unilateral encephalopathy/ 3 to 10 years Focal seizures that move to produce a series of
Rasmussen syndrome distinct focal seizures; moderate intellectual
decline
Benign rolandic epilepsy 4 to 10 years Seizure occurrence during sleep or onset;
remits in adolescence
Epilepsy with myoclonic absences 6 to 7 years Absence seizures with bilateral clonic jerks
Childhood absence epilepsy 7 years Frequent staring spells daily
Juvenile absence epilepsy 12 to 13 years Less frequent staring spells, fewer than one
per day
Juvenile myoclonic epilepsy 14 to 15 years Bilateral, irregular jerking on awakening from
sleep; frequently elicited by sleep deprivation
and fatigue
Infantile Myoclonic Epilepsy repeatedly within a 24-hour period. In ap-

proximately 90% of children, the duration
Infantile myoclonic epilepsy occurs in chil-
of the febrile seizure is less than 10 minutes;
dren during their first or second year of life
only approximately 10% of children experi-
who are otherwise normal in development
ence seizures lasting longer than 15 minutes
but who have a familial history of epilepsy.
(Berg & Shinnar, 1996).
Its etiology is usually symptomatic of some
Febrile seizures typically have an excel-
CNS abnormality, but may remain crypto- lent outcome and are associated with nor-
genic for some time. mal intellect and the absence of long-lasting,
The seizure manifestation, as its name detrimental effects. Therefore, treatment of
suggests, involves brief episodes of muscu- febrile seizures with AEDs is often discour-
lar contractions that can occur as one brief aged unless children exhibit recurrent pro-
episode or in clusters. The classic form of it longed seizures, due to the adverse effects
consists of a sudden flexion or extension of AEDs may have on behavior, cognitive pro-
the trunk and/or limbs. It is differentiated cesses, and intellectual development, as well
from infantile spasms by the lack of depend- as other health factors (e.g., they can cause
able serial clustering in contraction. The liver damage). However, acute treatment
EEG is often normal initially, but may later may be indicated for prolonged seizures last-
be characterized by bursts of spike–wave and ing longer than 5 minutes, including rectal
polyspike–wave complexes. Intellectual de- diazepam and buccal or intranasal midazo-
velopment may be mildly delayed, and some lam (Bhattacharyya, Kalra, & Gulati, 2006;
minor personality change may occur (Com- McIntyre et al., 2005).
mission on Classification and Terminology, Up to 30% of all children who experience
1989), but the general outlook is good. a febrile seizure may experience a second fe-
brile seizure (depending on a variety of pre-
Febrile Seizures disposing factors). Between 2% and 20% of
children who experience febrile seizures will
It is estimated that the prevalence of febrile develop a nonfebrile seizure disorder (epi-
seizures is between 3% and 8% in children lepsy).
under the age of 8 years old (Sadlier & Schef-
fer, 2007). The onset of febrile seizures most
commonly occurs between the ages of 6 Myoclonic–Astatic Epilepsy
months and 6 years; the median age of onset (Doose Syndrome)
is 18 months. More than half of the cases Myoclonic–astatic epilepsy (a.k.a. Doose
of febrile seizures occur between 12 and 30 syndrome) has a complex seizure manifesta-
months (American Academy of Pediatrics, tion, which can include myoclonic, astatic,
Committee on Quality Improvement, 1999; myoclonic–astatic, tonic absence, clonic ab-
Offringa et al., 1994). They are reliably elic- sence, and tonic–clonic seizures. It occurs in
ited by a rapidly evolving and very high fever, children between the ages of 7 months and
but their occurrence is also dependent on age 6 years, but prevalence rates peak in chil-
and cortical maturity, as well as familial his- dren between the ages of 2 and 5 years who
tory/genetic predisposition (Degan, Degan, & have developed normally up to that point.
Hans, 1991). Thus febrile seizures are often Those with myoclonic–astatic epilepsy usu-
considered the paradigm for age-dependent ally have a family history of idiopathic gen-
epilepsies because of their consistent and di- eralized epilepsy. The progression of the
rect interdependence on three factors; age, syndrome is variable, but status frequently
genetics, and environmental factors. occurs, and the progression into a tonic epi-
Febrile seizures can be subclassified into lepsy syndrome is not associated with a fa-
simple and complex categories, although the vorable prognosis.
use of the terms simple and complex can be
misleading. A simple febrile seizure is a pure-
Lennox–Gastaut Syndrome
ly reactive, single, uncomplicated febrile sei-
zure episode. Complex febrile seizures start Lennox–Gastaut syndrome usually appears
with a focal seizure, and the seizure episode in children at about age 3 or 4 (but spans
lasts longer than 15 minutes and occurs the ages from 1 to 8) who have previously
experienced uncontrolled infantile spasms. incident. A child then experiences focal sei-
However, the syndrome can also appear in zures that increase in frequency. These focal
otherwise healthy children and adolescents seizures will gradually become more intense
without any apparent precursor. The onset (but will not become multifocal), until more
of the syndrome may be accompanied by a than half of these children experience a con-
cessation of intellectual development. Devel- tinuous focal seizure (epilepsy partialis con-
opment after onset for some children may be tinua).
severely arrested; for other affected children, The syndrome then progresses to sur-
it may be less severely affected. The syn- rounding areas of the initial foci and will
drome is accompanied by a very abnormal spread in concentric circles until the entire
and easily recognizable EEG of spike-and- hemisphere is involved. Note, however, that
wave discharge superimposed on abnormal the seizure does not generalize. Rather, the
background activity. Thus it is characterized focal seizure will move from the initial loci
by a specific triad: seizures, abnormal EEG, to a conjoining area, and the function associ-
and some degree of mental retardation. ated with that cortical area will become the
The seizure manifestation is similar to in- manifestation of the seizure. The manifesta-
fantile spasms (sudden flexion of the body), tion will eventually change again to what-
but does not appear in definitive series. The ever behavior or function is associated with
child, who is now walking, experiences the the area adjoining the second foci.
sudden body flexion (a.k.a. myoclonic, aton- The progressive deterioration occurring
ic, or akinetic seizures) and often falls to the with Rasmussen syndrome usually results
ground. The syndrome is severe and appears in a variable degree of intellectual and lan-
to be a combination of seizure types, in- guage impairment that ranges from mild to
cluding focal and/or multifocal generalized severe. Its progression appears unstoppable,
tonic, tonic–clonic, myoclonic, atonic, and but some children have responded well to
absence seizures. These seizures are unpre- radical hemispherectomy. Such children
dictable, are difficult to control, and occur often experience some improvement in in-
with increased frequency as the syndrome tellectual functioning. Research has also
progresses. Thus many children with this pointed to the cause of Rasmussen encephal-
syndrome are very sheltered and wear pro- opathy as being an autoimmune disorder in
tective headgear. which antibodies bind to and overstimulate
It is notable, however, that although most gluatamate receptors in the brain. Promising
of the literature supports this severe se- but not yet definitive research has indicat-
quence of events associated with Lennox– ed that effective short-term treatment may
Gastaut syndrome, there have been reports be found in techniques such as plasma ex-
of less severe developmental sequelae. Lon- change, in which the antibodies are filtered
gitudinal studies following children with the from the blood (Palcoux et al., 2007). Thus
syndrome indicate that they may be capable far, however, this treatment has had limited
of attaining low-average intellect and full- success, and patients have relapsed after a
time work. It thus seems that these children few months. Although there does not appear
can fare reasonably well with a combination to be one course of action that is effective for
of educational, psychosocial, and pharma- all individuals with Rasmussen syndrome,
ceutical intervention (S. Goldstein, personal the European consensus group has pro-
communication, September 22, 1997; Yagi, vided a well thought-out algorithm for the
1996). clinical management of these patients. The
treatment model proposes immunotherapy,
hemispherectomy, medication, or minimal
Progressive Unilateral Encephalopathy/
therapy, based on the needs of each individ-
Rasmussen Syndrome
ual patient (Bien et al., 2005).
Progressive unilateral encephalopathy (a.k.a.
Rasmussen syndrome) is a devastating syn-
Benign Rolandic Epilepsy
drome that appears in healthy and appar-
ently typically developing children between The onset of benign rolandic epilepsy typi-
the ages of 3 and 10. It strikes without warn- cally occurs between the ages of 4 and 10.
ing, and the initial episode is usually a severe There is frequently a genetic component in-
generalized seizure that has no precipitating volved in cases of benign rolandic epilepsy,
and it is thought to be an autosomal domi- a peak onset at about age 12. Absence sei-
nant inherited disorder. Seizures most fre- zures may be accompanied by generalized
quently occur at night, during sleep or sleep tonic–clonic seizures or myoclonus seizures.
onset, and can be partial or generalized sei- Generalized tonic–clonic seizures also fre-
zures that are accompanied by centrotempo- quently precede the onset of a juvenile ab-
ral spikes in the EEG. The seizure disorder sence epilepsy syndrome. EEG study may
usually remits on its own in adolescence. reveal spike-and-wave discharges that are
greater than 3 Hz in frequency.
Epilepsy with Myoclonic Absences
Juvenile Myoclonic Epilepsy
The combination of absence seizures inter-
spersed with bilateral clonic jerks defines Juvenile myoclonic epilepsy is characterized
epilepsy with myoclonic absences. Seizures by bilateral, irregular jerking in the upper
may occur frequently throughout a typical extremities upon awakening. It appears at
day, but are thought to decrease in frequen- about puberty in normal adolescents and
cy as sleep stages progress. AED therapy is frequently persists into adulthood. It typi-
difficult, and cognitive impairment and pro- cally manifests itself between the ages of 12
gression to other forms of epilepsy (such as and 18, with a peak onset between the ages
Lennox–Gastaut syndrome) may occur. The of 14 and 15. Juvenile myoclonic epilepsy is
EEG is strikingly characteristic in that the frequently (approximately 90–95% of cases)
abnormal activity, similar to that of child- accompanied by generalized tonic–clonic
hood absence epilepsy, is characterized by seizures, and less frequently (approximately
reliably occurring bilateral synchronous 30% of cases) also by absence seizures (Bay-
spike-and-wave discharges. kan et al., 2008; Panayiotopoulos, Obeid,
& Waheed, 1989; Renganathan & Delaney,
2003). It has a fairly strong familial occur-
Childhood Absence Epilepsy
rence rate; it is thought to be transmitted
Childhood absence epilepsy (a.k.a. pyk- as a Mendelian dominant or recessive trait
noepilepsy or petit mal epilepsy) typically or possibly as complex oligogenic traits
occurs in children between the ages of 4 (Delgado-Escueta, 2007). Over half of in-
and 8, with peak manifestation between the dividuals with juvenile myoclonic epilepsy
ages of 6 and 7. It is thought to be a complex have first- and second-degree relatives with
polygenic disorder, and prevalence rates for some form of epilepsy (Delgado-Escueta et
childhood absence epilepsy are higher for al., 1989). Heavy consumption of alcohol,
those with a family history of epilepsy. Con- photosensitizing lights, fatigue, and sleep
cordance studies in monozygotic twins have deprivation have all been identified as pos-
been reported at 70–85% (Berkovic, 1998). sible precipitating factors, but sleep depriva-
The prevalence is thought to be higher in fe- tion has been identified as the most common
males than in males, although equal preva- trigger, accounting for approximately 75–
lence in girls and boys has been reported in 90% of juvenile myoclonic seizures (Dha-
numerous studies. Several absences (staring nuka, Jain, Daljit, & Maheshwari, 2001;
spells) a day are experienced, and EEG study Panayiotopoulos, Obeid, & Tahan, 1994).
may reveal spike-and-wave activity superim- The prognosis for intellectual development
posed on a normal background. Generalized is good. The presence of intellectual or neu-
tonic–clonic seizures may surface during ad- rological decline should lead one to suspect
olescence in approximately 40% of children progressive myoclonic epilepsy rather than
with absence seizures. juvenile myoclonic epilepsy.
Juvenile Absence Epilepsy

Neuropsychological Sequelae
The seizure manifestation of juvenile absence Associated with Epilepsy
epilepsy looks very much like that of child-
hood absence epilepsy, but the frequency of Intellectual and cognitive impairments in
seizure occurrence is much lower. Seizures people with epilepsy, especially memory
typically are fewer than one per day. Onset deficits, were observed and noted in the lit-
occurs between the ages of 10 and 17, with erature over 100 years ago. Unfortunately,
there is increasing evidence that cognitive a cognitive process approach to evaluating

deficits result not only from seizures them- cognitive abilities in epileptic populations.
selves, but from the use of many (if not most) The cognitive processes investigated have in-
AEDs. Therefore, AEDs may compound the cluded sensory functions, attention and sus-
cognitive difficulties and behavioral prob- tained concentration, learning and memory,
lems seen in persons with epilepsy (Ameri- language skills, perceptual abilities, concep-
can Academy of Pediatrics, Committee on tualization and reasoning, and motor abili-
Drugs, 1985; Bootsma et al., 2006; Drane ties. The majority of studies have not inves-
& Meador, 2002; Loring & Meador, 2001; tigated all of these processes, and within a
Ortinski & Meador, 2004). The following given process such as attention, one is struck
discussion is based in large part on Bennett by the fact that few investigators use the
(1992) and Bennett and Ho (1997). The spe- same task. Second, a test may not evaluate
cific cognitive effects of AEDs are not ad- what it purports to evaluate; for instance, a
dressed here, and the interested reader is “test of memory” may require high levels of
referred to Bennett and Ho for specific inattention for success. Poor performance may
formation. also be a consequence of impaired language
The apparent association between cogni- or conceptualization processes.
tive impairment and epilepsy has been ob- This last difficulty can potentially be cir-
served for several centuries. Dewhurst (1980) cumvented by utilizing a comprehensive
uncovered a reference in Thomas Willis’s battery approach in assessment, such as the
17th-century lectures at Oxford University Halstead–Reitan Neuropsychological Test
to the losses in memory, intellect, and real- Battery (Reitan & Wolfson, 1985). Reitan
ity testing that persons experience during (1974) believed that this approach would be
and after seizures. Physicians continued to sensitive to the aggregate of cognitive im-
note the frequent co-occurrence of cognitive pairments that might characterize a particu-
impairment with epilepsy throughout the lar type of epilepsy under investigation. Carl
19th century and into the middle of the 20th Dodrill further refined the battery approach
century. As research continued to examine in the assessment of individuals with epilepsy
the relationship of epilepsy and cognitive (see Dodrill, 1978, 1981) by expanding the
impairment, it became apparent that intel- Halstead–Reitan Battery to optimally assess
lectual decline was not as pervasive as was cognitive deficits associated with epilepsy.
formerly believed. Various sampling errors His Neuropsychological Battery for Epilep-
and design methodology oversights (e.g., sy uses 16 measures of performance (as well
studying institutionalized patients, lack of as other psychosocial and empirically per-
control for medication types and levels, lack tinent measures, such as familial history of
of control for type of seizures studied) were seizure disorders), and he established norms
proffered as explanations. Another major that reliably distinguish the performance of
issue was the rather primitive means of as- patients with epilepsy from that of closely
sessing cognitive functioning available in matched control subjects. Dodrill’s battery,
that era. Early studies largely depended on and the general application of neuropsycho-
IQ testing as their major objective measure. logical test battery approaches to evaluate
Although IQ testing can provide a relatively the cognitive effects associated with epilepsy,
sound measure of a person’s biological level represent advances. Unfortunately, the most
of adaptive functioning, it is highly depen- common approach still remains narrow, and
dent on achievement. In addition, IQ test- the majority of inquiries on this topic have
ing is not sensitive to the cognitive effects continued to focus on a single type, or only
of brain injury, and the relationship of re- a few types, of cognitive ability.
current seizure disorders to brain injury is When competently provided, a neurop-
obvious. sychological assessment can be a valuable
aid in establishing a severity of cognitive
impairments and monitoring the effects of
Neuropsychological Assessment
treatments for a seizure disorder. Although
in Childhood Epilepsy
the vast majority of children with epilepsy
Rather than using IQ as a measure of cogni- retain normal levels of intellectual func-
tive functions, recent research has adopted tioning, they are disproportionately skewed
toward the lower end of average IQ levels. executive functions. Note that this is a pro-
This is presumably due to the underlying cess model, not an anatomical model. With
pathophysiology of the epileptic syndrome. the exceptions of (1) language skills and (2)
The importance of understanding a child’s visual–spatial skills, visual construction,
intellectual capabilities is key to being able and perceptual–motor skills—which are
to decipher underlying causes of poor aca- primarily represented in the left and right
demic performance. Material beyond a hemispheres, respectively—these processes
child’s difficulty level, or boredom with are bilaterally represented. This model is
material beneath his or her level, can each diagrammed in Figure 24.1.
lead to poor academic performance. Frus- According to this model, the first level of
tration with these academic difficulties and neuropsychological processing is input to
with misplaced parental and teacher expec- the brain via one of the sensory systems. It
tations can lead the child to behave in im- should be remembered that input can also
proper manners during school and thus to arise endogenously from within the brain.
be classified as having behavioral problems. The input must be attended to or concentrat-
Pressures to perform at unrealistic levels by ed on for information processing to occur
parents and teachers may be alleviated early and for the significance of the input to be
in the child’s academic career by recogniz- ascertained (second level). Determining the
ing the contributions and appropriateness of significance of the stimulus or remembering
intelligence testing to academic placement it for later reference requires involvement of
and performance. Learning problems due to the memory system (third level).
interrupted auditory or visual information The interdependence of attention and
processing secondary to the seizure activity memory illustrates the fact that this neural
are common. Lack of concentration and dis- system is dynamic, with activity flowing in
tractibility are also more common in children both directions. In general, if information
with epilepsy than in children without such is to be remembered, it must be attended to
conditions. Particular care must be taken (although, on the other hand, attention is no
to evaluate the possible influences of AEDs guarantee for memory). Similarly, attention
on learning, behavioral, and attentional is dependent on memory in terms of atten-
deficiencies, as they all can cause problems tional processes’ being involved in such ac-
(Loring, Marino, & Meador, 2007; Ver- tivities as habituation and filtering of gated-
meulen & Aldenkamp, 1995). Such sequelae out, irrelevant information.
are common causes of academic difficulties Input material that is verbal in nature re-
in children with epilepsy, and careful evalu- quires the processing activities of a fourth
ation of the causes of academic problems neuropsychological category, language
must be made. skills. Nonverbal material similarly requires
processing mechanisms of a fifth category:
visual–spatial skills, visual construction,
A Neuropsychological Model
and perceptual–motor skills.
of Brain Functioning
Executive functions represent the highest
To appreciate fully the effects of epilepsy on level of information processing. These activ-
cognitive processes, it is helpful to consider ities are involved in logical analysis, concep-
these processes within a theoretical or con- tualization, planning, self-monitoring, and
ceptual model of the behavioral correlates of flexibility of thinking. Poor performance on
brain functioning. In our own conceptual- tests of executive functions can result from a
izations, we have found it helpful to expand primary deficit in these functions themselves,
on and modify the model presented by Re- or it can result from a primary deficit in one
itan and Wolfson (1985), which denotes six of the lower levels of processing on which
categories of brain–behavior relationships. executive functions depend. Executive func-
Bennett (1988) has expanded the number tions quickly become quite impaired in a
of categories to seven, in order to separate person who is distractible, forgetful, and/or
attention from memory and to emphasize language-impaired, or who cannot perform
the dependence of memory on attention and higher-level perceptual processes.
concentration. He has also expanded on Motor functions are the basis for respond-
their level of logical analysis and renamed it ing and represent the final common path of
FIGURE 24.1. Conceptual model of the behavioral correlates of brain functioning (after Reitan &
Wolfson, 1985). From Bennett (1988). Copyright 1988 by Journal of Cognitive Rehabilitation. Re-
printed by permission.
the neuropsychological processes. They re- of his or her surroundings, and stares with a
flect the output capabilities of the system. vacant expression. Sensory input occurring
This is the rationale for placing motor out- during these periods is neither attended to
put at the top of the diagram. With this neu- nor registered.
ropsychological model as a backdrop, the Complex partial seizures, on the other
effects of epilepsy on specific cognitive pro- hand, may be manifested as sensory misper-
cesses can be discussed. ceptions and/or hallucinations. Mispercep-
tions are often visual and complex. They
Effects of Epilepsy typically involve distortions in depth percep-
on Specific Cognitive Processes tions or size. Size misperceptions can result
in objects’ being perceived as much smaller
Sensory Input (micropsia) or larger (macropsia) than they
Both impairment and exaggeration of senso- are. Visual misperceptions reflect a posterior
ry input can be said to result from seizures. temporal lobe seizure focus. For example,
Absence or petit mal attacks are generalized they were observed to occur in a patient of
nonconvulsive seizures that occur particu- ours prior to discovery of a right temporal
larly in children. They are characterized by lobe astrocytoma, and they diminished fol-
brief episodes of loss of consciousness last- lowing its removal.
ing approximately 5–15 seconds. During Misperception of voices results from a
these episodes, a child seems to be unaware focal discharge of the anterior temporal lobe
neocortex, especially from the left hemi- reliably triggered whenever he played the ar-
sphere. Voices may be perceived as too high cade game Foosball! More typically for the
or too low in pitch, or as being too loud patient with complex partial seizures, the
or soft. The patient may complain that the ictal events begin spontaneously with an ar-
voices around him or her sound as if they are rest of all activity, and the aura and/or psy-
“coming out of a tunnel.” chomotor responses follow. Finally, while
Hallucinations or auras that are expe- attention is usually paid to the most salient
rienced by patients with complex partial attribute of the epileptic patient’s aura, the
seizures are typically simple. In general, dream-like quality of the epileptic aura will
olfactory–gustatory sensations, which are often encompass many experiences. For ex-
often quite displeasing, result from a focal ample, a patient of ours regularly experi-
discharge in the uncus of the hippocampus. enced a series of events including epigastric
Our patients who experience these auras sensations, time distortion, detachment from
most typically report salty or bitter taste her surroundings, and olfactory sensations
sensations, and/or olfactory sensations best as components of her seizure episodes.
described as “burning flesh” or “putrid.”
One patient—whose seizures were particu-
Attention and Concentration
larly refractory to AED therapy, and who
experienced secondary generalized seizures Impairment of attention and concentration,
that were correlated with menstruation— in the absence of overt clinical seizures, has
was anosmic except when she experienced been documented by several writers. Teach-
olfactory auras just prior to and during men- er and caretaker ratings for children with
struation each month. epilepsy frequently note marked inattentive-
Abdominal and epigastric sensations typi- ness and the detrimental effects of epilepsy-
cally arise from an amygdala focus. Simple associated inattention on academic success
auditory phenomena, such as buzzing, ring- (Huberty, Austin, Harezlak, Dunn, & Am-
ing, and hissing sounds, are produced by brosius, 2000; Titus, Kanive, Sanders, &
focal activity on the surface of the temporal Blackburn, 2008).
lobe, especially the primary auditory recep- Keene and colleagues (2005) studied 158
tion area. Complex visual hallucinations, al- children with epilepsy of varying etiologies
though uncommon, arise from pathological and found that attentional deficits were one
excitation of visual cortical areas, especially of the key problems noted in these children.
the posterior parietal or temporal association Specifically, approximately 30% of the chil-
cortex (Manford & Andermann, 1998). dren with epilepsy in this study were de-
Cephalgic auras reflect discharge origi- scribed by their parents as having attention
nating in the central regions of the temporal problems that were more than two standard
lobes. They consist of severe, sharp, stab- deviations above the mean for the normative
bing, knife-like head pains that are often as- sample. Fastenau and colleagues (2004) also
sociated with the head’s feeling too big, too found poorer performance on attentional
small, or off the body. Cephalgic auras will measures in children with chronic seizures
occasionally be misdiagnosed as migraine than in normative samples.
headaches and subsequently incorrectly Specific attentional difficulties in epilepsy
medicated. appear to be related to seizure type. Patients
An important feature of auras is that they with generalized seizures show greater im-
are passive experiences. The patient feels like pairment on measures of sustained attention
an observer of these ictal (seizure-related) than patients with focal seizures do. It has
events, dissociated from the actual experi- been argued that this occurs because gen-
ence. This is different from the experience of eralized seizures are more likely than focal
an individual with schizophrenia, who firm- seizures to affect the central subcortical
ly believes that his or her hallucinations are structures that are responsible for maintain-
“real” experiences. The ictal events are un- ing attention.
related to the environment, except for rare In contrast, limited studies have suggested
seizures that are triggered by specific stimuli that patients with focal seizures show more
(e.g., musicogenic seizures, sexual seizures). impairment on tests of selective attention
We once had a patient whose seizures were than patients with generalized seizures do
(Loiseau, Signoret, & Strube, 1984). One seizures to patients with focal complex par-
argument for this finding is that subcorti- tial seizures of temporal lobe origin, Quad-
cal structures are important in determining fasel and Pruyser (1955) found that memory
what to pay attention to (selective atten- impairment was significant only in the group
tion) (Stores, 1984). However, more recent with focal seizures. Since that original study,
research has argued that despite the signifi- a multitude of studies have been published
cant literature suggesting that individuals supporting the key role of the hippocampus
with epilepsy are at significant risk for atten- and temporal lobe in relationship to memory
tional deficits, results from studies assessing problems in epilepsy (Adda, Castro, Alem-
specific risk factors in terms of seizure type Mar, de Manreza, & Kashiara, 2008; Mes-
have not been consistent (Dunn & Kronen- sas, Mansur, & Castro, 2008; Powell et al.,
berger, 2006). Specifically, an example from 2007).
Dunn and Kronenberger’s review addresses There has also been a great deal of re-
seizure focus—a facet of seizures that might search on both adults and children suggest-
be expected to predict different types of ating that focal seizures of left temporal lobe
tentional deficits depending on the foci, but origin yield greater verbal than nonverbal
does not consistently suggest a fixed pattern deficits, and that the opposite pattern is ob-
of deficits across studies. For example, past tained with right temporal lobe dysfunction
findings suggest that frontal lobe foci may (Jambaque, Dellatolas, Dulac, Ponsot, &
pose a greater risk for attentional deficits Signoret, 1993; Majdan, Sziklas, & Jones-
(Hernandez et al., 2003; Sherman, Armit- Gotman, 1996; Powell et al., 2007). The
age, Connolly, Wambera, & Strauss, 2000); lateralizing effect on memory has also been
other researchers argue that in fact temporal supported in studies utilizing EEG and func-
lobe foci may pose more risk (Stores, 1978); tional magnetic resonance imaging (Binder
and the authors of two larger studies argue et al., 2008; Vannucci, 2007). However, in
that there is no association between foci and children specifically, several studies suggest
attentional problems (Dunn, Austin, Hare- that the lateralization effects seen in adults
zlak, & Ambrosius, 2003; Hesdorffer et al., are not as robust in early development (Bell
2004). Therefore, while there is consensus & Davies, 1998; Giovagnoli, Erbetta, Vil-
regarding the role of attentional deficits in lani, & Avanzini, 2005; Gonzalez, Ander-
epilepsy, there is still further research needed son, Mitchell, & Harvey, 2007).
to elucidate the role of chronicity, foci, medi- One potential argument for the discor-
cation, and comorbidity in the development dant findings in the literature regarding lat-
of attentional deficits in this population. eralization focuses on the disparity in tests
that have been used to assess verbal and
nonverbal skills. Gonzalez and colleagues
Learning and Memory
(2007) point out that tests assessing non-
Deficits in the ability to learn and remem- verbal skills (specifically, nonverbal memory
ber material on a daily basis have been measures) are likely to recruit several differ-
noted by teachers and parents of children ent neural mechanisms, depending on the re-
with epilepsy for many years. Wilson, Ivani- quirements of each task. For example, with-
Chalain, Besag, and Bryant (1993) have used in the epilepsy literature, nonverbal memory
a children’s version of the Rivermead Behav- tests requiring memory for the location of
ioral Memory Test to demonstrate everyday objects relative to the environment (i.e., al-
memory difficulties encountered by children locentric memory) and facial recognition
with severe epilepsies. More recent research have shown impairment more consistently
suggested that everyday memory problems than nonverbal memory measures requiring
may be a problem in children with epilepsy, recall of geometric designs have (Abrahams,
but noted that attention problems may be Pickering, Polkey, & Morris, 1997; Barr et
the core cognitive deficit underlying these al., 1997; Chiaravalloti & Glosser, 2004;
problems (Kadis, Stollstorff, Elliott, Lach, Feigenbaum & Morris, 2004). These dis-
& Smith, 2003). parities are probably due to specific cogni-
Evidence has accumulated associating tive requirements involved in each type of
memory deficits with temporal lobe epilepsy task and the areas of the brain recruited for
(TLE). In an early study that compared cog- each task. Gonzalez and colleagues point
nitive abilities in patients with generalized out that children with mesial versus lateral
temporal lobe epilepsy may exhibit very dif- Regardless of the mechanisms by which
ferent types of memory impairment, similar language skills are affected, it is well estab-
to the pattern seen in adults (Helmstaedter, lished that specific language skills can be af-
Grunwald, Lehnertz, Gleißner, & Elger, fected in epilepsy. Robinson (1991) has noted
1997). that over 20% of children with language
An additional difficulty in detecting and impairment have some history of seizures.
addressing the memory difficulties experi- This number is significantly greater than the
enced by persons with epilepsy is evidenced 5–7% seizure prevalence that has been noted
by their lack of insight into their own memo- in the general childhood population. The
ry difficulties. This “metamemory” deficit in possible explanations for the high prevalence
association with temporal lobe seizure foci in this population have included the follow-
has been noted over the years and suggests ing: Seizures may disturb language function-
that individuals with TLE have poorer ining in the brain; there may be a genetic link
sight and self-monitoring skills with regard between language disability and epilepsy; or
to memory (Deutsch, Saykin, & Sperling, brain abnormalities associated with seizures
1996; Prevey, Delaney, & Mattson, 1988). may also contribute to dysfunction in lan-
Taken together, these studies suggest a guage related skills (Robinson, 1991).
significant impairment of memory func- In regard to specific types of language
tions in patients with seizures of temporal impairment, Parkinson (2002) studied lan-
lobe origin. However, the vast research on guage and communication skills in over 100
memory processes alone illustrates the dif- children with epilepsy between the ages of
ficulties encountered in attempting to evalu- 5 and 17 years and found that more than
ate specific cognitive processes in patients 37% of the children had undiagnosed lan-
with epilepsy. guage impairments. These impairments in-
cluded (among others) overgeneralized use
of grammatical rules and structures; ignor-
Language Skills
ing morphological features and inflectional
Both experimental inquiry and clinical word endings in the absence of hearing loss;
observation have long indicated that epi- difficulties in comprehension of words with
lepsy may adversely affect language skills more than one meaning or syntactic role;
and reading acquisition. Williams and col- pragmatic impairment; and anomia. Ano-
leagues (1996) found that children with un- mia and dysnomia have been reported in in-
controlled seizures (absence or complex par- dividuals with epilepsy for years, and it has
tial) had more difficulty with complex verbal been suggested that dysnomia in this popula-
materials than children whose seizures were tion may be confused with poor memory by
well controlled. Butterbaugh and colleagues both an individual with epilepsy and others
(2004) noted learning disabilities in read- (Mayeux, Brandt, Rosen, & Benson, 1980).
ing comprehension and written language in Mayeux and colleagues (1980) further sug-
approximately half of presurgical patients gest that the verbosity and circumstantiality
with left temporal lobe epilepsy (52.6% and observed in some patients with complex par-
42.1%, respectively). An interesting case re- tial seizures (e.g., Bennett, 1987) may be the
ported by Vargha-K hadem and colleagues expression of a compensatory mechanism
(1997) involved an 8½-year-old child with for dysnomia.
uncontrolled seizures who underwent radi- Circumstantiality is seen in both the spo-
cal hemispherectomy of the left hemisphere. ken and written communication of these
Prior to his surgery, the child was mute and patients. Their spoken communications are
had the language comprehension skills of a often overinclusive and include excessive
3- to 4-year-old. Not only did his seizures background detailing, in addition to using
remit following the surgery, but he spon- excessive words and taking too much time to
taneously regained language development convey a thought (Bear, Freeman, & Green-
a month after withdrawal of AEDs! These berg, 1984; Field, Saling, & Berkovic, 2000).
results, among others, have prompted new These tendencies can prevent conversations
questions regarding whether the mechanisms from reaching a normal end, and this style
of seizure control (usually AEDs) actually can lead to such patients’ being shunned. Hy-
have detrimental effects on language skills pergraphia (i.e., a tendency toward excessive
as severe as those of the epilepsy itself. and compulsive writing) is also often seen in
patients with complex partial seizures and performance on such tests as the Trail Mak-
was first comprehensively documented in ing Tests, the Wisconsin Card Sorting Test
these patients by Waxman and Geschwind (WCST), and the Category Test.
(1980). It is often characterized by verbosity An interesting study by Martin and col-
and circumstantiality, but it facilitated the leagues (2002) investigated the relationship
writing of the legendary author and victim of various clinical variables and neuroana-
of complex partial seizures, Feodor Dostoi- tomic correlates in TLE to performance on
evsky (Geschwind, 1984). the WCST. Specifically, 89 patients with lat-
eralized TLE (47 left, 42 right) underwent
baseline testing on the WCST. Seventy-two
Perceptual–Motor Skills
patients completed both presurgical and
There has not been a great deal of research postsurgical assessment following an ante-
investigating the effects of epilepsy on per- rior temporal lobectomy (ATL). The results
ceptual–motor skills, but the following has indicated that those patients with a history
been reported. Early research noted total of secondary generalized seizures performed
time, memory, and localization scores from worse on the preoperative WCST than did
the Tactual Performance Test as sensitive patients without such a history. A more sur-
measures of the effects of epilepsy on cog- prising finding was that those patients who
nitive processes (Dodrill, 1978, 1981). The were seizure-free after ATL did not perform
total time score is a measure of perceptual– better on the WCST than those who did not
motor (manipulospatial) ability. A deficit in become seizure-free. The authors postulate
spatial memory can be evaluated via the lo- that the results suggest that temporal lobe
calization score if a significant discrepancy structural abnormalities associated with
exists between the localization score and the epilepsy do not significantly affect executive
memory score from this task. function as measured by the WCST. These
More recently, multiple studies have noted findings suggest that the critical neurocor-
visual-perceptual deficits in epilepsy, includ- relates of WCST performance in patients
ing facial recognition and spatial judgment. with TLE probably lie outside the temporal
Some studies localize these deficits to the lobe and most likely are related to metabolic
right hippocampal region in TLE, and sug- disruption to frontostriatal neural network
gest notably greater deficits in those whose systems.
seizures began earlier in life than in those Martin and colleagues (2000) also exam-
with later onsets (Getz et al., 2002; Her- ined the role of bilateral hippocampal scle-
mann et al., 2002; Martin et al., 1999). rosis, extrahippocampal mesial temporal
atrophy, and temporal neocortical lesions
on WCST performance and found that per-
Executive Functions
formance was not significantly affected by
Because of their dependence on lower-level any of the types of lesions or atrophy. This
neuropsychological functions, executive finding is in contrast to that of Corcoran
functions of the brain involved in such pro- and Upton (1993), who utilized a modified
cesses as conceptualization, logical analysis, WCST with patients who had hippocampal
reasoning, planning, sequential thinking, sclerosis associated with TLE. The authors
flexibility of thinking, and self-monitoring speculated that working memory might play
are especially sensitive to dysfunction, in- a critical role in WCST performance after
cluding the types of dysfunction associated they found that patients with hippocampal
with epilepsy. As indicated earlier in this sclerosis (particularly the patients with right
chapter, executive functions will typically be foci) performed more poorly than those with
impaired in a person who exhibits distracti- frontal lobe seizure foci (Upton & Corcoran,
bility, a poor memory, language impairment, 1995).
and/or difficulty with perceptual–motor The debate continues regarding the im-
skills. In a general sense, executive functions pact of TLE on tasks that are thought to as-
are the basis for a person’s ability to meet sess frontal or executive functions, as well as
the demands of his or her environment effec- in the conceptualization of executive func-
tively. Although these impairments may be tions. In fact, the central executive functions
easily overlooked, they are commonly seen conceptualized and referred to by many au-
in individuals with epilepsy, as indicated by thors often overlap with working memory
and attention. Thus, amidst the ongoing de- starts at an early age, if a patient has poor
bates concerning conceptualization and test- seizure control, if the individual has had the
ing of executive functions, there still is no disorder for a relatively long period of time,
consensus regarding the effects of epilepsy and if the person exhibits multiple seizure
on executive functions independent of other types. Complex partial seizures, particularly
cognitive functions. those of temporal lobe origin, are typically
believed to produce more obvious cognitive
and behavioral changes than most other sei-
Motor Output
zure types.
Decreased reaction time and psychomotor
speed are common difficulties for individu-
Etiology of the Seizure Disorder
als with epilepsy. Mitchell, Zhou, Chavez,
and Guzman (1992) studied simple reac- Of the intellectual correlates associated with
tion time, forced-choice reaction time, and epilepsy and the variables that alter them,
choice reaction time with distraction in 112 one of the most predictable relationships is
children with epilepsy. The children with ep- that between seizure etiology and IQ. The
ilepsy were significantly slower, were more IQ scores of individuals whose seizures are
variable, and made more omission errors idiopathic have long been established to be
than the controls. This pattern of perfor- significantly higher than scores attained by
mance was maintained even when the analy- patients whose seizures have known etiolo-
sis was limited to only those patients with gies; this is true of both institutionalized and
epilepsy who had IQs greater than 90. And noninstitutionalized children and adults.
although it was observed that reaction times The types of cognitive deficits associated
were related to IQ, they were not generally with epilepsy vary significantly, depending
related to seizure severity, duration of sei- on the origin of the seizures. A general de-
zure disorder, or duration of medication use. cline in cognitive functioning has been de-
In addition, untreated patients did not differ scribed as highly comorbid with epilepsy,
from those with AED levels in the therapeu- but particularly so for those individuals
tic range on the day of testing, but they did who have partial epilepsy with a temporal
differ significantly from controls. or frontal lobe origin (Oyegbile et al., 2004).
Although reaction time does not typically The literature focusing on the relationship
garner much attention as a core cognitive between the temporal lobes and cognitive
deficit associated with dysfunction in daily dysfunction is clearly the largest, given that
life, McGuckin (1980) has proposed that TLE has been the most frequently studied
lack of speed is one of the four main barriers type of epilepsy. Even within this literature,
to competitive employment faced by adults however, there is great disparity by the lo-
with epilepsy, and this same lack of speed calization of the focus. Gonzalez and col-
may also be conceptualized as a barrier to leagues (2007) studied 43 children with le-
academic success in children and adolescents sional TLE and noted significant differences
(Bennett-Levy & Stores, 1984). on a number of cognitive tasks, depending
on the localization of the lesion (i.e., left,
right, or intratemporal). Among the specific
Etiological Factors in the Cognitive deficits noted, facial recognition was signifi-
Deficits Associated with Epilepsy cantly worse in individuals with right TLE
than in those with left TLE. Notable dif-
The same factors that influence the devel- ferences were noted within the intratempo-
opment of epilepsy (age, genetics, and envi- ral group (i.e., mesial or lateral) in terms of
ronmental stressors) are also related to the arbitrary associative learning and complex
cognitive sequelae associated with epilepsy. figure recall.
In addition, the etiology and type of seizures In adults, the task of determining cogni-
associated with a child’s epileptic syndrome tive deficits resulting from specific areas of
have some differential effects on cognition. localization becomes even more compli-
These differential cognitive sequelae are dis- cated, due to the influence of other types of
cussed here. pathology and insult that may be introduced
In general, more significant effects are with age. Research in our laboratory on the
thought to result if they seizure disorder cognitive effects of epilepsy in adults with
clear evidence of focal left versus right tem- focus. In regard to AEDs, findings suggested
poral lobe seizures, but without prior head that those children receiving two or more
injury or neurological disease, indicated AEDs were less likely to receive mainstream
no lateralized deficits (Haynes & Bennett, schooling even when seizure frequency and
1991). The only trend that appeared was severity of the epilepsy were taken into ac-
that the subjects with epilepsy as a group count. Lastly, in terms of the effects of du-
exhibited generalized deficits in the areas of ration on cognitive functioning, the authors
psychomotor speed, selective attention, and found that IQ decreased with duration of
reasoning ability. This study emphasizes the epilepsy only in the individuals with symp-
importance of ruling out underlying cerebral tomatic or cryptogenic generalized epilepsies
pathology due to head injury or other neu- and epilepsies of undetermined origin; IQ re-
rological disease in studying cognitive pro- mained stable with duration in the two other
cesses in persons with epilepsy per se. types of epileptic syndromes.
Early studies also found seizure type to af-
fect selected cognitive functions differentially.
Seizure Type and Frequency
Regardless of seizure type, the performance
In addition to seizure etiology, the type and of children with epilepsy was below that of
frequency of seizures constitute important the control group. Of greater interest, howev-
variables influencing the nature and extent er, were past findings suggesting that children
of intellectual and cognitive dysfunction. A with left temporal lobe foci showed learning
number of studies have shown generalized and memory deficits on measures requiring
tonic–clonic seizures to be associated with delayed recall of verbal material, whereas
greater intellectual and cognitive impair- children with right temporal lobe foci had
ment than other types of seizures. Studies greater difficulty with recall tasks involving
over the years have also repeatedly demon- visual–spatial abilities. Significant differences
strated, in both children and adults, that between performances on measures of recent
frequent generalized seizures are associated memory were not evident between groups.
with the highest levels of cognitive impair- Furthermore, children whose seizures were
ment (vs. less frequent seizures and other centrecephalic in nature performed at a sig-
types of seizures). The detrimental effect nificantly lower level on tasks of sustained
of frequency of seizures on intellectual and attention than those in the temporal lobe
cognitive functioning has been shown to be groups, without exhibiting either short-term
consistent across all seizure types. or long-term memory impairment.
Bulteau and colleagues (2000) evaluated Patterns of intellectual performance on
251 children (98 girls and 153 boys) who the Wechsler Adult Intelligence Scale—
ranged in age from 3 to 17 years and who Revised (WAIS-R) or WISC-R that varied
all had documented diagnoses of an epileptic with seizure type have been observed in mul-
syndrome. Information was obtained regard- tiple studies (Bulteau et al., 2000; Giordani
ing IQ, school placement, age of onset of sei- et al., 1985, 1993). Bulteau and colleagues
zures, duration of epilepsy, seizure frequen- (2000) found that in children, depending on
cy, and number of AEDs. Results suggested the etiology of the seizure, different patterns
that, similar to past findings, age of onset of performances emerged. Specifically, those
and seizure frequency were both associated individuals within the frontal epilepsy group
with poor outcome. The children with idio- showed relative deficits on WISC-R Arith-
pathic generalized or localization-related ep- metic and Coding compared to other sub-
ilepsy not only had higher IQ scores, but they tests. Those with occipital epilepsy exhibited
also had a higher probability of mainstream relative weaknesses on image completion,
schooling, than those with symptomatic or image arrangement, and the Coding subtest.
cryptogenic generalized epilepsies or those Those with multifocal epilepsy exhibited
whose etiologies were classified as “undeter- varied performance across all subtests, and
mined.” When the researchers looked at per- those with TLE and rolandic epilepsy ex-
formance on measures within the Wechsler hibited rather consistent performance across
Intelligence Scale for Children—Revised subtests. Giordani and colleagues (1993)
(WISC-R), they found that subtests profile in studied adults and found that patients with
localization-related epilepsies were different, focal (temporal) seizures showed compro-
depending on the location of the epileptic mised performance on WAIS-R Vocabulary
when compared to patients with generalized substantial reduction in brain tissue volumes
seizures, whereas the generalized group per- and significantly impaired performance on
formed less well on Block Design. a number of cognitive measures when com-
Because seizure classification and their pared to the patients with late-onset TLE
inclusion criteria have not been consistent, (mean onset age, 23.3 years). On the neu-
particularly in the earlier studies, and be- ropsychological battery administered to the
cause populations tested have not been uni- groups, the early-onset patients performed
form across investigations (institutionalized significantly worse on 7 of the 12 tests (Full
vs. noninstitutionalized), direct comparisons Scale IQ; Performance IQ; naming; spa-
between studies are not always possible. The tial orientation; verbal and visual memory;
study of seizure type and frequency and its problem solving). Similar trends were noted
effect on intellectual and cognitive function- on a number of other measures.
ing is further complicated by the severity of Dodrill (1993) is careful to point out the
seizures and the levels of AEDs necessary to need for careful consideration of other possi-
achieve adequate seizure control. It is also ble factors that contribute to the poorer cog-
possible that in some cases, the association nitive outcome associated with early onset,
between observed cognitive deficits and fre- such as the fact that a lower age at onset usu-
quency of seizures is due to the extent of ce- ally means a much higher number of total
rebral damage that is responsible for both. seizure occurrences. In fact, Dodrill (1986)
When considered as a whole, however, cur- has previously found evidence that the total
rent studies suggest that the extent of intel- number of tonic–clonic seizures a person
lectual and cognitive dysfunction in epilepsy experiences may be as important as, if not
varies with the type of seizure and increases more important than, the age at onset.
with greater seizure frequency.
Summary
Age at Onset and Duration
of Disorder
Childhood epilepsy syndromes are wide and
The relationship between early onset of varied. Their seizure and behavioral mani-
a seizure disorder and poor prognosis for festations span the possibilities of syndromes
mental functioning has been noted for over classified by the ILAE (listed in Table 24.2).
a century, and current research continues to Moreover, childhood epilepsies have been
support this observation. Studies of intel- shown to exist both neonatally and even
lectual and neuropsychological functions in prenatally. Seizures at these age ranges have
children with epilepsy, regardless of seizure their own manifestation and classification.
type, indicate that onset of seizures early in What we know to be common about most
life with a consequently long duration of sei- childhood epilepsy disorders is that their
zure disorders place children at higher risk onset, whether a single seizure occurrence or
for cognitive dysfunction. a long-lasting epileptic disorder, usually has
Oyegbile and colleagues (2004) assessed some genetic component (i.e., there is a close
cognitive dysfunction in individuals with relative with a history of some type of seizure
chronic TLE compared to healthy control disorder). We know more about the genetic
subjects and determined that chronicity of inheritance modes of some epileptic disorders
epilepsy was related to greater impairment in than we do about others. We also know more
mental status, specifically in terms of intelli- about the cognitive and neuropsychological
gence, memory, language, visual-perceptual consequences of some syndromes than we do
skills, and motor skills. This finding was about others. However, it does appear that
even more striking for those with chronic the age at which the disorder began, the du-
epilepsy and less educational attainment. ration of the disorder, and the frequency and
To assess the role of early-onset versus late- duration of the seizures are all factors in a
onset TLE on brain structure and cognitive child’s long-term outcome. As basic and ap-
processing, Hermann and colleagues (2002) plied scientists continue to collaborate and
compared healthy controls to patients with compare notes, we come closer to reaching
early-onset and late-onset TLE. The findings answers about the neurodevelopmental and
suggested that the patients with early-onset physiological underpinnings of epilepsy and
TLE (mean onset age, 7.8 years) exhibited their impact on cognitive development.
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Chapter 25
Prader–Willi Syndrome
Elisabeth M. Dykens
Suzanne B. Cassidy
Melissa L. DeVries
Prader–Willi syndrome is a complex, mul- and the most common recognized genetic
tisystem disorder whose intriguing genetic form of obesity.
and behavioral features have attracted re- Prader–Willi syndrome is also the first
newed interest from researchers and clini- recognized human disorder in which it was
cians alike. The major manifestations of appreciated that the relevant genes are ex-
Prader–Willi syndrome include hypotonia; pressed differently, depending on whether
early failure to thrive, followed by later ex- they are inherited from the mother or the
cessive appetite and obesity; hypogonadism; father (Nicholls, Knoll, Butler, Karam, &
short stature; characteristic appearance; Lalande, 1989). This phenomenon of dif-
developmental disability; and significant ferential gene expression is known as ge-
behavioral dysfunction. Approximately 1 nomic imprinting. In addition, Prader–Willi
in 10,000–15,000 individuals is diagnosed syndrome is distinctive in being caused by
with Prader–Willi syndrome (Burd, Vesely, several different genetic alterations of the
Martsolf, & Kerbeshian, 1990; Wigren & relevant chromosomal region, which is the
Hansen, 2003a), and it occurs in both sexes long arm of chromosome 15. Prader–Willi
and all races. syndrome thus occupies an important place
Prader–Willi syndrome was first de- in the contemporary history of human ge-
scribed in 1956 (Prader, Labhart, & Willi, netic disorders.
1956). Twenty-five years later, the syndrome Clinical diagnostic criteria for Prader–
captured the interest of human geneticists Willi syndrome have been developed (Holm
because it was the first syndrome that was et al., 1993; Whittington et al., 2002), and
found to be caused by a small missing piece accurate, specific genetic testing has become
of chromosomal material called a microde- available (American Society of Human
letion; this discovery was made by research- Genetics [ASHG] & American College of
ers using the newly developed technique of Medical Genetics [ACMG], 1996; Crinò et
high-resolution chromosome analysis (Led- al., 2003). However, the diagnosis is still
better et al., 1981). Prader–Willi syndrome delayed in many cases because of a failure
is now known to be one of the most common to recognize the syndrome’s characteristic
microdeletion syndromes, one of the most physical and behavioral manifestations. In
frequent disorders seen in genetics clinics, addition to a distinctive physical phenotype,
484
Prader–Willi Syndrome 485
Prader–Willi syndrome has a characteris- feeding techniques. Infantile lethargy, with

tic behavioral phenotype, which includes a decreased arousal and weak cry, are also
blend of unusual cognitive findings, psychi- prominent findings, often leading to the ne-
atric vulnerabilities, and maladaptive behav- cessity to awaken the child to feed. Reflexes
iors (e.g., temper tantrums and argumenta- may be decreased or absent. Neuromuscular
tiveness). These features are as important to electrophysiological and biopsy studies are
quality of life and morbidity as are some of normal or nonspecific, and the hypotonia
the syndrome’s medical problems, and they gradually improves. Delayed motor mile-
are often the focus of intervention and treat- stones are evident; the average age of sitting
ment (Bellon-Harn, 2005; Cassidy, 1984; is 12 months and of walking is 24 months.
Durst, Rubin-Jabotinsky, Raskin, Katz, Adults remain mildly hypotonic, with de-
& Zislin, 2000; Dykens & Cassidy, 1995; creased muscle bulk and tone.
Dykens, Hodapp, Walsh, & Nash, 1992a;
Holm et al., 1993).
Hypogonadism
Since its identification over 50 years ago,
then, Prader–Willi syndrome has emerged Hypogonadism is prenatal in onset (Eiholz-
as a complicated disorder that highlights er & Lee, 2006; Lee, 1995), and is evident
the need for a multidisciplinary approach at birth as small genitalia. Males generally
to research and management. This chapter have undescended testes; a small, hypopig-
reviews many aspects of Prader–Willi syn- mented, and poorly rugated scrotum; and
drome, including its medical, genetic, cogni- sometimes a small penis. In females, the labia
tive, behavioral, developmental, and psychi- minora and clitoris are small. These findings
atric features. As appropriate management persist throughout life, though spontane-
often has a positive impact on the health ous descent of testes has been observed up
and quality of life of people affected with to adolescence. There is also evidence of hy-
Prader–Willi syndrome, the chapter also pogonadism in abnormal pubertal develop-
summarizes commonly used medical and ment. Although pubic and axillary hair may
behavioral interventions, especially those develop early or normally, the remainder of
aimed at controlling the syndrome’s char- pubertal development is delayed and usually
acteristic obesity and behavioral/psychiatric incomplete. Adult males only occasionally
dysfunction. have voice change, male body habitus, or
substantial facial or body hair. In females,
breast development generally begins at a
Clinical Findings normal age, but menstrual periods are either
and Natural History absent or infrequent (and, if occurring, they
are late in onset). In both males and females,
Although many of the physical manifesta- sexual activity is relatively rare, and infertil-
tions of Prader–Willi syndrome are related ity is the rule.
to functional hypothalamic deficiency, the The hypogonadism is hypothalamic in
disorder’s clinical appearance in infancy dif- origin, and both pituitary and gonadal hor-
fers considerably from that in childhood and mones are generally deficient (Cassidy, 1984;
adulthood. Lee, 1995). Since the pituitary gland and go-
nads are normal but understimulated, treat-
ment with pituitary or gonadal hormones
Hypotonia
can increase the development of secondary
Hypotonia of prenatal onset is nearly uni- sex characteristics.
formly present and is the likely cause of de-
creased fetal movement, frequent abnormal
Obesity
fetal position, and difficulty at the time of
delivery, often necessitating cesarean section Obesity is the major cause of morbidity
(Cassidy, 1984; Cassidy & Driscoll, 2009; and mortality in Prader–Willi syndrome,
Holm et al., 1993). The neonatal central hy- and longevity may be nearly normal if obe-
potonia is almost invariably associated with sity is avoided (Cassidy, Devi, & Mukaida,
poor suck, with consequent failure to thrive 1994; Einfeld et al., 2006; Greenswag,
and the necessity for gavage or other special 1987). Significant weight excess, if allowed
to occur, follows the early period of failure

to thrive; the onset of excessive eating, or
hyperphagia, typically begins between 1
and 6 years of age. Food-seeking behaviors
are common, including hoarding or forag-
ing for food; eating unappealing substances
such as garbage, pet food, and frozen food
and may vary by genetic subtype, based on
differences in how visual food stimuli are
perceived—see Key & Dykens, 2008); and
stealing food or money to buy food. Low
muscle tone and a disinclination to exercise
add to the effects of the drive to eat exces-
sively. A high threshold for vomiting may
complicate bingeing on spoiled food from
the garbage or items such as boxes of sugar
or frozen uncooked meat. Toxicity has oc-
curred from ineffective ipecac used to in-
duce vomiting.
As shown in Figure 25.1, the obesity in
Prader–Willi syndrome is central in distri-
bution, with relative sparing of the distal
extremities; even individuals who are not
overweight tend to deposit fat on the abdo-
men, buttocks, and thighs. Cardiopulmo-
nary compromise can result from excessive
obesity, as can type 2 diabetes mellitus, hy-
pertension, thrombophlebitis, and chronic
leg edema. Sleep apnea occurs at increased
FIGURE 25.1. A 27-year-old man with Prad-
frequency. er–Willi syndrome. Note the narrow bifrontal
The hyperphagia in Prader–Willi syn- diameter and typical body habitus, with central
drome is due to a hypothalamic abnormality obesity and small hands. Photograph used by
that results in lack of satiety (DelParigi et permission of the patient and his family.
al., 2002; Holland et al., 1993; Zipf & Bern-
ston, 1987). In addition, there is a decreased
caloric requirement (Holm & Pipes, 1976;
Kundert, 2008), probably related to hypoto- 1991). African Americans with Prader–Willi
nia and decreased activity. syndrome are less likely to have small hands
and feet, and they may also lack the typical
facial phenotype (Cassidy, Geer, Holm, &
Facial Features
Hudgins, 1996; Hudgins, Geer, & Cassidy,
Characteristic facial features either are pres- 1998).
ent from birth or evolve over time (Aughton & A characteristic body habitus, including
Cassidy, 1990; Butler, Hanchett, & Thomp- sloping shoulders, heavy midsection, and
son, 2006). As shown in Figure 25.2, facial genu valgus with straight lower-leg borders, is
features include narrow bifrontal diameter, usually present from toddlerhood (see Figure
almond-shaped palpebral fissures, narrow 25.1). Fairer coloring than other family mem-
nasal bridge, and downturned mouth with bers, manifested as lighter skin, hair, and eye
a thin upper lip. Small, narrow hands with a color, occurs in about a third of affected in-
straight ulnar border and sometimes taper- dividuals (Butler, 1989; Butler, Hanchett, &
ing fingers are usually present by age 10, as Thompson, 2006). Strabismus is often pres-
are short, often broad feet, with an average ent. Scoliosis, kyphosis, or both are common;
adult female shoe size of 3 and male shoe the former can occur at any age, and the lat-
size of 5 (Hudgins, McKillop, & Cassidy, ter develops in early adulthood.
disturbances, especially excessive daytime

sleepiness and oxygen desaturation in rapid-
eye-movement sleep, are common even in
the absence of obesity (Cotton & Richdale,
2006; Hertz, Cataletto, Feinsilver, & Angu-
lo, 1995). Osteoporosis is also frequent.
Despite the multisystem nature of Prader–
Willi syndrome, people with this condition
generally enjoy good health if morbid obe-
sity is avoided. Indeed, parents often report
that their child with Prader–Willi syndrome
is healthier than the child’s unaffected sib-
lings.
Origin and Genetic Basis
FIGURE 25.2. Face of a typical 10-year-old girl Since the first description of Prader–Willi
with Prader–Willi syndrome. Note the relatively syndrome, it has been apparent that many
narrow bifrontal diameter, almond-shaped eyes, of its features arise from insufficient func-
and downturned corners of the mouth. Photo- tioning of the hypothalamus. Thus many of
graph used by permission of the patient’s family. the functions of this part of the brain are
disturbed in Prader–Willi syndrome, includ-
ing control of homeostatic functions such as
hunger, thirst, sleep–wake cycles, and tem-
Short Stature
perature regulation. The hypothalamus also
Birthweight and birth length are usually releases hormones that travel to the pitu-
within normal limits, but the early period of itary gland, controlling the release of other
failure to thrive may mean that both weight hormones such as growth hormone, the sex
and length fall below the 3rd percentile. hormones (gonadotropins), and thyroid-
Short stature, if not apparent in childhood, stimulating hormones (which regulate basal
is almost always present by the second half metabolic rate). Studies of the destruction of
of the second decade, associated with lack the hypothalamus in animals, particularly
of a pubertal growth spurt. Average height cats, show that many of the functional ab-
is 155 cm for males and 148 cm for females. normalities seen in Prader–Willi syndrome
African Americans tend to be taller (Cassidy occur in these animals. Prader–Willi syn-
et al., 1996; Hudgins et al., 1998). Growth drome symptoms are seen as well in cases
hormone deficiency has been demonstrated of previously normal persons with acquired
in most tested patients with Prader–Willi damage to the hypothalamus due to an in-
syndrome, and treatment with growth hor- jury, stroke, or tumor. Even the personal-
mone increases height and lean body mass, ity characteristics seen in Prader–Willi syn-
often resulting in decreased body mass index drome, including the temper tantrums, may
(Angulo et al., 1996; Dudley, McManus, result.
Vogels, Whittington, & Muscatelli, 2008; Because the hypothalamus was a logi-
Lee, 1995). cal place to look for a structural defect in
Prader–Willi syndrome, the few reported
Other Medical Issues autopsy studies have focused on that part
of the brain. Unfortunately, no visible gross
Numerous more minofr physical findings or microscopic structural defect or other ab-
characterize this condition, including thick, normality has been documented that could
viscous saliva that may predispose to den- explain the clinical features of the syndrome.
tal caries and contribute to articulation ab- The hypothalamic deficiency is thus likely
normalities; high pain threshold; skin pick- to be functional, with preliminary findings
ing; and high threshold for vomiting. Sleep suggesting altered function of oxytocin-
s ecreting neurons (putative satiety cells) in termined with the more accurate molecular
the hypothalamic paraventricular nucleus techniques (Delach et al., 1994). However,
(Swaab, 2004; Swaab, Purba, & Hofman, this was the case in only a small propor-
1995). tion of individuals without a visible dele-
Although the exact hypothalamic deficit tion. More interestingly, a seminal study by
has yet to be identified, considerable prog- Nicholls and colleagues (1989) found via
ress has been made in identifying the genetic molecular techniques that most of the re-
basis of Prader–Willi syndrome. At the end of maining patients without a deletion had two
the 1970s, a new technique, high-resolution maternally derived chromosome 15s and
chromosome banding, was developed for no paternally derived chromosome 15—a
analyzing chromosomes in more detail than situation called uniparental disomy (UPD).
was previously possible. This technique op- Thus, instead of inheriting one paternal and
erates by capturing the chromosome in an one maternal chromosome 15 (which is the
earlier stage of the cell cycle, when it is more usual situation), people with Prader–Willi
elongated, thus allowing much greater visi- syndrome who do not have a deletion have
bility of fine chromosome structure. Prior to the syndrome because they have received no
this time, researchers had noted that a num- paternal chromosome 15, but instead have
ber of people with Prader–Willi syndrome two maternal chromosome 15s. The chro-
had a rearrangement of the chromosomes mosomes themselves are normal in number
that involved chromosome 15. Using high- and structure, but the inheritance pattern is
resolution chromosome analysis, Ledbetter wrong.
and colleagues (1981) reported the presence In effect, whether there is a paternal de-
of a small deletion within the long arm of letion or maternal UPD, Prader–Willi syn-
chromosome 15—called del 15(q11—13) drome results from the lack of paternal
in standard chromosome nomenclature— contribution to the specific region of chro-
in about half the people with Prader–Willi mosome 15’s long arm associated with this
syndrome whom they studied. This deletion disorder. Sometimes a person with Prader–
was found to represent a new change in an Willi syndrome due to maternal UPD has
affected individual (de novo deletion), since two copies of the same member of the ma-
neither parent was found to have it. Subse- ternal chromosome 15 pair (isodisomy),
quently, many workers studied series of pa- sometimes both members of the maternal
tients to further delineate the exact location chromosome 15 pair (heterodisomy), and
and frequency of the deletion, which is now sometimes a complicated combination of the
known to occur in approximately 70% of two. However, the composition of the ma-
those with Prader–Willi syndrome (ASHG ternal chromosomes really does not affect
& ACMG, 1996; Butler, 1996). With a the final result, since all the chromosome
few exceptions, the remainder of patients 15s are normal.
with Prader–Willi syndrome have normal- The genetic findings in Prader–Willi
appearing chromosomes under the micro- syndrome can be explained by a phenom-
scope. enon called genomic imprinting. This is a
The development of molecular genetic process whereby genes or groups of neigh-
technology in the late 1980s allowed de- boring genes are modified differently, and
termination of the basis for Prader–Willi thereby expressed differently, depending on
syndrome in patients with normal chromo- the sex of the parent from whom they were
somes. First, molecular techniques allowed inherited. The genes themselves are not al-
investigators to confirm the observation pre- tered, since imprinting is a reversible pro-
viously made under the microscope that the cess. Rather, some genes are inactivated or
deletion, when it was found, occurred solely switched off, so that they no longer produce
in the paternally inherited chromosome 15, RNA and then protein in the process of de-
even though the blood chromosomes of the coding that constitutes gene expression. Al-
father were normal (Butler, 1990; Nicholls though imprinting has been recognized for
et al., 1989). Second, as expected, it was several years in some genes of other animals
found that some people who did not have and plants, Prader–Willi syndrome was the
a deletion visible with chromosomal tech- first human disorder in which it was recog-
niques did have a deletion that could be de- nized. Several other human conditions have
subsequently been found to be related to Several genes have been mapped within
imprinting. The maternally derived copies the Prader–Willi/Angelman region, and oth-
of chromosome 15 in the region critical for ers that are not maternally inactivated have
Prader–Willi syndrome are inactivated in the been mapped between the common deletion
normal situation, and only the paternally de- breakpoints. The first mapped gene, consid-
rived region is expressed in cells. When the ered an important candidate gene, is small
paternal copy of this region is missing—by nuclear ribonucleoprotein N (SNRPN).
deletion or by complete absence, as in ma- This gene is expressed from the paternally
ternal UPD—there is no active copy of the inherited chromosome only (Glenn et al.,
genetic information, and an abnormality 1996; Ozcelik et al., 1992), and is expressed
in development therefore results in Prader– abundantly in the brain. The other identified
Willi syndrome (Kundert, 2008; Nicholls, genes are currently of unknown function.
1993). The nonimprinted P gene, which also resides
Thus, again, Prader–Willi syndrome is in this region, codes for tyrosinase-positive
caused by the absence of the normally ac- albinism, and its deletion probably causes
tive paternally inherited genes at chromo- the hypopigmentation seen in one-third of
some 15(q11-13). In about 70% of cases, it patients with Prader–Willi syndrome (Spritz
is due to a deletion; in most individuals the et al., 1997).
deletion is of the same size, with the same Recently, some clinical differences have
breakpoints on the chromosome. Most of been reported between patients with Prad-
the remaining patients have maternal UPD er–Willi syndrome due to deletion and those
for chromosome 15 (Nicholls et al., 1989; with the syndrome due to UPD (Cassidy et
Mascari et al., 1992; Poyatos et al., 2009; al., 1997; Gillessen-Kaesbach et al., 1995;
Robinson et al., 1991). Approximately 5% Kundert, 2008; Mitchell et al., 1996). Per-
of patients with Prader–Willi syndrome have haps the most clinically significant of these
a translocation or other structural abnor- are that patients with UPD may lack the typ-
mality involving chromosome 15 that has ical facial phenotype (Cassidy et al., 1997),
caused either a deletion or maternal UPD for and that they may have delayed diagnosis
the critical region. UPD usually affects the (Gunay-Aygun & Cassidy, 1997).
whole chromosome 15, but only in the small
region of imprinted genes related to Prader–
Willi syndrome does it matter which parent Diagnosis, Differential Diagnosis,
the chromosome comes from. and Diagnostic Testing
Approximately 1–5% of patients with
Prader–Willi syndrome—including virtually Prior to the availability of complete sensitive
all studied families in which there has been and specific laboratory testing, diagnostic
a recurrence of the syndrome—have neither criteria for Prader–Willi syndrome were de-
deletion nor UPD, but rather have a very veloped through a consensus process (Butler,
small deletion in the center controlling the Hanchett, & Thompson, 2006; Hagerman,
imprinting process within 15q11–13 (Buit- 1999; Holm et al., 1993). These criteria, list-
ing et al., 1994; Poyatos et al., 2009; Saitoh ed in Table 25.1, are still extremely valuable
et al., 1997). Methylation is one mechanism in suggesting the diagnosis and indicating
by which genomic imprinting can occur, and the need for diagnostic testing. It should be
methylation has been demonstrated for sev- emphasized that no one individual will have
eral genes identified within the Prader–Willi all the manifestations of the disorder, and
critical region. Interestingly, a clinically very that there is considerable variability in the
different disorder, Angelman syndrome, is severity of each of the findings.
the result of an oppositely imprinted gene The differential diagnosis for Prader–Wil-
in the same region of chromosome 15 (Wil- li syndrome in infancy includes many causes
liams et al., 1995). In contrast to Prader– of neonatal hypotonia, particularly neuro-
Willi syndrome, people with Angelman muscular disorders. Later in childhood and
syndrome typically have severe to profound adulthood, a number of conditions involving
mental retardation, limited expressive lan- mental retardation with associated obesity
guage, seizure disorder, an ataxic gait, and may be included in the differential diagnosis,
bouts of inappropriate laughter. including Bardet–Biedl syndrome, Albright
TABLE 25.1. Summary of the Clinical Diagnostic Criteria for Prader–Willi Syndrome
Major criteria (1 point each) Minor criteria (½ point each) Supportive criteria (no points)
Infantile central hypotonia Decreased fetal movement and High pain threshold
Infantile feeding problems/failure infantile lethargy Decreased vomiting
to thrive Typical behavior problems Temperature control problems
Rapid weight gain between 1 and Sleep disturbance/sleep apnea Scoliosis and/or kyphosis
6 years Short stature for the family by Early adrenarche
Characteristic facial features age 15 years
Osteoporosis
Hypogonadism: genital Hypopigmentation
hypoplasia, pubertal deficiency Unusual skill with jigsaw puzzles
Small hands and feet for height,
Developmental delay/mental age Normal neuromuscular studies
retardation Narrow hands with straight
ulnar border
Esotropia, myopia
Thick, viscous saliva
Speech articulation difficulties
Skin picking
Note. The diagnosis should be strongly suspected in children under 3 years of age with 5 points, 3 from major criteria; or
in those above 3 years of age with 8 points, 4 from major criteria. The original diagnostic criteria, developed before the
availability of sensitive and specific genetic testing, included a major criteria of chromosome 15 deletion or other chromo-
some 15 anomaly. Items from Holm et al. (1993).
hereditary osteodystrophy, and Cohen syn- with a translocation or inherited microde-

drome (see Gunay-Aygun, Cassidy, & Nich- letion. High-resolution cytogenetic analy-
olls, 1997, for a review). Other disorders sis can often detect the 15q11–13 deletion;
causing mental retardation in which obesity however, this technique has unacceptably
is an occasional finding, such as fragile X, high false-negative and false-positive rates,
Smith–Magenis, and Angelman syndromes, and it is no longer considered sufficient for
may also be confused with Prader–Willi syn- diagnostic purposes. The definitive diagnos-
drome. Acquired hypothalamic injury from tic test for the common size deletion causing
accidents, tumors, or surgical complications Prader–Willi syndrome is fluorescent in situ
can closely mimic Prader–Willi syndrome. hybridization (FISH), using probes within
Two important organizations in genetic the Prader–Willi/Angelman critical region
research, the ASHG and the ACMG, pub- (SNRPN or D15S11). UPD can be detected
lished a statement in 1996 regarding the sta- with polymerase chain reaction; informative
tus of genetic testing for Prader–Willi and microsatellite markers from the Prader–Wil-
Angelman syndromes. Currently, the most li/Angelman region are used to study both
efficient molecular diagnostic test for Prad- parents and the child. Additional markers
er–Willi syndrome examines the parent- from other chromosomes can confirm cor-
specific methylation pattern within the rect paternity.
Prader–Willi/Angelman region, using South- Prenatal detection of Prader–Willi syn-
ern hybridization and methylation-sensitive drome is now possible. FISH is indicated
probes (SNRPN and PW71) (ASHG & when a cytogenetic 15q deletion is suspect-
ACMG, 1996). If the methylation pattern is ed after chorionic villus sampling (CVS) or
characteristic of maternal-only inheritance, amniocentesis. If trisomy 15 is detected on
Prader–Willi syndrome is confirmed; if not, CVS and the fetus survives, parent-of-origin
Prader–Willi due to deletion, UPD, or an studies (methylation analysis or microsat-
imprinting mutation is ruled out. Knowing ellite marker) are indicated and validated
whether the Prader–Willi syndrome is due to (Christian et al., 1996; Kubota et al., 1996).
deletion, UPD, or an imprinting mutation is FISH and parent-of-origin studies are also
important for genetic counseling purposes, indicated if an inherited or de novo translo-
as well as for identifying those few cases cation involving chromosome 15 is detected
prenatally. Parents should be studied in cases Cognitive, Adaptive,

with an identified imprinting mutation, since and Behavioral Phenotype
a healthy parent can carry this abnormality
Cognitive and Adaptive Functioning
and may be at increased risk for recurrence
(Saitoh et al., 1997). Prenatal detection is Cognitive and Adaptive Levels
possible through identification of the muta-
The average IQ reported in most studies of
tion or maternal-only methylation pattern in
a fetus (Kubota et al., 1996). people with Prader–Willi syndrome is about
Prader–Willi syndrome due either to the 70 (e.g., Butler, Hanchett, & Thompson,
large deletion in the absence of a structural 2006; Dykens, Hodapp, Walsh, & Nash,
chromosome abnormality or to UPD has not 1992b). The mean IQ in Prader–Willi syn-
been reported to recur, though a theoretical drome is thus high relative to those in other
recurrence risk of approximately 1% or less genetic disorders (Rosner, Hodapp, Fidler,
is appropriate for genetic counseling pur- Sagun, & Dykens, 2004), including preva-
poses. UPD is caused by nondisjunction, as lent conditions such as fragile X syndrome
evidenced by advanced maternal age in this (Dykens, Hodapp, & Leckman, 1994) or
group (Dudley & Muscatelli, 2007; Mascari Down syndrome (Hodapp, 1996), and less
et al., 1992; Robinson et al., 1991), and by prevalent disorders, such as 5p– syndrome
documentation of cases of trisomy 15 on (Dykens & Clarke, 1997) or Smith–Magenis
CVS and maternal UPD at birth. Since non- syndrome (Dykens, Finucane, & Gayley,
disjunction can recur, a recurrence risk of 1997).
1% is appropriate for genetic counseling. In Although on average people with Prader–
families with an imprinting mutation, a re- Willi syndrome show mild levels of mental
currence risk of up to 50% pertains, as this retardation, their IQ scores range from av-
probably involves a dominant mutation in erage levels to profound mental retardation.
the paternal grandmother’s germ line. Extrapolating IQ data from 575 subjects in
In many ways, then, Prader–Willi syn- 57 published studies, Curfs (1992) found
drome is a model genetic disorder—the that 34% showed mild mental retardation,
source of remarkable new genetic discover- 27% had moderate delays, and only 6%
ies. Now cast as the most common recog- showed severe to profound levels of impair-
nized genetic form of obesity, Prader–Willi ment. Approximately one-third of subjects
has also made genetic history by being the were relatively high-functioning, or with IQs
first recognized human disease associated above 70; 27% showed borderline levels of
with UPD, with genomic imprinting, and intelligence (IQs of 70–84); and 5% showed
with a clinically distinct yet genetically relat- average IQ scores. Whitman and Thompson
ed “sister” syndrome (Angelman syndrome). (2006) have noted a similar distribution.
Furthermore, the search for specific genes in Whittington, Holland, and Webb (2009)
the Prader–Willi/Angelman critical region is have demonstrated that the IQs of patients
now well underway. with Prader–Willi syndrome, considered as
In contrast to these genetic advances, we one diagnostic group, have a low correla-
know much less about Prader–Willi’s com- tion with the IQs of their siblings. However,
plex cognitive and behavioral phenotype. when genetic subtypes are considered, the
Findings to date, however, suggest that IQ scores of patients with UPD are just as
Prader–Willi syndrome is also a promising correlated with those of their siblings as the
condition for studying behavioral pheno- IQs of siblings without the syndrome would
types of mental retardation syndromes in be, whereas the IQ scores of patients with
general (Dykens, 1995; Hodapp & Fidler, the deletion subtype show almost no correla-
1999; Holland et al., 2003; Martin et al., tion with those of their siblings.
1998). As described in the remainder of the Even high-functioning individuals, how-
chapter, many people with Prader–Willi ever, rarely perform adaptively at a level
syndrome show a blend of unusual cognitive commensurate with their IQs. Adaptive
styles, maladaptive behaviors, and psychi- functioning is typically viewed as the per-
atric vulnerabilities that may prove unique, formance of behaviors required for personal
and that open up specific avenues of treat- or social sufficiency (Sparrow, Balla, & Cic-
ment and intervention. chetti, 1984). Clinical observations in Prad-
er–Willi syndrome often suggest impaired Achievement studies, however, do not

adaptive functioning, yet only one study has provide overwhelming support for a specific
formally assessed adaptive behavior in this learning disability profile in Prader–Willi
population. Dykens and colleagues (1992b) syndrome. Administering the Kaufman As-
administered a standardized assessment in- sessment Battery for Children (K-ABC; Kauf-
strument, the Vineland Adaptive Behavior man & Kaufman, 1983) to 21 adolescents
Scales (Sparrow et al., 1984), to caregivers and adults with Prader–Willi syndrome,
of 21 adolescents and young adults with Dykens and colleagues (1992b) found a non-
Prader–Willi syndrome. These subjects significant discrepancy in age-equivalent
showed adaptive behavior composite stan- scores in arithmetic versus reading (7.68
dard scores that ranged from 20 to 50, all years vs. 8.55 years, respectively). Further-
in the moderate to severe range of delay. The more, Taylor (1988) examined an unspeci-
mean Vineland composite standard score fied number of individuals with Prader–Wil-
was 37, which fell more than two standard li syndrome, and reported a mean standard
deviations (31 points) below subjects’ mean achievement test score of 70 in math and 73
IQ of 68. As discussed later, low adaptive in reading. More recent data from studies by
performance is probably associated with in- Whittington and colleagues (2004a), which
terference from significant behavioral dys- demonstrated a pattern of greater academic
function and a persistent drive to eat. underachievement in arithmetic as compared
to reading or spelling in a population-based
sample of individuals with Prader–Willi
Cognitive Level and Weight
syndrome, and by Bartella and colleagues
Early work in Prader–Willi syndrome sug- (2005), which documented impairments in
gested a significant inverse correlation be- mathematical abilities in a sample of indi-
tween IQ and weight (Crnic, Sulzbacher, viduals with Prader–Willi syndrome, sup-
Snow, & Holm, 1980); that is, lower IQ port findings from earlier studies. However,
scores were believed to be associated with such findings only hint at uneven academic
increased weight. It was even suggested that performance. Clearly, more studies are need-
prevention of obesity might also prevent ed on the extent to which individuals with
mental retardation. Yet common lore in the Prader–Willi syndrome show discrepancies
Prader–Willi syndrome community actually across areas of academic achievement, as
suggests the opposite relationship; that is, well as between achievement and IQ.
brighter individuals may be more clever or Only a few studies have moved beyond ac-
ingenious about obtaining food, and thus ademic achievement to identify other aspects
may be at increased risk of obesity. More re- of cognitive processing in people with Prad-
cent data do not support either hypothesis: er–Willi syndrome. Examining global cogni-
Dykens and colleagues (1992b) and Whit- tive patterns on Wechsler tests, Borghgraef,
tington and colleagues (2004b) found no Fryns, and Van den Berghe (1990) reported
significant relations between IQ and body “great differences” (p. 148) in Verbal versus
mass index (a measure of obesity). Persons Performance IQ scores in 8 of their 12 sub-
with relatively high versus low IQ scores thus jects with Prader–Willi syndrome. Three of
seem similarly vulnerable to the syndrome’s these individuals showed at least a 15-point
problems with obesity. discrepancy in favor of the Verbal IQ. Sig-
nificant Verbal versus Performance IQ dif-
ferences were also found in a study of 26
Cognitive Profiles
children with Prader–Willi syndrome (ages
Early clinical observations suggested that 7–15 years); 10 subjects showed elevations in
many children with Prader–Willi syndrome the Performance IQ, and 3 in the Verbal IQ
showed significant relative strengths in (Curfs, Wiegers, Sommers, Borghgraef, &
reading and weaknesses in arithmetic (e.g., Fryns, 1991). In contrast, Whittington and
Holm, 1981; Sulzbacher, Crnic, & Snow, colleagues (2004b) noted that individuals
1981). These informal observations led to with Prader–Willi syndrome due to deletion
the idea that cognition in this syndrome performed better on verbal measures. Find-
was best characterized by uneven academic ings are thus inconsistent.
performance, as found in youngsters with More detailed studies of specific cognitive
learning disabilities. processes shed some light on these inconsis-
tent findings. Table 25.2 summarizes these the form of leisure activities has been corre-
studies. Taylor (1988) compared Wechsler lated with decreased maladaptive behaviors
subtest scores in an unspecified number of in such individuals (Sellinger, Hodapp, &
subjects with Prader–Willi syndrome to Dykens, 2006). This skill is so striking that
those in a sample of individuals with obesity it is noted as a supportive finding in the con-
and mental retardation but without Prader– sensus diagnostic criteria for Prader–Willi
Willi syndrome. The two groups showed syndrome (Holm et al., 1993). Clinically, we
comparable subtest scores, with just one ex- observe as well that many adolescents and
ception: Relative to the controls, the subjects young adults have a strong propensity for
with Prader–Willi syndrome showed signifi- “word search” puzzles, often carrying their
cantly higher scores on Block Design, a task word-fi nding books with them to school or
tapping visual–motor integration. Similar- work. Individuals with Prader–Willi syn-
ly, Curfs and colleagues (1991) found that drome have been noted to perform on par
one-half of their sample showed significant with their typical peers on word search tasks
Wechsler subtest scatter, and that 9 of these (Dykens, 2002). We also found that subject
13 children had relative strengths in Block performance on a visual memory task was
Design. These findings suggest strengths in correlated with parental reports of subject
some individuals in perceptual–spatial orga- interest and facility with jigsaw and word
nization and visual–motor integration. search puzzles. Recent studies have exam-
Consistent with these strengths, many ined parents’ attributions of jigsaw puzzle
people with Prader–Willi syndrome show an performance and how performance is related
unusual facility with jigsaw puzzles (Dykens, to parent assistance on such visual–spatial
2002). In addition, engaging these skills in tasks (Ly & Hodapp, 2005a, 2005b), as well
TABLE 25.2. Summary of Cognitive and Adaptive Studies in People

with Prader–Willi Syndrome
Study Number and age of subjects Key findings
Cognitive processing
Curfs et al. 26 with PWS, 7–15 years WISC-R Performance IQ > Verbal IQ in 10 subjects.
(1991) Verbal IQ > Performance IQ in 3 subjects. Block
Design high in 9 subjects.
Dykens et al. 21 with PWS, 13–26 years K-ABC Simultaneous Processing > Sequential
(1992a) 31 with PWS, 5–30 years Processing. Strengths: Visual-perceptual. Weaknesses:
Visual–motor short-term memory. Stable IQ in
childhood and adulthood.
Gabel et al. 15 with PWS, M = 12 years Controls exceeded PWS on all measures. For PWS
(1986) 15 nondisabled controls on Detroit Test of Learning Aptitude, visual recall of
objects, letters > auditory recall of words.
Taylor (1988) Unspecified with PWS On WISC-R, PWS > controls on Block Design only.
Controls with obesity/mental
retardation
Warren and Hunt 11 with PWS, age unknown On pictorial memory tasks, PWS < nonspecific
(1981) 12 with nonspecific etiologies, group in visual short-term memory; PWS had no
matched on age and IQ improvements in Performance with increasing age or
IQ; PWS on par with nonspecific group in long-term
memory for well-known information.
Adaptive behavior
Dykens et al. 21 with PWS, 13–26 years On Vineland, strengths in Daily Living Skills
(1992b) (especially domestic skills), weaknesses in
Socialization (especially coping skills); modest
increases in adaptive skills with advancing age.
Note. PWS, Prader–Willi syndrome; WISC-R, Wechsler Intelligence Scale for Children—Revised; K-ABC, Kaufman
Assessment Battery for Children.
as strategies and correlates of jigsaw puzzle tive to their counterparts, the children with
performance in individuals with Prader– Prader–Willi syndrome showed more dif-
Willi syndrome (Verdine, Troseth, Hodapp, ficulties with immediate visual memory, no
& Dykens, 2008). However, additional stud- improvements in recall of stimuli with either
ies are needed that better relate facility with increasing mental or chronological age, and
puzzles to cognitive profiles, and that deter- a greater loss of information over time. In
mine exactly how widespread puzzle-solving contrast to these short-term memory deficits,
skills are in this population. the children with Prader–Willi performed
Visual processing strengths are also sug- on par with the control group in a long-
gested by Gabel and colleagues (1986), term memory task assessing how quickly
who administered a battery of attentional, subjects recalled well-known information.
visual–spatial, and psychomotor tasks to 15 Interestingly, parents often report that their
children with Prader–Willi syndrome and offspring with Prader–Willi syndrome can
15 age- and sex-matched nondisabled chil- recall well-known or more obscure facts
dren. Not surprisingly, the children with with a remarkable level of detail (e.g., where
Prader–Willi scored consistently lower than people parked as they arrived for a family
the controls; however, they also showed dis- party years ago). As suggested by Warren
crepancies in scores on subtests of the De- and Hunt’s (1981) findings, however, this
troit Tests of Learning Aptitude (Baker & type of recall is not likely to prove unique to
Leland, 1967). Specifically, these subjects Prader–Willi syndrome.
had relatively low scores on tasks assess- In summary, then, some people with Prad-
ing auditory attention and recall for words, er–Willi syndrome show relative strengths
and high scores on tasks measuring visual in spatial–perceptual organization and vi-
attention and recall for objects and letters. sual processing. Relative weaknesses may
Gabel and colleagues conclude that young- be apparent in short-term memory, includ-
sters with Prader–Willi syndrome may have ing visual, motoric, and auditory short-term
strengths in visual processing relative to au- processing. Although findings suggest a dis-
ditory processing. tinctive cognitive profile, not all persons with
Further work has clarified and expanded Prader–Willi syndrome show this profile.
certain aspects of the apparent strengths Studies are needed that identify the range
in visual processing. In the administration of cognitive profiles seen in this syndrome,
of the K-ABC to 21 subjects, Dykens and including how variables such as age or IQ
colleagues (1992b) found that Simultane- may relate to different cognitive patterns.
ous Processing was better developed than Cognitive profiles identified to date in Prad-
Sequential Processing. High scores were er–Willi syndrome may be shared among
noted in tasks assessing perceptual closure, people with other genetic syndromes or with
long-term memory, spatial organization, at- nonspecific etiologies. Additional compara-
tention to visual detail, and visual–motor tive studies are thus necessary to settle the
integration. Among the Sequential Process- issue of whether Prader–Willi syndrome is
ing tasks, which rely on short-term memory, associated with a unique profile of cognitive
subjects showed particular difficulties with or academic strengths or weaknesses.
visual–motor and auditory–visual short-
term memory. A profile is thus suggested
Adaptive Profiles
for some individuals with Prader–Willi syn-
drome: relative strengths in perceptual orga- Deficits in specific domains of adaptive be-
nization, and difficulties in visual and other havior are salient in the definition and di-
short-term memory tasks. agnosis of mental retardation (see Hodapp
Indeed, visual processing strengths may & Dykens, 1994, for a review). Despite their
not always be readily apparent, especially nosological prominence, however, little is
in short-term memory tasks. In a series of known about the adaptive strengths and
studies assessing pictorial short-term mem- weaknesses of people with specific syn-
ory, Warren and Hunt (1981) compared dromes, including those with Prader–Willi
11 children with Prader–Willi syndrome to syndrome (Dykens, 1995). In one study of
age- and IQ-matched children with mental adolescents and adults with Prader–Willi
retardation of nonspecific etiologies. Rela- syndrome, relative strengths were found
on the Daily Living Skills domain of the nesses (e.g., Van Borsel, Defloor, & Curfs,
Vineland Adaptive Behavior Scales, espe- 2007). Branson (1981) found no common
cially in domestic skills such as cooking and features in the language profiles of 21 chil-
cleaning (Dykens et al., 1992a). As noted dren with Prader–Willi syndrome. Similarly,
in Table 25.2, these same subjects showed various linguistic profiles were observed in
significant relative weaknesses in the Social- 18 children by Kleppe, Katayama, Shipley,
ization domain, notably in the coping skills and Foushee (1990). Differences were seen
subdomain. across subjects’ severity of speech and lan-
Although distinctive, these profiles are guage problems, and in the range of their
not unique to Prader–Willi syndrome. intelligibility, fluency, and voice problems.
Males with fragile X syndrome, for exam- Kleppe and colleagues did, however, find
ple, showed relative strengths in Daily Liv- some common speech–language character-
ing Skills on the Vineland (Dykens, Hod- istics, primarily hypernasality, errors with
app, & Leckman, 1994), and females with certain speech sounds and complex syntax,
fragile X syndrome had relative weaknesses and reduced vocabulary skills relative to age
in Socialization (Freund, Reiss, & Abrams, expectations. The speech and articulation
1993). However, the reasons for these simi- difficulties are likely to be associated with
lar profiles are likely to be different across hypotonia, and perhaps with thick, viscous
syndromes. In individuals with Prader–Willi saliva (Kleppe et al., 1990). More recent
syndrome, strengths in cooking or clean- findings further support the presence of ar-
ing seem consistent with interests in food, ticulation errors, oral–motor difficulties,
whereas these same skills in males with frag- and hypernasality in young children with
ile X syndrome may be related to the repeti- Prader–Willi syndrome (Lewis, Freebairn,
tive, rote nature of these daily living tasks Heeger, & Cassidy, 2002). Speech problems,
(Dykens, Hodapp, & Leckman, 1994). The primarily with articulation and intelligibil-
weaknesses in coping skills seen in Prader– ity, were also noted by 33 out of 43 parents
Willi syndrome are likely to be associated of children with Prader–Willi syndrome
with the impulsivity, temper tantrums, and ages 4–19 years (Dykens & Kasari, 1997).
compulsive tendencies that characterize this Akefeldt, Akefeldt, and Gillberg (1997), in
syndrome (Dykens & Cassidy, 1995; Oliver, addition to Defloor, Van Borsel, and Curfs
Woodcock, & Humphreys, 2009; Wood- (2000), have documented significant impair-
cock, Oliver, & Humphreys, 2009). Among ments in word recall and syntax. In addition,
females with fragile X syndrome, however, individuals with Prader–Willi syndrome
problems with Socialization are seen pri- often talk too much and verbally persever-
marily in the interpersonal subdomain, ate on a narrow range of topics (Dykens,
and are probably related to that syndrome’s Leckman, & Cassidy, 1996). It remains un-
proneness to shyness, gaze aversion, and so- known, however, how perseveration relates
cial anxiety (Freund et al., 1993). Although to such linguistic features as pragmatics, dis-
Vineland profiles may thus be similar across course, and the social uses of language.
these or other syndromes, the factors associ-
ated with these profiles are likely to be dif-
Cognitive and Adaptive Development
ferent.
Data are limited on how cognition in people
with Prader–Willi syndrome changes over
Linguistic Profiles
the course of development. An early study of
Language development in children with eight children with the syndrome reported
Prader–Willi syndrome is typically delayed, that IQ declined in early childhood (Dunn,
though expressive vocabulary and language 1968). It was unclear, however, whether
may eventually emerge as areas of strength for these declines were assessed by formal IQ
many youngsters with the syndrome. Studies tests or by a failure to achieve certain devel-
that have examined speech–language issues opmental milestones.
in people with Prader–Willi syndrome have Using standardized IQ scores, Dykens
noted significant variability across individu- and colleagues (1992b) conducted both
als with regard to speech–language develop- cross-sectional and longitudinal analyses of
ment and patterns of strengths and weak- IQ change in children and adults. IQ scores
were cross-sectionally examined in 21 ado- ies need to be conducted that examine how
lescents and adults, and longitudinal analy- the onset or severity of hyperphagia affects
ses included 31 subjects ages 5–30 years who a young child’s developing cognitive or be-
had been given the same IQ test twice. IQ havioral schemas. Given the central role of
scores showed nonsignificant fluctuations in hyperphagia in Prader–Willi syndrome, we
both cross-sectional and longitudinal analy- suspect that this effect is far-reaching. It
ses, with no evidence of IQ declines in child- may be, for example, that the young child
hood or early adulthood. Overall IQ scores with Prader–Willi syndrome develops cogni-
thus appear relatively stable in school-age tive or behavioral schemas to accommodate
children with Prader–Willi syndrome, re- to hyperphagia, such as more attention to
flecting slow and steady gains in mental age some stimuli than to others, or tantrums or
that then stabilize in the adult years. anxiety when food is denied. These strate-
Regarding their levels of adaptive skills, gies may then stay with the child over time;
adolescents and young adults with Prader– may spill over into areas unrelated to food;
Willi syndrome seem to show steady gains and may ultimately contribute to the per-
in certain aspects of their adaptive behavior, severative, compulsive-like behaviors, tan-
primarily their daily living and socialization trums, and other problems that characterize
skills (Dykens et al., 1992a; Holland et al., Prader–Willi syndrome.
2003). Longitudinal studies are necessary to
clarify these preliminary findings, as well as
to identify how gains in adaptive skills relate Maladaptive Behavior
to age, IQ, residential placement, and educa- and Psychopathology
tional or vocational programming. Range of Maladaptive Behavior
Findings to date thus point to a different
course of cognitive and adaptive develop- Most behavioral work in Prader–Willi syn-
ment in people with Prader–Willi syndrome, drome focuses on maladaptive features and
compared to people with some other genetic psychopathology. These problems are often
syndromes. Some children with Down syn- severe, and they immediately capture our at-
drome, for example, show alternating peri- tention as both clinicians and researchers.
ods of growth and stability in their cogni- Although the behavioral dysfunction is com-
tive, adaptive, and linguistic development pelling, studies of it have been accomplished
(Dykens, Hodapp, & Evans, 1994; Hodapp at the expense of research on the personality
& Zigler, 1990). Many males with fragile X and psychosocial strengths of people with
syndrome show slow, steady gains in cogni- Prader–Willi syndrome. Although studies of
tive and adaptive functioning that seem to strengths in people with Prader–Willi syn-
stabilize in late childhood or early adoles- drome are now underway, at this time we
cence, resulting in a plateau in mental age know very little about how social competen-
scores and decline in IQ and adaptive be- cies or personality strengths relate to behav-
havior standard scores (Dykens, Hodapp, ioral dysfunction and psychopathology.
& Leckman, 1994). Different trajectories Anecdotally, young children with Prad-
across Prader–Willi and other syndromes er–Willi syndrome are described as pleas-
call into question the idea that people with ant, friendly, social, and somewhat placid
mental retardation are uniform in their (Cassidy, 1984). These features do not nec-
course of slowed development, regardless of essarily disappear, but older children and
their etiology (Hodapp, 2004; Hodapp & adults are routinely described as showing a
Fidler, 1999; Silverstein, 1982). host of negative or maladaptive behaviors,
In addition to comparative studies, lon- with young adults showing the greatest
gitudinal work is sorely needed that relates risk (Dykens, 2004; Steinhausen, Eiholzer,
cognitive and adaptive development to the Hauffa, & Malin, 2004). Often these behav-
onset of hyperphagia in young children iors are more difficult to manage than food
with Prader–Willi syndrome. The severity of seeking, and they pose multiple challenges to
non-food-related maladaptive behaviors has families, teachers, and clinicians (Dykens &
been shown to be related to the severity of Hodapp, 1997).
eating behavior (Dimitropoulos, Blackford, Characteristic behavior problems are noted
Walden, & Thompson, 2006). More stud- as minor criteria in the consensus diagnostic
criteria for Prader–Willi syndrome (Holm those of Achenbach’s (1991) clinically re-
et al., 1993), with often-noted problems in- ferred sample. Among the 61 adolescents
cluding temper tantrums, stubbornness, op- and adults, 85% had one or more clinically
positionality, rigidity, lying, and stealing. elevated subtest scores on the Reiss Screen,
Many persons with this syndrome are also with most (72%) showing two or more clini-
described as quite clever and manipulative, cal elevations (Dykens & Cassidy, 1995).
especially in regard to obtaining food. Maladaptive behaviors thus often reach a
The frequency and severity of maladap- point where further clinical evaluation and
tive behaviors were examined in more de- interventions are necessary (Dykens & Hod-
tail in two different samples of subjects app, 1997).
with Prader–Willi syndrome. We adminis-
tered the Child Behavior Checklist (CBCL;
Specificity of Maladaptive Features
Achenbach, 1991) to parents and caregivers
of 91 subjects with Prader–Willi syndrome Although certain behaviors are both salient
(subjects were ages 4–47 years). Maladap- and clinically significant in Prader–Willi syn-
tive behaviors that occurred in 50% or more drome, studies have yet to compare these fea-
of the sample are summarized in Table 25.3. tures to those of other persons with mental
Certain behaviors were seen in 75% to al- retardation. In particular, we do not know
most 100% of subjects, including skin pick- which maladaptive features are specific to
ing, argumentativeness, stubbornness, ob- Prader–Willi syndrome, which are shown by
sessions, tantrums, underactivity, excessive many persons with mental retardation, and
sleep, compulsions, and anxiety. which are shared by persons with only a few
We administered a different measure, the other etiologies of mental retardation.
Reiss Screen for Maladaptive Behavior, to At first glance, hyperphagia appears a
parents and caregivers of 61 adolescents and unique aspect of Prader–Willi syndrome. Al-
adults with Prader–Willi syndrome (subjects though some people with mental retardation
were ages 13–49 years) (Dykens & Cassidy, show increased interests in food or propen-
1995). Certain behaviors were remarkably sities to being overweight (Prasher, 1995),
consistent across samples and measures, in- these generally do not occur to the same
cluding temper tantrums (84%), overeating degree as in Prader–Willi syndrome. Other
(81%), impulsivity (74%), and aggression behaviors, such as temper tantrums, argu-
(64%). mentativeness, or stubbornness, are seen in
The majority of subjects in both samples many persons with mental retardation in
had scores that reached clinically significant general.
levels. Among the 91 children and adults, Although persons with Prader–Willi syn-
82% had CBCL T-scores consistent with drome are not unique in all aspects of mal-
TABLE 25.3. Frequently Occurring CBCL Behaviors in 91

Individuals with Prader–Willi Syndrome (Ages 4–47 Years)
Behavior % Behavior %
Skin picking 97 Mood changes 76
Argues a lot 95 Excessive sleep 75
Stubborn 95 Steals (food) 71
Obsessions 94 Compulsions 71
Overeating 93 Worried, anxious 70
Tantrums 88 Talks too much 68
Underactive 87 Prefers being alone 67
Overtired 81 Can’t concentrate 66
Clumsy 80 Gets teased a lot 65
Disobedient 78 Speech problems 65
Demands attention 78 Peers don’t like 60
Lies (food-related) 78 Hoards 55
Overweight 77 Withdrawn 53
Impulsive 76 Unhappy, sad 51
adaptive behavior, certain behaviors may like behaviors also seem to be central distin-
be more common in this population than in guishing features of this syndrome.
others with mental retardation. Dykens and
Kasari (1997) compared 43 subjects with
Correlates of Maladaptive Behavior
Prader–Willi syndrome (ages 4–19 years) to
age- and sex-matched subjects with Down Most studies do not find significant gender
syndrome and nonspecific mental retarda- differences in the maladaptive behavior of
tion. On the CBCL (Achenbach, 1991), sub- people with Prader–Willi syndrome. Three
jects with Prader–Willi syndrome showed other variables, however, do relate to mal-
significantly higher levels of internalizing, adaptive behavior, sometimes in unexpected
externalizing, and overall problem behav- ways: IQ scores, weight, and family stress.
iors. These individuals were also more apt to
overeat and be overweight; to be teased by
IQ Scores
peers; and to show skin picking, argumen-
tativeness, verbal perseveration, obsessions, A central issue is whether people with rela-
compulsions, fatigue, sleep problems, un- tively high IQ scores are somehow protected
deractivity, and stealing at home (primarily from some of the syndrome’s more trouble-
food or money to buy food). some maladaptive behaviors. A high IQ
A discriminant-function analysis of these often emerges as a protective factor in chil-
CBCL data suggested a relatively distinct dren who are at risk for delay or adjustment
Prader–Willi syndrome behavioral pheno- problems, or who are experiencing psycho-
type, with 91% of the persons with Prader– social adversities (Garmezy, Masten, & Tel-
Willi syndrome correctly classified, and just legen, 1984; although see also Luthar, 1991,
3 of the 86 comparison group subjects mis- and Werner, 2005). We (Dykens & Cassidy,
takenly assigned to the Prader–Willi group. 1995) tested this possibility by comparing 43
As shown in Table 25.4, seven behaviors subjects with relatively high IQs (mean IQ of
best discriminated the three groups, with 79) to 43 subjects with lower IQs (mean IQ
the Prader–Willi group being singularly of 59). No significant differences were found
high in skin picking, fatigue, obsessions, and in either the type or severity of maladaptive
talking too much. Thus a blend of certain behavior across groups.
maladaptive behaviors appears quite distinc- These data, which are consistent with
tive to Prader–Willi syndrome, and may be clinical observations of patients with Prad-
highly predictive of this disorder. Overeat- er–Willi syndrome, have important implica-
ing, food obsessions, and sleep disturbances tions for service delivery. In particular, state
are salient in Prader–Willi syndrome; yet or other agencies that use low IQ scores
other obsessions and repetitive, compulsion- (usually below 70) as a service eligibility re-
TABLE 25.4. Seven Behaviors That Discriminated Children

with Prader–Willi Syndrome from Those with Down Syndrome
and Nonspecific Mental Retardation with 91% Accuracy
Prader–Willi Nonspecific
Behavior syndrome Down syndrome mental retardation
Skin picking High Low Low
Overtired High Low Low
Obsessions High Low Low
Impulsivity High Low High
Speech problem High Low Low/high a
Hyperactive Low Low High
Note. Items from Dykens and Kasari (1997).

a“Lower than subjects with Prader–Willi syndrome, higher than subjects with Down syn-
drome.
quirement may exclude higher-functioning shift and change over the course of devel-
persons whose treatment needs are similar opment. The beginning of hyperphagia in
to those of lower-functioning persons. In early childhood is often associated with
Prader–Willi syndrome, then, IQ may be the onset or worsening of such behaviors
a less meaningful entry point into state or as temper tantrums and aggression (Dim-
other systems of care than are the behavioral itropoulos, Fuerer, Butler, & Thompson,
needs of the persons being served. 2001; Dykens, Maxwell, Pantino, Kossler,
& Roof, 2007). These behaviors then seem
fairly stable across the developmental years.
Weight
Dykens and Cassidy (1995) found similar
Unlike IQ, maladaptive behavior may be rates of tantrums and other “externalizing”
related to weight, but in a way that is op- behaviors in young children (ages 4–7 years)
posite to general expectations. Dykens and and in older children (ages 8–12 years). Yet
Cassidy (1995) found that thinner adults advancing age in these same children was
(i.e., those with lower body mass indices) correlated with heightened internal distress
had significantly higher maladaptive behav- and features of depression, including with-
ior scores than heavier persons (i.e., those drawal, isolation, negative self-image, and
with higher body mass indices), notably in pessimism.
internalizing symptoms. Specifically, thin- Some clinical reports note that behavior-
ner subjects showed more distressful affect al problems increase in the adolescent and
and problems in thinking—confused and adult years, due to growing physical and
distorted thinking, anxiety, sadness, fearful- psychosocial pressures (Greenswag, 1987;
ness, and crying. These findings need to be Whitman & Accardo, 1987). In contrast,
further explored, including how they relate others observe clinically that behavioral and
to the stress of losing weight, as well as to emotional problems lessen with advancing
changes in brain chemistry and physical ac- age, and that older adults with Prader–Willi
tivity level. syndrome may be more amenable to inter-
vention (Waters, 1990).
Yet changes in maladaptive behavior
Family Stress
may not follow a simple linear function. In-
Finally, maladaptive behaviors are signifi- stead, these behaviors may wax and wane
cantly related to heightened levels of familial throughout adulthood (Dykens & Cassidy,
stress (Dykens et al., 1996; Hodapp, Dykens, 1995; Dykens et al., 1992a). Whereas some
& Masino, 1997). Behavior problems in behaviors may increase with age, others may
offspring with Prader–Willi syndrome (es- improve or remain fairly stable. Examining
pecially externalizing problems, such as 21 adolescents and adults cross-sectionally
tantrums and aggression) are the best pre- with the CBCL, Dykens and colleagues
dictors of familial stress, even in comparison (1992a) found that underactivity and fatigue
with such features as the offspring’s age, sex, increased with age, whereas certain “exter-
IQ level, or degree of obesity. Furthermore, nalizing” difficulties (e.g., running away and
stress in families of children with Prader– destroying property) decreased from ado-
Willi syndrome is high relative to stress lescence to adulthood. Still other behaviors
in families of children with other types of seemed to be fairly stable, such as temper
mental retardation (Hodapp et al., 1997). tantrums, stubbornness, skin picking, and
Although parents are often most concerned hoarding (Dykens et al., 1992a).
about their children’s tantrums and compul- The waxing and waning of behavior prob-
siveness, these problems probably interact lems may sometimes be associated with spe-
with hyperphagia and the lifelong need for cific psychosocial stressors. Many young
dietary management to create high levels of adults, for example, experience increased
stress. behavioral difficulties when they leave home
and move into a group home setting, or
when they make the transition from one job
Development of Maladaptive Behavior
to another. In other persons, however, psy-
It is not yet clear how maladaptive features chosocial precipitants for behavioral shifts
in persons with Prader–Willi syndrome are not apparent.
Psychiatric Features mental retardation and psychiatric disorder

across behavioral domains; an exception
The vast majority of studies in dual diagno-
was that the Prader–Willi sample displayed
sis, or co-occurring mental retardation and
less severe mood symptoms than the dual-
psychiatric illness, have used heterogeneous diagnosis group.
groups of subjects with mental retardation Furthermore, Prader–Willi syndrome
of mixed or unknown etiologies (Dykens, does not appear to include a heightened risk
1996). As a result, more is known about psy- of autism or pervasive developmental dis-
chiatric illness in the general, heterogeneous order not otherwise specified (PDD-NOS),
population of people with mental retarda- beyond the risk due to mental retardation.
tion than in persons whose mental retarda- Of the handful of patients with Prader–
tion has specific genetic etiologies. Willi syndrome and co-occurring autism or
Partly because of this mixed-group ap- PDD NOS that we have seen in the clinical
proach, little is yet known about the prev- setting, however, all had maternal UPD of
alence rates of psychiatric disorders in the chromosome 15. These clinical observations
population of persons with Prader–Willi are consistent with those of Rogan and col-
syndrome. Although population-based prev- leagues (1994) and Veltman and colleagues
alence studies have yet to be done, clinically (2004), who suggested increased risks of au-
we find that certain psychiatric disorders tism or other, rare disorders in Prader–Willi
occur infrequently. For example, although syndrome cases involving maternal UPD of
many people with Prader–Willi syndrome chromosome 15.
steal food, and are impulsive and distract- However, several other psychiatric disor-
ible, rates seem low for full-blown conduct ders may occur with increased frequency in
disorder or attention-deficit/hyperactiv- persons with Prader–Willi syndrome. These
ity disorder. Tic disorders, dementia, and include mood disorders, as well as obsessive–
schizophrenia also appear relatively infre- compulsive disorder (OCD) and other anxi-
quently in this population. However, Clarke ety disorders. Depressive features such as
(1993) and Clarke, Webb, and Brachmann- sadness and low self-esteem, as well as anxi-
Clarke (1995) reported on psychotic epi- ety, fears, and worries, have all been noted
sodes in four young adults with Prader– in several studies of maladaptive behavior in
Willi syndrome; all cases showed a paternal Prader–Willi syndrome (e.g., Dykens et al.,
deletion of chromosome 15. These patients 1992a; Dykens & Cassidy, 1995; Dykens &
had a sudden onset of hallucinations and Kasari, 1997; Stein, Keating, Zar, & Hol-
other psychotic symptoms, with no obvious lander, 1994; Whitman & Accardo, 1987).
precipitating events. All showed good out- Among 91 children and adults assessed with
come following milieu and pharmacological the CBCL, for example, we found that 76%
treatment. These cases suggest a need for showed mood lability; 70% were worried or
large-scale studies that can identify whether anxious; and 51% showed sadness, depres-
Prader–Willi syndrome involves a particular sion, and withdrawal.
vulnerability to schizophrenia-spectrum dis- Only recently have studies examined
orders, above and beyond the risk associated samples with Prader–Willi syndrome using
with mental retardation. formal Diagnostic and Statistical Manual
Reddy and Pfeiffer (2007) compared a of Mental Disorders, fourth edition, text
sample of patients with Prader–Willi syn- revision (DSM-IV-TR; American Psychiatric
drome to a sample with mental retardation Association [APA], 2000) or International
only and another having mental retardation Classification of Diseases, 10th revision
and comorbid psychiatric disorder. Their (ICD-10; World Health Organization, 1992)
findings suggested that youth with Prader– diagnostic criteria for depressive disorders,
Willi syndrome displayed significantly high- or for anxiety disorders other than OCD.
er rates of psychopathology, both of an in- Soni and colleagues (2007) confirmed ear-
ternalizing and externalizing nature, when lier work suggesting that psychiatric illness
compared to peers with mental retardation in individuals with Prader–Willi is predomi-
only. In fact, the behaviors noted in the nantly mood- or anxiety-related in nature. In
sample with Prader–Willi were comparable addition, those participants with UPD were
to those seen in the sample with comorbid shown to have greater severity, risk of recur-
rence, and number of episodes, and a worse trash, and toiletries (58%); rewriting and re-
response to medication, than the partici- doing things (37%); and concerns with sym-
pants with deletion had. It thus remains un- metry, exactness, ordering, and arranging
known to what extent the sadness or worry (35–40%). Over half of the subjects (53%)
shown by some persons with Prader–Willi also had to tell, ask, or say things, often
syndrome might lead to full-blown cases of perseverating on a narrow range of top-
these disorders. It is also unclear what fac- ics. Relatively fewer subjects had cleaning,
tors might predispose some persons with the contamination, or checking symptoms (15–
syndrome to be more or less susceptible to 24%). Thus, for instance, many subjects in
mood or anxiety disorders. this study often ordered and arranged toys
Increased risks of OCD have been found in or objects according to specific rules based
persons with Prader–Willi syndrome. Com- on size, shape, or color, or simply until they
pulsive-like symptoms have long been hall- were “just right.” Others rewrote letters or
mark features of Prader–Willi syndrome— words until they were just right, or could not
primarily skin picking, food preoccupations, tolerate slight imperfections in the environ-
and repetitive food-seeking behaviors (e.g., ment.
Didden, Korzilius, & Curfs, 2007; Dykens Furthermore, as specified in the DSM-IV
et al., 1992a; Hellings & Warnock, 1994; criteria for OCD (APA, 1994), a remarkably
Holm et al., 1993; Stein et al., 1994). Yet high proportion of subjects had moderate
many persons show repetitive thoughts and to severe levels of obsessive and compulsive
compulsive behaviors not related to skin symptomatology. Indeed, 64% showed at
picking or food (Clarke et al., 2002; Greaves, least a moderate level of symptom-related
Prince, Evans, & Charman, 2006; Wigren distress, and 80% had symptom-related
& Hansen, 2005) that may not subside with adaptive impairment. Other ties between
age (Wigren & Hansen, 2003b). Prader–Willi syndrome and OCD were
Dykens and colleagues (1996) identified found by comparing 43 adults with Prader–
a wide range of non-food-related obsessions Willi syndrome to age- and sex-matched
and compulsions in a study of 91 children nonretarded adults with OCD (Dykens et
and adults with Prader–Willi syndrome. As al., 1996). As shown in Table 25.5, the two
measured by the Yale–Brown Obsessive– groups showed similar levels of symptom se-
Compulsive Scale (Goodman et al., 1989), verity, similar numbers of compulsions, and
prominent compulsions in this sample in- more areas of symptom similarity than dif-
cluded hoarding items such as paper, pens, ference.
TABLE 25.5. Comparison of Compulsions in 43 Adults with Prader–Willi

Syndrome versus Age- and Gender-Matched Adults with OCD
PWS OCD
Y-BOCS features M SD M SD F
Number of compulsions 3.75 2.11 4.02 2.81 NS
Severity of compulsions 10.77 3.90 9.09 4.44 NS
Specific symptoms % % c2
Cleaning 33% 37% NS
Checking 16% 55% 21.16**
Repeating rituals 40% 54% NS
Counting 19% 28% NS
Ordering/arranging 29% 28% NS
Hoarding 79% 7% 46.75**
Need to tell, ask 51% 23% 7.16*
Note. Y-BOCS, Yale–Brown Obsessive–Compulsive Scale; NS, nonsignificant. Items from Dykens,
Leckman, and Cassidy (1996).
*p < .01; **p < .001.
Increased risks of OCD are thus strongly dividual with Prader–Willi syndrome on a
indicated in persons with Prader–Willi syn- long-term basis, to help maintain continu-
drome (State, Dykens, Rosner, Martin, & ity of care and to coordinate services. Table
King, 1999); these individuals exhibit a wide 25.6 summarizes many of the intervention
range of severe symptoms, and are similar recommendations discussed below. More
to adults without mental retardation but detailed information on the management
with OCD. In contrast, studies with hetero- of Prader–Willi syndrome may be found in
geneous groups of persons with mental re- an edited volume written for care providers
tardation find that only 1–3% meet criteria of all types, now in its third edition (Butler,
for OCD (e.g., Davis, Saeed, & Antonacci, Lee, & Whitman, 2006).
2008; Meyers, 1987; Vitiello, Spreat, &
Behar, 1989). It may be that one or more
genes associated with this increased vulner-
ability to OCD will be found in the Prader– TABLE 25.6. Salient Treatment
Willi critical region on chromosome 15, or Recommendations in Prader–Willi
that the pathogenesis of Prader–Willi syn- Syndrome
drome in some way predisposes individuals
to obsessive and compulsive behaviors. •• Maintain well-balanced, reduced-calorie
diet (1,000–1,200 kilocalories/day), assuring
Further work needs to identify the extent adequate calcium intake.
to which Prader–Willi syndrome also in-
•• Encourage regular, sustained exercise (30
volves heightened risks of mood, non-OCD minutes daily).
anxiety, impulse control, or psychotic dis-
•• Restrict access to food (e.g., locked cabinets,
orders, above and beyond the risks associ- refrigerator).
ated with mental retardation per se. It also
•• Provide close supervision, especially in the
remains unknown how any of these psychi- school cafeteria, at work, and in the
atric features relate to molecular genetic sta- community.
tus. Behavioral or cognitive differences have •• Maintain external food supports even when
generally not been found between subjects people lose weight or have high IQs.
with chromosome 15 paternal deletion and •• Be aware of possible conflict between food
those with maternal UPD (Cassidy et al., restrictions and choice/personal rights.
1997). Although Cassidy (1995) reported •• Assess feasibility of growth hormone treatment.
that those with deletion may be more prone
•• Consider over-the-counter products to increase
to repetitive skin picking and perhaps other saliva production.
compulsive symptoms, other findings fail to
•• Appreciate impact of tantrums and other
support this conclusion (Milner et al., 2005). maladaptive behaviors on family stress.
Persons with maternal UPD may be more
•• Provide clear behavioral expectations and limits,
prone to autism or PDD symptoms (Milner beginning at an early age; apply consistent limits
et al., 2005; Rogan et al., 1994), however, across home and school or work.
more research is still needed to clarify these •• Maintain consistency in daily routines.
preliminary observations.
•• Assess for increased risks of OCD/other anxiety
disorders, impulse control problems, and
depressive disorders.
Interventions : •• Determine whether compulsive tendencies lead
Medical and Behavioral to getting “stuck,” and provide extra support
with transitions.
Managing Prader–Willi syndrome’s charac- •• Check for sadness even in persons with adequate
teristic obesity and significant behavioral/ weight control.
psychiatric dysfunction constitutes a major •• Ensure appropriate special education, and be
treatment challenge, requiring cooperative sure that IEPs address needs for speech and
input from geneticists, primary care physi- physical therapies, as well as needs for increased
cians, endocrinologists, nutritionists, psy- physical activity.
chologists, psychiatrists, educators, families, •• Provide ample planning for school-to-work
group home staff members, and other care transition; consider need for food supports in
providers. It is often helpful for a health or transition plans; assess feasibility of dedicated
group homes versus other living settings.
mental health professional to follow an in-
Medical Management Other Medical Concerns

Obesity Management of other physical problems
associated with Prader–Willi syndrome is
With good reason, weight and dietary man-
largely problem-oriented. Although the use
agement have long been targets of interven-
of growth hormone in Prader–Willi syn-
tion in Prader–Willi syndrome. Experience
drome is still somewhat controversial, ongo-
in almost 30 years of managing Prader–
ing controlled studies suggest great benefit
Willi syndrome in an interdisciplinary clinic
from growth hormone replacement thera-
has demonstrated that obesity prevention or
py. Not only does such treatment result in
weight reduction and maintenance can be
increased height; perhaps more importantly,
achieved with the following:
it causes an improvement in body compo-
sition and increased muscle mass, thus de-
•• A well-balanced, low-calorie diet of about
creasing the body mass index (Angulo et al.,
1,000–1,200 kilocalories/day (assuring
1996).
adequate calcium intake).
Sex hormone replacement therapy will
•• Periodic weigh-ins (e.g., once a week).
increase the development of secondary sex
•• Regular exercise to increase muscle mass
characteristics and theoretically may im-
and thus efficiently burn calories (30 min-
prove osteoporosis, but testosterone treat-
utes per day is an appropriate goal).
ment is sometimes associated with an in-
•• Environmental modification as needed,
crease in aggressive behavior. No controlled
such as locking kitchen cabinets and the
trials of treatment with sex hormones have
refrigerator.
yet been published.
•• Close supervision to minimize access to
Products to increase saliva production
food (e.g., supervision of spending money;
have proved of benefit in treating the dry
supervision of meals in the school cafete-
mouth associated with Prader–Willi syn-
ria, on the job, or in the community).
drome, and are also likely to improve den-
tal hygiene and perhaps articulation as well.
Although these techniques are considered
Speech therapy can be beneficial to people
state-of-the-art in treating hyperphagia in
with Prader–Willi syndrome of all ages to
Prader–Willi syndrome, they are increasing-
address speech production abnormalities,
ly viewed by advocates in the developmental
and physical and occupational therapies
disability field as being too restrictive, and
have also proven helpful in treating hypoto-
as limiting the personal rights and choices of
nia and poor coordination.
adults with this syndrome (see Dykens, Goff,
et al., 1997, for a discussion). Clinicians
thus need to be aware of possible conflicts Educational, Behavioral,
between some interventions (e.g., locking and Psychiatric Management
the refrigerator or limiting spending money)
Educational and Vocational Management
with their clients’ right to food and to their
paychecks. Furthermore, external food sup- Most children with Prader–Willi syndrome
ports and interventions should be continued need special education services that address
even when people lose weight or show needs their unique cognitive and behavioral needs
for less supervision in the non-food-related (Fidler, Hodapp, & Dykens, 2002; Levine
parts of their lives. & Wharton, 1993). Although individual-
To date, no medication has shown long- ized education programs (IEPs) should be
term effectiveness in controlling appetites in based on a careful assessment of each stu-
people with Prader–Willi syndrome, despite dent’s cognitive strengths and weaknesses,
the widespread interest in such a medication most IEPs include speech–language and
in the Prader–Willi syndrome community. physical therapies; supervision around food;
Therefore, behavioral approaches continue and extra physical education classes or other
to be of considerable value in helping parents ways of increasing physical activity during
and other care providers set limits concern- the school day (e.g., walking). Many stu-
ing food, and supporting them in the lifelong dents do well with “hands-on” lessons and
effort to prevent the health consequences of techniques that capitalize on their visual–
obesity (Dykens & Cassidy, 1995). spatial strengths, and that minimize their
weaknesses in auditory–verbal short-term perphagia in the toddler or preschool years.

memory and sequential processing. Clinically, we find that setting behavioral
Students with Prader–Willi syndrome limits at a young age paves the way for more
are placed in both inclusive and specialized successful responses to limit setting over the
or segregated educational settings; often a developmental and adolescent years.
combination of these settings works well. But families often have difficulty adhering
Parents of students with Prader–Willi syn- to and enforcing behavioral and food lim-
drome tend to view their children’s ideal its over the long term. Some families benefit
educational placement as specialized rather from occasional or more sustained support
than inclusive (Hodapp, Freeman, & Kasa- from behavioral, family, and other thera-
ri, 1998). Compared to parents of children pists, as well as from the support of other
with Down syndrome, parents of students families of persons with Prader–Willi syn-
with Prader–Willi syndrome request more drome. Ongoing parent support groups are
specialized services (e.g., speech or physical now offered through the state chapters of the
therapies), even if this means leaving their Prader–Willi Syndrome Association (www.
local neighborhood school; they are also pwsausa.org) and through the Prader–Willi
more concerned with the transition from Foundation (www.fpwr.org); toll-free num-
school to work in the adolescent years (Hod- bers for these organizations are 800-926-
app et al., 1998). 4797 and 800-253-7993, respectively. Sup-
Adults with Prader–Willi syndrome need port groups can also be accessed through
careful vocational planning. Successful job state and national meetings, as well as the
placements typically require job coaches and Internet. These formal and informal parent-
extra support to address food seeking and to-parent support mechanisms are often of
other behavioral difficulties. Many adults enormous help to families.
also do well in group homes, especially In addition to behavioral interventions
ones designed specifically for persons with and family support, many persons with
Prader–Willi syndrome. Compared to fam- Prader–Willi syndrome need extra help get-
ily homes or less supervised community setting “unstuck” from their obsessions and
tings, group homes dedicated to adults with compulsions. Indeed, tantrums and stub-
Prader–Willi syndrome appear to be the bornness in persons with this syndrome
most effective in reducing and maintaining often seem related to their being “stuck” and
weight over time, as well as in managing unable to move from one activity or thought
behavioral difficulties (Cassidy et al., 1994; to the next. Consistent limit setting across
Greenswag, 1987). home and school settings often helps reduce
tantrums, as do predictable daily routines.
Other tantrums may be circumvented by
Behavioral and Psychiatric Management
distraction and by giving individuals ample
Clinicians need to be aware that even though warning about transitions, including spe-
food-related behavior is a significant issue in cial auditory or visual transitional cues. If
Prader–Willi syndrome, other maladaptive tantrums are inevitable, it is typically help-
behaviors are likely to be the major reasons ful for parents or teachers to avoid talking
why many families seek professional help. about the issue until well after the individual
We have noted earlier that even as compared has settled down.
to food issues, obesity, age, or IQ level, the Although the prevalence of mood disor-
best predictors of family stress are maladap- ders in the population with Prader–Willi
tive behaviors such as temper tantrums, com- syndrome remains unknown, depressive
pulsion, and needs for sameness in routine features need to be carefully assessed in cli-
(Dykens et al., 1996; Hodapp et al., 1997). ents with this syndrome (Deescheemaeker et
Improved behavior both at home and at al., 2002). As they develop, children may be
school is often the result of strict reinforce- particularly vulnerable to increased negative
ment of behavioral limits, clear delineation self-evaluation, isolation, and withdrawal
of behavioral expectations, and establish- (Dykens & Cassidy, 1995); these features
ment of regular routines. Establishing clear may reflect the children’s growing awareness
limits regarding food and behavior is espe- of their differences from peers. Depressive
cially important with the emergence of hy- features and disorganized thinking may also
be heightened among adolescents and adults With its genetic and behavioral complexi-
who have achieved adequate weight control ties, Prader–Willi syndrome is an ideal con-
(Dykens & Cassidy, 1995). Many children dition to pave the way for more syndrome-
and adults benefit from school, clinic, or specific behavioral research. Although
recreational programs that target improved studies on maladaptive behavior and psychi-
self-esteem, social skills, and peer relations atric problems are now emerging, research
(Dykens & Cassidy, 1995; Kundert, 2008; is also needed on the strengths and com-
Levine & Wharton, 1993). petencies of people with this disorder. Fur-
In addition, pharmacology is often used to thermore, approaches are needed that tie to-
address depressive or obsessive–compulsive gether genetics and behavior in Prader–Willi
features, as well as severe aggression and syndrome. Studies might, for example, sys-
temper tantrums. Several case studies report tematically compare behavior, development,
that selective serotonin reuptake inhibitors and hypothalamic function across persons
(SSRIs) have helped some individuals gain with deletions as opposed to UPD. Finally,
better control of tantrums and compul- treatment outcome research is sorely needed,
sive symptoms such as skin picking (Benja- including studies of how early diagnosis and
min & Buot-Smith, 1993; Dech & Budow, intervention affect subsequent health, men-
1991; Eiholzer, 2001; Hellings & Warnock, tal health, and quality of life. Such research
1994; Warnock & Kestenbaum, 1992). Al- offers much promise for improving the long-
though SSRIs are currently quite popular term success of people with Prader–Willi
in the Prader–Willi syndrome community, syndrome and their families.
controlled studies have yet to be published.
More recently, open-label small-scale studies
have documented the effectiveness of topi- Acknowledgments
ramate, an anticonvulsant, in the reduction
of self-injurious behavior among individuals We are grateful to the families of patients affected
with Prader–Willi syndrome for their continuing
with Prader–Willi syndrome (Shapira, Les- support and participation in Prader–Willi syndrome
sig, Lewis, Goodman, & Driscoll, 2004; clinics and clinical research. Particular appreciation
Shapira, Lessig, Murphy, Driscoll, & Good- goes to those who are willing to have photographs
man, 2002). Risperidone has also been used published. We are grateful as well to the many pro-
in the reduction of disruptive behavioral fessionals who help run the Prader–Willi syndrome
symptoms (Durst et al., 2000). clinics at the University of Connecticut, the Univer-
sity of California at Los Angeles, and Case Western
Reserve University. We also thank Robert M. Hod-
app for his helpful comments on this chapter. This
Next Steps work was supported in part by Grant No. 03008
from the National Institute of Child Health and
Although Prader–Willi syndrome was iden- Human Development.
tified just over 50 years ago, research on it is
accumulating at a growing rate, particularly
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Chapter 26
Disorders of Mitochondrial Metabolism
Russell P. Saneto
Mitochondria are eukaryotic cytoplasmic children. Ultimately, however, all true pri-
organelles that are essential for almost all mary mitochondrial disorders are associated
of a cell’s energy production, via oxidative with abnormalities of OXPHOS.
phosphorylation (OXPHOS). Disorders that The unique genetics and physiology of mi-
alter OXPHOS function can compromise tochondrial function create a variety of clini-
energy-demanding cellular functions. When cal manifestations, which range from single-
critically low adenosine triphosphate (ATP) organ defects to multisystemic involvement.
levels are reached, cellular function is altered, Disease onset ranges from the neonatal pe-
and organ failure can ultimately occur. The riod to old age. The variety of phenotypic
most vulnerable organs, such as brain and expression is impressive, yet many diverse
muscle, are those that rely on high levels of genetic and biochemical defects have simi-
energy. So many mitochondrial disorders lar presentations. These diseases are truly “a
involve brain and muscle dysfunction that puzzle wrapped in an enigma.” This chapter
mitochondrial diseases were once exclusive- focuses on mitochondrial diseases that are
ly labeled mitochondrial encephalomyopa- significantly expressed during infancy and
thies. As the field of mitochondrial medicine childhood. I highlight putative genotype–
has evolved with enhanced and expanded phenotype correlations when they exist, as
diagnostic testing, and as research on mito- well as the pathophysiology for each group
chondrial function unfolds, it is becoming of diseases when appropriate.
clear that this small organelle plays a very
important role in multisystemic disease and
not just diseases related to direct OXPHOS Background
function. Diseases due to impaired impor-
tation of mitochondrial proteins, defects of I begin by describing some clinical aspects
mitochondrial dynamics (e.g., fusion and of mitochondrial physiology and genetics,
fission), and alteration of maintenance and to shed some light on the reasons for the
expression of mitochondrial DNA (mtDNA) variety and breadth of mitochondrial dis-
have all become more evident in infants and ease.
512
Disorders of Mitochondrial Metabolism 513
Mitochondrial Biology distinct codons. It lacks histones, and genes

are transcribed from both strands as large
The mitochondria are double-membrane
polycistrons. All of the exons are continu-
organelles found in every cell type, with
ous with each other (Anderson et al., 1981).
the exception of the mature red blood cell.
Furthermore, mtDNA is almost exclusively
There are from two to thousands of mito-
maternally inherited (Taylor & Turnbull,
chondria within each cell, depending on
2005). In humans, the mitochondrial genome
the bioenergetic needs of the cell. The inner
is a 16,569-base-pair, multicopy, double-
membrane provides a highly efficient barrier
stranded molecule (Figure 26.1). It encodes
to ionic diffusion, which is an important fac-
13 polypeptides of the OXPHOS system, 7
tor in generating the proton electromagnet-
subunits of complex I, 1 subunit of complex
ic gradient responsible for the final step of
III, 3 subunits of complex IV, and 2 subunits
ATP generation (Saraste, 1999). Within the
of complex V. The other (approximately 75)
inner mitochondrial membrane lies the ma-
subunits are encoded by the nuclear genome.
trix. The matrix contains multiple enzymes
In addition, the mtDNA encodes 2 ribo-
involved in the tricarboxylic acid cycle and
somal RNA (rRNA) and 22 transfer RNA
beta-oxidation (carbohydrate and fat metab-
(tRNA) genes, which are necessary for the
olism, respectively). There are also compo-
intramitochondrial synthesis of the 13 mito-
nents for lipid and cholesterol synthesis, as
chondrial proteins. Both rRNA and tRNA
well as multiple copies of mtDNA that pro-
are specific to mitochondria and are distinct
vide specific mitochondrion proteins.
from cellular RNA.
The electron transport chain is composed
The mitochondrion remains entirely de-
of five enzymatic multisubunit polypeptide
pendent on the nuclear genome for most of
complexes located within the inner mito-
its functional machinery. It requires nuclear-
chondrial membrane. Approximately 88
encoded products for provision of enzymes
proteins make up this chain. With the ex-
for replication, DNA repair, transcription,
ception of complex II, all of the complexes
and translation. In fact, integrative analysis
have subunits that are encoded by nuclear
estimates the mitochondrial proteome to be
and mitochondrial genomes. Only 13 of
approximately 1,500 gene products (Calvo
these polypeptides are encoded by mtDNA
et al., 2006). This dependency on two ge-
(Figure 26.1); the rest are nuclear-encoded.
nomes creates some very interesting func-
Complex II is entirely encoded by the nu-
tional consequences of mtDNA and nuclear
clear genome. Subunits are assembled with
mutations, in the form of heterogeneous dis-
prosthetic groups and metal-containing cen-
eases seemingly unexplained by their genetic
ters by a set of assembly factors, which are
abnormalities.
unique to each subunit. Together with spe-
cific “electron shuttles” of coenzyme Q10
(ubiquinone) and cytochrome c, electrons mtDNA Replication
are shuttled among complexes I–IV in the
mtDNA undergoes continuous replication,
oxidative process to reduce molecular oxy-
which is independent from the cell cycle
gen (Wallace, 1999). Utilizing the produced
and occurs in dividing and nondividing cells
proton gradient, complex V (ATP synthase)
(Taanman, Muddle, & Muntau, 2003). The
forms ATP from adenosine diphosphate
replisome consists of unique proteins: the
(ADP) and inorganic phosphate—the phos-
heterodimeric mtDNA specific polymerase
phorylation step in the process of OX-
gamma (POLG), containing a polymerase
PHOS.
subunit, linker region, and proofreading
subunit (Graziewicz, Longley, & Cope-
Mitochondrial DNA land, 2006); accessory protein polymerase
gamma B (POLG 2; Carrodeguas, Theis,
The mtDNA genome is extraordinarily con-
Bogenhagen, & Kisker, 2001); 5’-3’ helicase
cise and is distinct from nuclear DNA. Un-
Twinkle (Spelbrink et al., 2001); and other
like nuclear DNA, mtDNA is almost entirely
single-stranded replication factors (Cope-
(93%) made up of exons and consists of sever-
land, 2008). The exact process and complete
al thousand copies per cell (polyploidy) with
structure are still unclear (Holt, 2009).
OH
PH T
12s F
rRNA D-Loop Cyt b
V
0 / 16569 P
16s
rRNA PL
E
DEAF 1555G ND6
MELAS 3243G LHON 14484C

L
LHON 14459A
ND5
ND1
LHON 3460A
I Q
M L
S
H
LHON 11778A
ND2
AN ND4
OL
C
W Y
NARP 8993G/C
MERRF 8344G ND4L
R
S ND3
G
COI
COIII
D ATPase6
COII K
http://www.mitomap.org/MITOMAP/mitomapgenome.pdf ATPase8
Copyright 2002 @ Mitomap.org 5 kb deletion
KSS
Complex I genes Complex III genes

(ubiquinol: Transfer RNA genes
(NADH
dehydrogenase) cytochrome c
oxidoreductase)
Complex IV genes Complex V genes Ribosomal RNA genes

(cytochrome c (ATP synthase)
oxidase )
FIGURE 26.1. A map of the mitochondrial genome. The mitochondrial genome is circular and com-
prises 16,569 base pairs. It codes for 7 subunits of complex I (ND1–ND6 and ND4L), 1 subunit of
complex III (cytochrome b), 3 subunits of complex IV (COI–COIII), and 2 subunits of complex V (AT-
Pase 6 and 8). It also codes for 2 ribosomal RNA (rRNA) genes and 22 transfer RNA (tRNA) genes,
which are required for intramitochondrial protein synthesis. Nine of the most common mitochondrial
mutations are given at their approximate positions within the genome. The displacement loop (D-
loop), or noncoding region, contains sequences needed for the initiation of both mtDNA replication
and transcription. The proposed origin of the heavy-strand replication is shown as OH , and that of the
light-strand replication is noted as OL . From mitomap.org. Copyright 2002 by mitomap.org. Reprinted
by permission.
Homoplasmy, Heteroplasmy, The evidence is overwhelming that paternal

and Threshold inheritance is exceedingly rare.
During cell division, the proportion of mu-
There are up to several thousand copies of
tant mtDNA may shift, resulting in daughter
mtDNA molecules (polyploidy) per cell.
cells with varying heteroplasmy ratios. Pre-
When all the copies of the mtDNA genome
sumably this process is random, and during
are identical, this is termed homoplasmy.
oogenesis the predicted 100,000–150,000
When there are two or more mtDNA geno- mtDNA molecules within a single oocyte
types mixed within a cell, the term hetero- are segregated through a “bottleneck,”
plasmy is used. A mutation within mtDNA where only a small proportion of mtDNA
can be considered either a homoplasmic is transmitted to the primary oocyte. Thus
mutation (all the mtDNA contain the muta- one daughter oocyte may inherit signifi-
tion) or a heteroplasmic mutation (a mixed cantly more or less mutated mtDNA, with
population of normal and mutated mtDNA the resulting offspring having a significant
is present). An important concept is thresh- variation in the mutational load of mtDNA
old. Threshold represents the percentage (or compared to the mother. Not only can
load) of mutation mtDNA that determines whole organisms develop with various levels
or contributes to disease expression—both of heteroplasmy, but during organogenesis,
clinical and biochemical defects of a partic- mitotic segregation can lead to significantly
ular tissue. Numerous studies have shown altered levels of mutated mtDNA in some
that almost all mutations are functionally tissues compared to others (Lightowlers,
recessive, and that a biochemical phenotype Chinnery, & Howell, 1997). In postmitotic
is associated with high levels of mutations tissues (e.g., muscle and brain), the propor-
above a critical threshold, usually in the tion of heteroplasmy can increase over time;
range of 70–95% (Rossignol et al., 2003; in rapidly dividing cells (e.g., blood), some
Sciacco, Bonilla, Schon, DiMauro, & Mo- mutations may be lost (Rahman, Brown,
raes, 1994). There has been a single report Chong, Wilson, & Brown, 2001). This
of a dominant mutation-inducing disease process of mtDNA segregation may not be
with low levels of heteroplasmy (Sacconi et random. There is animal evidence suggest-
al., 2008). ing that segregation of mtDNA is not a
random event (Battersby, Loredo-Osti, &
mtDNA Inheritance Shoubridge, 2003). Whether this exists and
and Bottleneck Effect can alter pathological mutations in humans
is not clear, but the process of bottleneck in
The current model of mtDNA inheritance oocytes and mitotic segregation in tissues
is that all mtDNA is inherited through the has important implications for varying phe-
maternal line and is therefore clonal (Giles, notypic expression within various tissues as
Blanc, Cann, & Wallace, 1980). However, well as among patients.
there has been a single report of paternal A recent study demonstrated that puta-
transmission of a 2-base-pair deletion in sub- tive pathological mtDNA mutations may be
unit ND2 of complex I in muscle of a patient present at higher than expected levels in the
with mitochondrial myopathy (Schwart & healthy population. Elliott, Samuels, Eden,
Vissing, 2002). Haplotype analysis proved Relton, and Chinnery (2008) found that in
that this deletion was from the father’s over 3,000 sequential samples of umbilical
mtDNA, although the deletion was not cord blood, 1 in 200 live births harbored
found in the father, nor was it found in any one of the 10 most common pathologi-
tissue in the patient other than the muscle. cal mtDNA mutations. The most common
Subsequent studies have not shown evidence pathological mutation, m.3243A>G, had a
of paternal mtDNA transmission in myo- mutational load of roughly 30%, which is
pathies, demonstrating the rare occurrence well below the putative disease threshold
of paternal inheritance (Filosto et al., 2003; of 70–80% (DiMauro & Schon, 2008). Of
Schwartz & Vissing, 2004). There is some these live births, only 0.00107% harbored a
evidence that paternal mtDNA is selected mutation not detected in the mother’s blood.
for degradation by the ovum (Sutovsky, Van This suggests that pathological mtDNA mu-
Leyen, McCauley, Day, & Sutovsky, 2004). tations are common in the healthy popula-
tion. Since population studies suggest that almost all caused by alterations in the nucle-
the prevalence of patients with mitochon- otide pools required to synthesize mtDNA
drial encephalopathy, lactic acidosis, and or in the enzymes associated with mtDNA
stroke-like episodes (MELAS) who have the replication that function at the replication
m.3243A>G mutation is approximately 3.65 fork (Spinazzola & Zeviani, 2005).
per 100,000 (Di Donato, 2009), the factors Multiple mtDNA deletions are due to fail-
modifying disease expression remain un- ure of homeostasis of mitochondrial nucle-
known. Certainly the numbers of carriers otide pools. However, the exact mechanism
would predict a larger population. underlying the formation of mtDNA dele-
tions is unclear. There is a close association
with accumulation of deletions and segmen-
Nuclear DNA Mutations
tal ragged red fibers in complex IV negative
The genetic etiology responsible for the pre- fibers. Deletions are usually absent in rap-
sentation of mitochondrial disease changes idly dividing cells, but are detected in heart,
with age: mtDNA mutations are more likely brain, muscle, and kidney cells (Spinazzola
to be found with increased age, compared & Zeviani, 2009). Clinically, mtDNA dele-
to nuclear DNA mutations (Schaefer, Tay- tion syndromes are almost always associated
lor, Turnbull, & Chinnery, 2004; Tulinius, with ocular problems (progressive external
Holme, Kristiansson, Larsson, & Oldfors, ophthalmoplegia and ptosis) and limb myo-
1991). Molecular investigation thus far has pathy (proximal weakness), and invariably
failed to identify the responsible gene defect with peripheral neuropathy, brain dysfunc-
in 50% of adults and 80–90% of pediatric tion (ataxia, dementia, and psychosis), sen-
disorders (Zeviani & Di Donato, 2004). sorineural hearing loss, and cataracts. Bio-
Partial responsibility for this discrepancy chemically, most of the deletion syndromes,
may be the high proportion of pediatric pa- as well as mtDNA depletion syndromes, are
tients having nuclear DNA mutations, which involved in the salvage pathways of mito-
are estimated to cause 75–90% of primary chondrial deoxynucleotides, which consti-
mitochondrial disease (DiMauro & Hirano, tute the major source of DNA precursors in
2008). An interesting study evaluated the liver, brain, and muscle.
clinical differences in young patients with Depletion of mtDNA results in severe re-
nuclear versus mtDNA mutations in OX- duction of the mtDNA copy number. This
PHOS (Rubio-Gozalbo et al., 2000). Sib- group of mitochondrial diseases is trans-
lings with nuclear mutations showed similar mitted as autosomal recessive disorders.
clinical manifestations, a more severe clini- They are phenotypically heterogeneous and
cal course, and an earlier onset of disease, invariably affect infants and children. The
compared to siblings with mtDNA muta- depletion of mtDNA copy number may af-
tions. Although only small numbers were in- fect either a specific tissue (usually muscle
vestigated, this study suggests that diseases or liver and brain) or a combination of tis-
due to nuclear mutations occur earlier and sues (including muscle, liver, brain, and kid-
are more severe, whereas mtDNA mutations ney). Three main clinical presentations are
cause a more diverse set of clinical findings described: myopathic, encephalomyopathic,
and expressed later in life. and hepatocerebral. Myopathic phenotype is
associated with mutations in the thymidine
kinase 2 (TK2) and p53-induced ribonucle-
Nuclear–Mitochondrial
otide reductase B subunit (RRM2B) genes.
Intergenomic Communication
Encephalomyopathies are associated with
Proper mtDNA replication, maintenance, the succinate synthase A and B genes. The
and translation rely on the coordinated in- hepatocerebral phenotype is associated with
teraction between nuclear- and mtDNA-syn- mutations in the Twinkle, POLG, DGUOK,
thesized products. When nuclear mutations and MPV17 genes. Not all gene mutations are
alter these processes, qualitative (multiple in proteins involved with nucleotide pool ho-
deletions) or quantitative (depletion) altera- meostasis; for example, some children with
tions of mtDNA or defective translations of hepatocerebral syndrome have mutations in
mtDNA products occur. These defects are MPV17, a gene that encodes an inner mito-
chondrial matrix protein of unclear func- 3.13 per 100,000, and MELAS, estimated
tion. Furthermore, there remain unknown to have a miminum prevalence of 3.65 per
genes responsible for mtDNA depletion syn- 100,000 (Schaefer et al., 2008). The most
dromes, as patients having severely reduced common childhood presentation of a mito-
mtDNA copy number have no mutations in chondrial disease is Leigh syndrome, but this
known depletion genes (Spinazzola et al., syndrome has multiple etiologies of mtDNA
2008). and nuclear mutations (Castro-Gago et al.,
2006).
Epidemiology
The minimum prevalence of OXPHOS dis- History
ease is estimated to be 1 in 5,000 live births
(Smeitink, Zeviani, Turnbull, & Jackobs, The field of mitochondrial medicine has a
2006). This is probably a low estimate, due long history, but its evolution into an inde-
to the wide spectrum of clinical presenta- pendent specialty is only in its infancy. The
tions, which may elude diagnosis in some study of mitochondrial physiology is filled
patients. Diagnostic modalities also may with Nobel Prize laureates who described
lower detection rates. For example, muscle the structure, location, and bioenergetics
biopsy is often used for diagnosis, especially of mitochondria. These studies formed the
in children; parents will sometimes decline foundation of our present knowledge about
this surgical procedure for their children, the mechanisms of ATP production via
thereby limiting diagnosis. Gene testing is OXPHOS coupled to proton motive force.
still in its infancy in mitochondrial disease, However, the understanding of how errors
as only recently has whole mtDNA genome in these mechanisms translate into disease
sequencing become available. Furthermore, is only beginning to be unraveled. The two
gene analysis in the pediatric population seminal discoveries that have been the build-
is difficult to perform, in part because un- ing blocks of mitochondrial medicine were
identified nuclear mutations account for the that mitochondria possess their own DNA
majority of cases. Gene testing is also ex- (Nass & Nass, 1963) and that ragged red
pensive, and insurance companies often do fibers are present in some mitochondrial dis-
not cover costs, which can restrict the use eases (Engel & Cunningham, 1963).
of genetic analysis. These epidemiological Although this can be debated, the initial
problems are further complicated by early clinical descriptions of mitochondrial dis-
infant deaths and ethical considerations of eases were published by Theodore Leber
presymptomatic genetic testing. All these (1871) for mtDNA-based disorders and Ber-
factors impede accurate epidemiological de- nard Alpers (1931) for nuclear-DNA-based
termination of prevalence. diseases. Leber described four families with
The estimate of mtDNA contribution to a unique and characteristic pattern of visual
the prevalence of mitochondrial disease in loss that contradicted the traditional con-
England has revealed the minimum preva- cept of Mendelian inheritance. It would be
lence of pathological mutations for adults to over 100 years until the genetic era of mi-
be 9.2 in 100,000 (Schaefer et al., 2008). As tochondrial disease was ushered in by Wal-
described above, although a relatively high lace and colleagues (1988), who showed that
percentage of healthy females carry one of the mutation m.11778G>A in mtDNA was
the 10 most common mtDNA pathological the cause of what was called LHON. Alp-
mutations, the frequency of mtDNA disease ers (1931) described three children who dis-
in England is not proportional to the prev- played rapidly progressive neurodegenera-
alence of mtDNA mutations (Elliott et al., tion with liver involvement. It was not until
2008). This is another piece of this puzzle of Naviaux and Nguyen (2004) determined
mitochondrial disease. that Alpers–Huttenlocher syndrome, also
The two most common mtDNA diseas- called Alpers syndrome, was caused by mu-
es are Leber hereditary optic neuropathy tations in the POLG gene.
(LHON), estimated to have a minimum The initial protocols of mitochondrial dis-
point prevalence in northern England of ease diagnosis have remained essentially un-
changed over the years; they have tradition- TABLE 26.1. Clinical Manifestations
ally consisted of a muscle biopsy, enzyme of Mitochondrial Disease
assays of the five electron transport chain in the Neonatal Period
complexes, and histochemical analysis of the Neurological
muscle specimen for ragged red fibers. The
Unexplained encephalopathy
genetic era has enabled diagnosis of a wide Nystagmus/abnormal eye movement
variety of pathological mtDNA mutations, Seizures
numbering over 200 at this writing (consult Hypotonia
mitomap.org for the current number). Only Coma
55 or so nuclear genes have been described Basal ganglia disease
to cause disease (Haas et al., 2008), but be- MRI abnormalities (Leigh syndrome)
Abnormal movements
tween 1,300 and 1,500 genes involved in mi- Microcephaly
tochondrion structure and function remain Hearing loss
unknown. So the genetic tools to diagnose Ataxia
mitochondrial disease are still evolving. I
think we are in a very exciting period of im- Respiratory
proved diagnosis and understanding of mi- Breathing abnormalities
tochondrial disease.
Cardiovascular
Cardiomyopathy (especially hypertrophic)
Developmental Course Unexplained cardiac failure
Superventricular tachycardia
The expression of mitochondrial disease can
Gastroenterological
occur at any time during life, with involve-
ment of any organ system. As with most Intestinal dysmotility
Cyclic vomiting
other diseases that are expressed at various
Hepatomegaly
times of life, the earlier the presentation, Liver failure
the more severe the mitochondrial disease. Hypoglycemia
Onset of mitochondrial disease seems to Poor feeding and failure to thrive
occur mainly at two distinct time periods:
the neonatal period and later infancy/child- Hematological
hood. As noted numerous times in this chap- Anemia (especially sideroblastic)
ter, however, there are no firm rules regard- Pancytopenia
ing either the presentation of symptoms or Other
Arhrogryposis
the time periods of onset. The constellation
Unexplained clinical collapse
of signs and symptoms is what alerts a cli-
nician that a possible mitochondrial disease Note. The more systems involved, the greater the clinical
exists in an individual patient. suspicion of mitochondrial disease.
Neonatal Presentation Demographics

Mitochondrial diseases that present in the The male–female ratio across studies of pa-
neonatal period are severe. Such diseases tients presenting during the neonatal period
can present very soon after birth, and most is approximately 1:1 (Table 26.2). Studies
involve multiple systems (Table 26.1). Mor- that include older children show a greater
tality is high. Males and females are equally male–female ratio, 1.5:1 (Table 26.3).
affected. Most neonatal presentations are
thought to have nuclear DNA mutations; Pregnancy
only a small percentage have been found
to have mtDNA mutations. Because many Prematurity (gestational age < 37 weeks)
infants are not tested and many unknown was noted in 8 of 32 neonatal patients re-
nuclear genes may be responsible for such ported by an Australian group (Gibson,
diseases, the true prevalence of these diseas- Halliday, Kirby, Yaplito-Lee, & Thorburn,
es is unknown. 2008). The population rate for prematurity
TABLE 26.2. Neonatal Onset of Mitochondrial Disease

Garcia-Cazorla
Skadal et al. Gibson et al. et al. Wortmann et al.
(2003) (2008) (2005) (2009)
Patients 29 32 57 6
Male–female ratio 1.8:1a 1:1 1:1 1:1
ETC 21 24b 56 3c
mtDNA 0 2 1 0
nDNA 8 6 0 3
Neurological symptomsd 29 17 48 6
Death (<3 years) 20 28 33 1
Note. Studies listed are representative studies investigating neonatal onset of disease. Two studies (Skadal et al., 2003;
Wortmann et al., 2009) represent data derived from larger pediatric cohorts. SUCLA2, gene encoding the ATP-dependent
succinyl-CoA synthase; RYR1, gene encoding the type 1 ryanodine receptor; ETC, electron transport chain; mtDNA,
mitochondrial DNA; nDNA: nuclear DNA.
a Data are derived from neonatal- and childhood-onset populations.
b Data represents patients with ETC abnormalities, minus one patient with a complex I defect and a mutation in a nuclear-
DNA-encoded subunit of complex I, NDUFS6.

c Data represent ETC abnormalities, minus 1 patient with a complex I defect and 1 patient with a mutation in a nuclear-
encoded protein, SUCLA2; and 1 patient with a complex V defect and mutation in a nuclear-encoded protein, RYR1. The
nuclear mutations in the Skladal et al. (2003) paper represent 8 patients with pyruvate dehydrogenase deficiency. Nuclear
mutations cited in Gibson et al. (2008) represent patients with mutations in NDUFS6, polymerase gamma 1, and tafazzin
genes.
d Movement disorder (dystonia, choreoathetoid, myoclonus), encephalopathy, epilepsy, hearing loss, peripheral neuropa-
thy, developmental delay, ophthalmological disease, ataxia, and migraine.
TABLE 26.3. Childhood Onset of Mitochondrial Disease

Skladal et al. Scaglia et al. Darin et al. Kirby et al. Debray et al.
(2003) (2004) (2001) (1999) (2007)
Patients 44 113a 32 51 73a
Male–female ratio 1.8:1b 1.4:1 1:1 1.4:1 1.4:1b
ETC 28c 80 23d 45e 44f
mtDNA 11 13 6 6 15
nDNA 5 2 2 0 13
Neurological symptomsg 37 99 29 40 66
Death (< 3 years) 32 4 5 16 27
Note. Studies listed are retrospective studies of pediatric patients referred to specialty centers for diagnosis and treatment.
Two studies represent studies derived from pediatric cohorts, including significant percentages from neonatal onset (see
Table 26.2). The other studies have a small percentage, but not completely identified, of patients who presented during the
neonatal period. See Table 26.2 for abbreviations.
a Designation of mitochondrial disease is based on modified Walker criteria (Bernier et al., 2002) and not exclusively on
ETC defect or pathological mtDNA or nDNA mutation.

b Data represent both neonatal- and childhood-onset patients.
c Data represents patients with ETC abnormalities, minus 11 patients with mtDNA mutations (p.3243A>G, p.8344A>G,
p.8993T>C) and large mtDNA deletions.

d Data represent one pair of twins (one of the twins was not formally tested) and three siblings of index cases, who demon-
strated phenotypes similar to those of the tested siblings.

e Data represent all patients with complex I defects at a single referral center. ETC data represent ETC abnormalities minus
6 patients with mtDNA mutations (m.3243A>G, m.14459G>A, m.3303C>T, m.3242G>A).

f Data represent three sets of siblings where one of the siblings had an enzymatically proven ETC defect. mtDNA defects:
m.3243A>G, m.8993T>G, m.8993A>C, m.14484T>C, m.9984G>A, m.260G>X, 7466_747delC, and large mtDNA dele-
tions.
g Movement disorder (dystonia, choreoathetoid, myoclonus), encephalopathy, epilepsy, hearing loss, peripheral neuropa-
thy, developmental delay, ophthalmological disease, ataxia, and migraine.

for the general population in Victoria, Aus- high proportion of neonatal deaths. Early
tralia, was approximately 8% (Riley, Davey, death may preclude diagnostic attempts, and
& King, 2005). Even compared to the pre- therefore the true prevalence of neonatal-
maturity rate in the United States during a onset mitochondrial disease is likely to re-
similar time period of 11.1% of single births main underestimated.
(Martin et al., 2010), the rate of prematurity
in this patient group was more than double
Clinical Manifestations
that in the general population. In the Gib-
son and colleagues (2008) study, there was Initial presentations usually evolves into
no significant association between prematu- multisystemic involvement in the neonatal
rity and any particular clinical, enzymatic, period (Table 26.1). Nonspecific features
or molecular defect. Although there was a of feeding difficulties, failure to thrive, sei-
higher rate of prematurity and intrauterine zures, hypotonia, persistent vomiting, and
growth retardation observed in complex I respiratory symptoms are common initial
deficiency, this was not statistically signifi- manifestations (Garcia-Cazorla et al., 2005;
cant. Low birthweight (<10% mean weight) Gibson et al., 2008; Skladal et al., 2003; Sue,
was seen in 7 of the 32 patients (Gibson et Hirano, DiMauro, & De Vivo, 1999; Wort-
al., 2008). The low-birthweight data de- mann et al., 2009). As time passes, most
scribed by von Kleist-Retzow and colleagues cases either segregate into three categories,
(2003) were similar to those for the Austra- with major involvement in specific organ
lian cohort. Larger cohort studies are needed systems (encephalomyopathic, hepatodiges-
to verify and extend the Australian data. tive, and isolated myopathic) (Gibson et al.,
2008) or are diagnosed with a common mi-
tochondrial syndromic disease. My experi-
Mortality
ence, however, is that most patients have at
The data from the literature (Table 26.2) least minor involvement in other systems, so
suggest that mortality has a break at the although disease expression may predomi-
3-year mark; that is, if an infant survives be- nantly involve specific organ systems, most
yond 3 years of age, the prognosis for longer cases include involvement of other organs.
survival is good. However, neonatal onset is Some patients present very early, even on
accompanied by a high early mortality rate the first day of life. A “collapse” on day 1 of
(66% mortality by age 3 years). In one study, life was reported in 8 of 32 neonates, most
onset after the neonatal period, but before 6 of whom required full resuscitation (Gibson
months of age, was also predictive of early et al., 2008). Skladal and colleagues (2003)
mortality (Debray et al., 2007). Death with- described a “fulminant course” in 10 out of
in 3 months of birth is common—13 of 32 29 neonates (symptomatic in the first month
infants in one study (Gibson et al., 2008) and of life), with death occurring by 6 months
16 of 57 in another (Garcia-Cazorla et al., of age. Unfortunately, this latter report
2005). Mortality was not related to organ did not indicate the age of symptom onset.
system involved, prematurity, or birthweight Other reports do not identify this category
in the Australian group (Gibson et al., 2008). of neonatal presentation. It may reflect the
However, another study showed that higher catastrophic presentation just after birth, so
mortality was related to initial hyperlact- that a diagnostic workup did not or could
acidemia and combined enzyme deficien- not occur.
cies (Garcia-Cazorla et al., 2005). Further Most patients develop neurological
research is needed before conclusions about symptoms, including hypotonia, seizures,
specific biochemical markers for early mor- and global developmental delay/enceph-
tality can be drawn. alopathy. In the studies reviewed here, 17
There are limited data on prognosis for of 32 patients (Gibson et al., 2008), 21 of
survivors after the 3-year mark, but patient 57 (Garcia-Cazorla et al., 2005), 28 of 29
survival up to 18 years of age (6 out of 57 (Skladal et al., 2003), and 5 out of 6 (Wort-
patients) has been reported (Garcia-Cazorla mann et al., 2009) presented with neurologi-
et al., 2005). The high mortality rate in the cal symptoms. As time procedes, up to 97%
neonatal presentation group suggests that develop developmental delay/encephalopa-
mitochondrial disease may account for a thy (Garcia-Cazorla et al., 2005). However,
again, multisystemic involvement is the rule 26 mtDNA mutations have been described to
(Table 26.1). In several studies, those pre- produce Leigh syndrome (Finsterer, 2008),
senting in the neonatal period and having but whether all of these mutations can give
the best outcomes tended to have multisys- rise to Leigh syndrome during the neonatal
temic manifestations without significant ac- period remains unknown.
centuated encephalomyopathy, or primarily Denis Leigh (1951) described a syndrome
hepatodigestive (Garcia-Cazorla et al., 2005; of focal, bilaterally symmetrical, spongiform,
Gibson et al., 2008) or primarily myopathic necrotic lesions associated with demyelina-
involvement (Garcia-Cazorla et al., 2005). tion, vascular proliferation, and gliosis in
Unfortunately, even in this population, only the brainstem, diencephalons, basal ganglia,
rare patients had normal IQ (Garcia-Cazorla and cerebellum, with or without cerebral
et al., 2005). The vast majority of patients white matter changes. Magnetic resonance
did not express classic mitochondrial syn- imaging (MRI) mimics pathological find-
drome phenotypes, with the exception of ings and shows hallmark progressive signal
Leigh and Alpers syndromes. abnormalities within the lentiform and cau-
Most patients have deficits in enzyme date nuclei, with changes in the thalamus,
activity of one or multiple electron trans- periaquiductal gray, tementum, red nuclei,
port chain complexes (Darin et al., 2001; and dentate nuclei (Figure 26.2; Saneto,
Garcia-Cazorla et al, 2005; Rubio-Gozalbo Friedman, & Shaw, 2008). Typically, onset
et al., 2000; Skladal et al., 2003; Wortmann is within the first 2 years of life (Ostergaard
et al., 2009). The electron transport chain et al., 2007), but adult onset has been de-
complex I is the most commonly involved scribed (Van Maldergem et al., 2002). How-
(Garcia-Cazorla et al., 2005; Gibson et al., ever, most patients present in the first month
2008; Skladal et al., 2003). In total, isolated of life (Piao, Tang, Yang, & Liu, 2006).
electron transport chain complex defects Phenotypically, there is a range of findings
outnumbered combined complex deficien- from severe neurological involvement (e.g.,
cies in these studies: 67 of 93 patients had
single-complex deficiencies. Unfortunately,
the genetics of all the components of the five
electron transport chain complexes remain
unknown.
Genetic Etiologies
Presumably most of the electron transport
chain complex defects represent nuclear
mutations. In the majority of studies cit-
ing specific mtDNA mutations, the extent
of analysis was not given, suggesting that
full mtDNA sequencing was not performed.
Full sequencing has only become commer-
cially available in the last several years. So
mtDNA-derived electron transport chain
complex gene mutations cannot be com-
pletely ruled out; however, the probability is
low, given that these mutations are relatively
rare (Zeviani & Di Donato, 2004).
FIGURE 26.2. Magnetic resonance imaging
(MRI) of a boy with Leigh syndrome. This is an
Leigh Syndrome axial image acquired using a 3-tesla MRI scan-
ner (Siemens Trio). The patient was 6 years of age
The only mtDNA syndrome described in and had an mtDNA mutation in the ATPase 6
the neonatal-onset group is Leigh syn- subunit of complex V. The axial image demon-
drome. All neonates described to date with strates hyperintense signal on fluid-attenuated
mtDNA-derived Leigh syndrome have had inversion recovery (FLAIR) sequence bilaterally
the mtDNA mutation m.8996A>G. At least within the putamen and caudate.
psychomotor delay, muscle weakness, hypo- mutation within the Faroe Island popula-
tonia, truncal ataxia, intention tremor, sei- tion was found in patients with phenotypic
zures, ophthalmoparesis, optic atrophy, or Leigh syndrome, with an incidence of 1 in
dystonia) to near-normal neurological find- 1,700 (Ostergaard et al., 2007). However,
ings (Bugiani, Tiranti, Farina, Uziel, & Ze- other mutations within the SUCLA2 gene
viani, 2005; Finsterer, 2008). Some patients are found in other ethnic groups, suggest-
demonstrate multisystem disease with mini- ing a wider occurrence (Wortmann et al.,
mal neurological involvement (Martin et al., 2009). It is not clear how a defect in the tri-
1990). Non-neurological manifestations in- carboxylic acid cycle can cause depletion in
clude short stature, cardiomyopathy, severe mtDNA.
constipation/diarrhea, respiratory failure,
and dysmorphic features (Finsterer, 2008).
Pyruvate Dehydrogenase Complex Deficits
Due to such phenotypic heterogeneity, crite-
ria for specific diagnosis of Leigh syndrome Several case series have noted defects in the
has been proposed (Rahman et al., 1996). pyruvate dehydrogenase complex (PDHC) as
There is also marked genetic heterogene- a source of neonatal mitochondrial disease
ity in Leigh syndrome. In addition to the (Skladal et al., 2003). These patients present-
more than 26 mtDNA mutations, at least ed mainly during the neonatal period (n = 8
22 nuclear gene mutations can be involved of 13). Only several hundred cases of these
in the etiology of Leigh syndrome (Finsterer, defects have been reported. Most mutations
2008). Nuclear mutations in electron trans- are sporadic, and recurrence rate is very low.
port chain subunits (complex I and complex The most common form, a mutation in E1a,
II) and in assembly factors (complex I and behaves as an X-linked dominant disorder;
complex IV) have been described. In addi- other causes are due to autosomal recessive
tion, mutations in the heme synthesis enzyme genes within the protein supercomplex. This
(complex IV function), coenzyme Q10 pro- complex catalyzes the oxidation of pyruvate
duction, pyruvate dehydrogenase complex, to CO2 and acetyl CoA and generates nico-
elongation factors G1 and Tu, transcription- tinamide adenine dinucleotide. The most se-
al coactivator LRP130, succinate coenzyme- vere presentation occurs during the neonatal
A ligase A2 (SUCLA2), and biotinidase have period, with metabolic acidosis and lactic
been found to produce Leigh syndrome. The acidemia. There is often hyperammonemia,
fairly consistent pathological findings in the and death occurs prior to 6 months of age
context of such a wide variety of genetic (Stromme, Borud, & Moe, 1976). There is
and phenotypic presentations suggest that a more indolent presentation with a chronic
a developmentally sensitive period of mito- modest lactate acidemia that initially comes
chondrial insult gives rise to many cases of to medical attention due to delayed psycho-
Leigh syndrome. However, adult-onset cases motor development (Hansen, Christensen,
are also seen, so alternative mechanisms for & Brandt, 1982). The majority of these pa-
pathological development of lesions must tients have clinical, MRI, and neuropatho-
exist. logical findings similar to those in Leigh
One of the nuclear DNA etiologies of syndrome (Leigh, 1951). Most will die be-
Leigh syndrome is a class of mitochondri- tween 10 months and 3 years of age. Patients
al diseases known as disorders of mtDNA with milder presentations tend to be females
maintenance or nuclear–mitochondrial in- with a slowly progressive Leigh syndrome or
tergenomic communication (Table 26.4). males with ataxia (Blass, Lansdale, Uhlen-
These disorders are so called because the dorf, & Hom, 1971).
primary disorder resides in a nuclear gene,
but the target is mtDNA. Gene mutation re-
Deletion and Depletion mtDNA Disorders
sults in multiple mtDNA deletions or deple-
tion of mtDNA copy number. SUCLA2 is a In addition to Leigh syndrome due to
mitochondrial matrix enzyme that catalyzes SUCLA2 mutations (see above), there are at
the formation of succinate and ATP from least four other enzyme defects that induce
succinyl-CoA and ADP in the tricarboxy- neonatal mitochondrial disease and mtDNA
lic acid cycle. SUCLA2 is the ß-subunit of depletion. Mutations in succinate-CoA syn-
succinyl-CoA synthase. A founder effect thase B (SUCLG1), deoxyguanosine kinase
TABLE 26.4. Disorders of Mitochondrial Maintenance (Nuclear–Mitochondrial

Intergenomic Communication)
Gene Age at onset CNS features Systemic features Depletion organ(s)
POLG1 Infancy–adulthood Ataxia, seizures, Liver failure a , Liver, muscle
dementia, blindness, gastrointestinal
PEO, neuropathy dysmotility, vomiting,
myopathy
DGUOK Neonatal Dystonia, nystagmus, Liver failure Liver

hypotonia
MPV17 Neonatal– Ataxia, neuropathy, Liver failure, mental Liver

adulthood dystonia, hypotonia retardation, scoliosis,
corneal scarring
Twinkle Infancy Athetosis, seizures, Liver failure Liver

myopathy, mental
retardation, PEO,
psychosis, neuropathy,
ataxia, hypotonia
TK2 Infancy–childhood Seizures, PEO Myopathy Muscle
RRM2B Neonatal Microcephaly, mental Myopathy, tubulopathy, Muscle, kidney

retardation, hearing nephrocalcinosis
loss, hypotonia
SUCLG1 Neonatal Hypotonia, severe Lactic acidosis Liver, muscle

early encephalopathy hepatomegaly
SUCLA2 Neonatal–infancy Dystonia, hearing loss, Short stature Muscle

encephalopathy, PEO,
neuropathy, mental
retardation, hypotonia
Note. POLG1, polymerase gamma 1; PEO, progressive external opthalmoplegia; DGUOK, deoxyguanosine kinase;
MPV17, encodes a small mitochondrial membrane protein of unclear function; TWINKLE, mitochondrial DNA helicase;
TK2, thymidine kinase; RRM2B, p53-dependent ribonucleotide reductase; SUCLG1, GTP-dependent succinyl-CoA syn-
thase; SUCLA2, ATP-dependent succinyl-CoA synthase.
a Liver failure is induced by valproic acid exposure, but will occur without exposure. All mitochondrial DNA depletion
syndromes are inherited as autosomal recessive traits. There are also autosomal dominant forms of POLG1 mutations that
have adult onset.
(DGUOK), MPV17, and RRM2B have all al., 2007). Patients demonstrated intrauter-
been found to cause neonatal-onset disease ine growth retardation, premature birth,
(Table 26.4). The depletion disorders are dysmorphic features, and a combination of
presented here because they are of recent muscle and liver electron transport chain
discovery, and their description may help abnormalities; this is similar to other early
clinical investigators diagnose early-onset neonatal presentations. Whether other neo-
mitochondrial disorders. nates with this disorder will be found re-
There is a single report of a rare disorder mains unknown.
involving early onset of severe lactic acidosis Two depletion hepatocerebral syndromes
on the first day of life and death within sev- are caused by mutations in DGUOK and
eral days of life. This disorder presents with MPV17. Both syndromes present with com-
dysfunction in multiple electron transport binations of persistent vomiting, failure to
chains and mtDNA depletion. The mutation thrive, hypotonia, hypoglycemia, and pro-
was found in SUCLG1 in multiple members gressive neurological symptoms, especially
of a consanguineous family (Ostergaard et nystagmus (Copeland, 2008; Dimmock et
al., 2007; Freisinger et al., 2006; Parini et al., other electron transport chain defects has
2009; Spinazzola et al., 2008). In DGUOK been proven to be a homoplasmic tRNA-
deficiency, liver cirrhosis leads to early-onset Glu mutation, m.14674T>C. If clinicians are
liver failure and is the most prominent fea- not aware of this mutation, withdrawal of
ture. The type of mutation seems to deter- medical care may occur. Infants presenting
mine age of onset; frameshift or nonsense with severe muscle weakness and hypotonia
mutations have neonatal onset, whereas mis- should be actively worked up for this pos-
sense mutations present later in infancy (Fre- sible mutation, as prognosis and further
isinger et al., 2006). A rare neonatal-onset heroic medical efforts are warranted if the
hepatocerebral syndrome arises from muta- m.14674T>C mutation is found.
tions in MPV17, with hepatomegaly and pro-
gressive liver failure in the first weeks of life.
Infancy and Childhood
There is also a milder form with less liver
involvement, but progressive neurological After the neonatal period, the median age of
involvement, and survival into adulthood; mitochondrial disease onset was 7 months
this is known as Navajo neurohepatopathy in one study (Debray et al., 2007) and 44
(Karadimas et al., 2006). months in another (Scaglia et al., 2004),
The fourth depletion syndrome in the with a range of presentation from 2 weeks
neonatal age group results from mutations to 18 years (Darin et al., 2001; Debray et al.,
in RRM2B. The most severe form is a ho- 2007; Kirby et al., 1999; Scaglia et al., 2004;
mozygous loss-of-function mutation in- Skladal et al., 2003). Nuclear mutations rep-
ducing severe mtDNA depletion in muscle. resent the majority of disease etiology, with
Clinical presentation varies, but often in- a small proportion of mtDNA-derived mito-
cludes hypotonia, diarrhea, renal tubulopa- chondrial syndromes (but larger and more
thy, seizures, respiratory distress, and lactic diverse than the proportion in the neonatal
acidosis (Bornstein et al., 2008; Bourdon et presentation) (Table 26.3). Those patients
al., 2007). In the majority, death can occur having nuclear mutations tend to present
before 4 months of age. However, there is a with symptoms during early childhood,
range of disease from early infancy to adult- whereas those possessing mtDNA mutations
hood, with varying symptoms (Tyynismaa tend to present later in life (Rubio-Gozalbo
et al., 2009). et al., 2000; Skladal et al., 2003).
Infantile Reversible Cytochrome c Oxidase Demographics

Deficiency Myopathy
There is a male–female ratio of approxi-
One very interesting and important neona- mately 1.5:1 across most studies in patients
tal mitochondrial disease needs to be men- presenting during infancy and childhood
tioned. It is rare, but the identification of (Table 26.3). The reason for the slight male
this entity can literally be life-saving. As predominance is not clear.
described throughout this section, children
with early-onset disease often die early. A
Pregnancy and Delivery
particular form of complex IV deficiency
presents soon after birth with severe muscle In one study, birthweight was below the 3rd
weakness and hypotonia in the first few days percentile in 13 of 66 patients (Debray et al.,
to weeks of life, often requiring mechanical 2007). This would be significantly higher
ventilation. What is surprising about this than the proportion of such births in the
disorder is that it spontaneously remits, with general population, if compared to the Unit-
recovery to normal (in most cases) by 2–3 ed States and Australian data (see above).
years of age (DiMauro et al., 1981; Horvath This facet of mitochondrial disease in this
et al., 2009). At presentation, this disor- age group needs further study, but when
der is potentially life-threatening and often taken together with neonatal-onset data, it
necessitates life-sustaining measures. The suggests that in utero growth compromise
defect that induces complex IV deficiency, may be significant in some forms of mito-
ragged red fibers within muscle, and often chondrial disease.
Mortality TABLE 26.5. Clinical Manifestations

of Mitochondrial Disease in Children
Mortality is lower in the infancy/childhood-
onset population than in the neonatal-onset Neurological
population but still high, with median age at Encephalopathy
death 13 months in one study (Debray et al., Encephalopathy with low/moderate dosing
2007) and 5.3 years in another (Scaglia et of valproate
al., 2004). Approximately 50% live beyond Nonspecific psychomotor delay
Basal ganglia disease
3 years of age, without any association with MRI abnormalities (Leigh syndrome)
biochemical defect associated with mortality Abnormal movements (especially dystonia)
(Table 26.3). Debray and colleagues (2007) Seizures
found that patients having their first symp- Epilepsia partialis continua
toms before 6 months of age were 10 times Status epilepticus (especially if unexplained)
Myoclonic seizures
more likely to die early, and that even when
Myoclonus
patients with LHON were excluded, the Myopathy
presence of a pathological mtDNA mutation Peripheral neuropathy
was associated with a lower mortality rate. Ataxia
Migraine headache
Cerebellar
Clinical Manifestations Hypotonia
Loss of deep tendon reflexes
There is a wide spectrum of clinical manifes- Atrophy (especially vermial)
tations (Table 26.5) in this group of patients, Neurodegeneration (especially after a viral illness)
from multisystemic disorders to isolated my- Stroke-like events (nonvascular territory)
opathy or liver disease. The most frequent Proton resonance spectroscopy finding of lactate
presentation involves the central nervous peaks
Hearing loss
system (CNS) and muscle; CNS involvement
is mostly diagnosed as developmental delay, Cardiovascular
encephalopathy, and hypotonia, and muscle
Cardiomyopathy (hypertrophic, dilated,
involvement is described as myopathy or ex- noncompaction)
ercise intolerance (Darin et al., 2001; Deb- Unexplained heart block
ray et al., 2007; Kirby et al., 1999; Scaglia et Wolff–Parkinson–White arrhythmia
al., 2004; Skladal et al., 2003). Neurologi-
cal involvement was as high as 90% in two Ophthalmological
studies (Debray et al., 2007; Scaglia et al., Retinal degeneration with signs of night blindness,
2004). Cerebral involvement, noted as devel- color vision defects, or pigmentary retinopathy
opmental delay, was less common in patients Ophthalmoplegia/paresis
Ptosis
with pure myopathy (50%) and not found in Eye movement abnormalities
the group with LHON (Debray et al., 2007), Sudden or insidious optic neuropathy/atrophy
which may cause the prevalence of mito-
chondrial disease to be underestimated in Gastroenterological
these groups. Common problems cited were Unexplained valproate-induced liver failure
liver and gastrointestinal tract difficulties; Gastrointestinal dysmotility
sensorineural hearing loss; ophthalmologi- Pseudo-obstructive episodes
cal abnormalities; renal problems; and heart
problems, including cardiomyopathy and Renal
cardiac arrhythmias. There do not seem to Fanconi syndrome
be significant associations between type of Glomerular proteinuria
electron transport chain defect and clinical Endocrine
presentation or organ involvement. Micro-
cephaly, though only described in one study, Diabetes
Exocrine pancreas dysfunction
was found in 32% of patients and was pro-
gressive in 20% (Debray et al., 2007). Note. As abnormalities are found in multiple systems, the
The clinical phenotypes within the group more systems involved, the greater the clinical suspicion of
of electron transport chain defects are broad, mitochondrial disease.
with no clearly demarcated subgroups. Most Genetic Etiologies (mtDNA)

involve muscle and brain, but various other
mtDNA mutation diseases account for 14–
organ systems are also involved. The excep-
20%, with a mean of 17.2%, of the infancy/
tions are mostly mtDNA syndromes, dele-
childhood-onset population. One must re-
tion/depletion syndromes, and the more clas- member that these diseases are almost all
sical mitochondrial syndromes. There are a classic mitochondrial disease syndromes
few rare exceptions in children presenting in (Table 26.6). One of these syndromes found
this age group, with some patients present- in this population is LHON, described
ing solely with cardiomyopathy (Kirby et al., above.
1999). As noted above, pure myopathy with The most common mitochondrial syn-
or without cerebral involvement is possible drome in infancy and childhood is MELAS.
(Debray et al., 2007). Approximately 80% of cases have a muta-
The presence of cardiomyopathy de- tion at position m.3243A>G within the
serves special mention because of its high tRNA for leucine (tRNA leu; Goto, Nonaka,
frequency (18–40%) and increased mor- & Horai, 1990). The other genetic etiolo-
tality (Debray et al., 2007; Scaglia et al., gies of MELAS involve other mtDNA and
2004). In the largest pediatric study, 40% nuclear DNA mutations (Janssen, Nijtmans,
of patients demonstrated cardiac disease van den Heuvel, & Smeitink, 2006; Malfatti
(Scaglia et al., 2004). The majority of these et al., 2007). The age of onset varies, but
patients exhibited hypertrophic cardiomyo- the syndrome usually occurs before the age
pathy (58%), with dilated cardiomyopathy of 40 years. MELAS presents as a progres-
and left ventricular noncompaction seen sive neurodegenerative disorder associated
in the rest. This patient group had only with headache, treatment resistant partial
an 18% survival rate at 16 years of age, seizures, short stature, exercise intolerance
whereas patients without cardiomyopathy and muscle weakness, sensorineural hearing
had a 95% survival rate at the same age. loss, diabetes, and slowly progressing de-
Eleven percent of patients with a complex I mentia (Hirano & Pavlakis, 1994; Hirano et
defect presented with cardiomyopathy, 4% al., 1992). Migraine headache with nausea
with hypertrophic cardiomyopathy, and and vomiting is common and often precedes
2% with dilated cardiomyopathy (Kirby et stroke-like events. Respiratory depression
al., 1999). In this latter study, all presented may be the presenting symptom, particular-
within the first year of life and died early, ly in the context of a viral infection (Saneto
with the exception of one patient alive at & Bouldin, 2006). Partial seizures or epi-
11 years of age. Treatment options such as lepsia partialis continua may also precede
cardiac transplant may be possible in this or accompany stroke-like events (Ribacoba,
group (see “Treatment,” below). Salas-Puig, Gonzalez, & Astudillo, 2006).
In this patient population (Table 26.3), On MRI, the stroke-like lesions are often
the majority of patients had electron trans- transient, with lesions predominantly affect-
port chain defects (without mtDNA or nu- ing gray matter and not confined to vascular
clear mutations), with percentages ranging territories (Figure 26.3; Barkovich, Good,
from 56% to 86%. In two studies, complex Koch, & Berg, 1993; Hirano & Pavlakis,
IV defects were the most common (27% and 1994; Saneto et al., 2008).
46%), and complex I defects were the most The second most frequent mtDNA syn-
common in the other three studies (39%, drome is Kearns–Sayre syndrome, with
32%, and 86%). It should be noted that the rare cases evolving into this syndrome from
Kirby and colleagues (1999) study repre- Pearson syndrome. Of historical interest,
sented a cohort of patients with complex I the mtDNA deletion causing Kearns–Sayre
defects, and the percentage was calculated syndrome was one of the first mutations to
based on those patients with complex I de- be described and associated with human
fects without pathological mtDNA muta- disease (Holt, Harding, & Morgan-Hughes,
tion. When this latter study is excluded, the 1988; Kearns & Sayre, 1958). Although not
next most common electron transport chain usually presenting during childhood, pro-
defects were combinations of dysfunctional gressive external ophthalmoplegia (PEO)
complexes. falls into this deletion syndrome. Pearson,
TABLE 26.6. Classic Mitochondrial Disease Syndromes

Syndrome Age of onset Neurological phenotype Systemic phenotype
PEO Adolescence PEO, myopathy, ptosis Cardiomyopathy
KSS Childhood PEO, retinitis pigmentosa, ataxia, Cardiomyopathy, conduction

neuropathy block, short stature, diabetes
Pearson Infancy None Siderblastic anemia, exocrine

pancreatic insufficiency
MELAS Childhood Stroke-like episodes, seizures, ataxia, Cardiomyopathy, short stature,

myoclonus, cortical blindness, migraine, gastrointestinal dysmotility
ragged red fibers
MERRF Childhood Myoclonus, seizures, ataxia, ragged red Diabetes

fibers, dementia, sensorineural hearing loss
NARP Adult Ataxia, neuropathy, myopathy, retinitis Neuropathy

pigmentosa
Leigh Infancy Seizures, neuropathy, developmental delay, Cardiomyopathy, respiratory

dystonia, hypotonia failure
LHON Adolescent Blindness (central), circumpapillary None

telangiectatic microangiopathy
Note. PEO, progressive external ophthalmoplegia; KSS, Kearns–Sayre syndrome; MELAS, mitochondrial, encephalopa-
thy, lactic acidosis, and stroke-like episodes; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike
episodes; MERRF, myoclonus, epilepsy with ragged red fibers; NARP, neuropathy, ataxia, retinitis pigmentosa; LHON,
Leber hereditary optic neuropathy.
Kearns–Sayre, and PEO syndromes can rep- usually presents in childhood (< 20 years of
resent a continuum from infancy through age), whereas PEO is most often an adult
childhood/early adolescence. All three syn- disorder but rarely is seen during childhood
dromes are due to mtDNA deletion/duplica- (Scaglia et al., 2004). Again, symptoms re-
tion. The size of mtDNA rearrangement can flect the degree of heteroplasmy. Pearson
vary from a few base pairs to seven kilobases, syndrome is characterized by refractory sid-
with the large deletions spanning the genes erblastic anemia, vaculization of bone mar-
between cytochrome b and cytochrome oxi- row precursor cells, and often death during
dase subunit II (Holt et al., 1988; McShane infancy. Kearns–Sayre syndrome presents
et al., 1991; Moraes et al., 1989; Rotig et with ophthalmoplegia, ptosis, retinitis pig-
al., 1989). Disease severity is due to the de- mentosa, and multisystemic involvement
gree of heteroplasmy and not to the size of including complete heart block. PEO usu-
the deletion. Heteroplasmy varies between ally only involves muscle problems of oph-
tissues, and the degree of it shifts over time thalmoplegia, ptosis, and possibly proximal
(Larsson, Holme, Kristiansson, Oldfors, & muscle weakness. The single deletions/dupli-
Tulinius, 1990). This is due to the postfer- cations arise as primary mtDNA mutational
tilization origin of the deletion/duplication. events within the oocyte and therefore, are
The higher the percentage of heteroplasmy, usually not maternally transmitted. The risk
the more severe and earlier the onset of the of subsequent transmission from an affected
clinical syndrome, from Pearson syndrome woman has been estimated to be 4% (Chin-
to PEO. Pearson syndrome presents dur- nery et al., 2000).
ing infancy (Pearson et al., 1979; Rotig et Myoclonus, epilepsy with ragged red fibers
al., 1990); if the infant survives, then the (MERRF) is maternally inherited from a mu-
disorder often develops into Kearns–Sayre tation of mtDNA at position m.8344A>G in
syndrome. Isolated Kearns–Sayre syndrome the tRNA Lys (Wallace et al., 1988). Other
A
FIGURE 26.3. MRI and [1H] proton magnetic resonance spectroscopy (MRS) of a patient with mito-
chondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Panel A is an MRS axial
image acquired with a 3-tesla MRI scanner (Siemens Trio, TE 80, TR 1700, FOV, 16 cm) showing dra-
matically elevated lactate. The voxel is placed in the deep gray matter just superior to the midtemporal
structures. Panel B is an axial view of an 11-year-old boy who presented with headache that progressed
to focal seizures. This T2-weighted image acquired with a 3-tesla MRI scanner (Siemens Trio) dem-
onstrates hyperintense T2 signal within the cortical gray matter of the occipital region that does not
correspond to a known vascular territory. There is also some subcortical white matter involvement.
528
mutations with the tRNA Lys have been as- can be seen in infancy and childhood (Table
sociated with MERRF (Silvestri, Moraes, 26.4). One distinctive disorder presenting in
Shanske, Oh, & DiMauro, 1992). This mi- the first year of life with severe myopathy is
tochondrial syndrome is the most clearly caused by mutations in TK2 (Spinazzola &
correlated with clinical, biochemical, and Zeviani, 2009). This syndrome presents with
molecular findings. There are positive corre- feeding difficulty, failure to thrive, hypoto-
lations with age of onset, severity of disease, nia, and muscle weakness, and infrequently
mtDNA heteroplasmy, and reduced activity with ophthalmoplegia. For unclear reasons,
of electron transport chain complex activity a spectrum of muscle involvement can pro-
(Hammans et al., 1993). This syndrome is duce spinal muscular atrophy-like motor
clinically characterized by myoclonus, myo- neuron disease (Mancuso et al., 2002), rigid
clonic seizures, muscle weakness, dementia, spine myopathy (Oskoui et al., 2006), iso-
and wasting (Shoffner et al., 1990). Unlike lated myopathy (Oskoui et al., 2006), or a
most mitochondrial diseases expressed in severe myopathy with marked weakness
childhood, this syndrome usually demon- that may be accompanied by encephalopa-
strates ragged red fibers on muscle biopsy thy and seizures (Galbiati et al., 2006). Un-
(Shoffner et al., 1990). Although not com- fortunately, death usually occurs in infancy
pletely understood, symmetrical lipoma- or childhood, but some patients live into the
tosis, especially in the trunk, is frequently teenage years (Moraes et al., 1991; Oskoui
found (Zeviani & Di Donato, 2004). et al., 2006). A helpful lab finding is elevated
The onset of Leigh syndrome can be seen serum creatine kinase with multiple electron
in this age range as well. Whereas the mu- transport chain complex defects (Spinaz-
tation of m.8993T>G within mtDNA and zola & Zeviani, 2009). Organ specificity is
PDHC mutations in nuclear DNA cause related to the need of nondividing cells for
the vast majority of neonatal-onset cases of deoxynucleosiol triphosphates (dNTP) pool
Leigh syndrome, other mutations in mtDNA synthesis via the salvage pathway and the
and nuclear DNA begin to be expressed as activity of the mitochondrial enzyme TK2
Leigh syndrome during infancy and child- in muscle (Copeland, 2008). There are un-
hood (see the earlier discussion). More than known genes involved in the myopathic form
26 mtDNA mutations and 22 nuclear DNA of mtDNA depletion, as fewer than 30% of
mutations have been described; mutations in the cases are associated with TK2 mutations
the SURF1 gene are the most common nucle- (Spinazzola & Zeviani, 2009).
ar mutations (Finsterer, 2008). The mutation Mitochondrial neurogastrointestinal en-
at 8993 demonstrates the concept of hetero- cephalopathy (MNGIE) is an autosomal
plasmy: Two mitochondrial syndromes can recessive multisystem syndrome that is char-
arise from the same mtDNA mutation—in acterized by both mtDNA deletions and
this case, Leigh syndrome and neurogenic partial mtDNA depletion (Hirano et al.,
weakness, ataxia, and retinitis pigmentosa 2001). Patients demonstrate PEO, periph-
(NARP). NARP is associated with a hetero- eral neuropathy, leukodystrophy, and severe
plasmic T>G transversion at position 8993 gastrointestinal dysmotility (Hirano et al.,
(Holt et al., 1990). In patients with over 1994). The severe gastrointestinal dysmo-
90% heteroplasmy, Leigh syndrome is ex- tility produces frequent diarrhea and intes-
pressed, whereas those with a lower percent- tinal pseudo-obstruction, leading to severe
age of heteroplasmy express NARP. NARP cachexia and early death. This dysmotility is
is uncommonly seen in the infant and child due to mtDNA depletion in the external layer
population (Debray et al., 2007; Scaglia et of muscularis propria. The onset of MNGIE
al., 2004). is usually in the second to fifth decade, but
it has been reported to occur in childhood
(Debray et al., 2007; Scaglia et al., 2004).
Genetic Etiologies (Nuclear DNA)
The genetic defect lies in the pyrimidine sal-
A large group of disorders result from faulty vage pathway required for the conversion of
intergenomic communication producing de- thymidine and phosphate to thymine and
pletion of mtDNA. Five mtDNA depletion deoxyribose-1-phosphate (Nishino, Spinna-
disorders due to mutations within MPV17, zola, & Hirano, 1999). Autosomal recessive
RRM2B, DGUOK, SUCLA2, and SCULG1 or compound heterozygous mutations in the
thymidine phosphoryalase gene, ECGF1, mitochondrial diseases. POLG mutations

cause accumulation of thymidine and uracil can cause Alpers syndrome in the infant
in blood. The increased concentration in cir- (Naviaux & Nguyen, 2004) and either au-
culating deoxythymidine results in increased tosomal recessive or dominant PEO in the
mtDNA mutagenesis (Song, Wheeler, & adult population (Hirano et al., 2001; Van
Matthews, 2003). MNGIE is one of the few Goethem, Dermaut, Lofgren, Martin, &
mitochondrial diseases with an effective Van Broeckhoven, 2001). Mutations in the
treatment (see “Treatment,” below). POLG gene alter its activity, but the mecha-
Mutations in the POLG gene result in a nisms involved in producing various pheno-
spectrum of neurological syndromes, en- types and onset of symptoms is unknown.
compassing hepatocerebral, encephalomyo- Special comments on POLG are needed.
pathic, and isolated-PEO phenotypes. When This protein is the only DNA polymerase
such mutations are expressed during infancy found in mitochondria. The POLG gene has
to early childhood, the severe disorder of two domains: the N-terminal exonuclease
Alpers–Huttenlocher or Alpers syndrome and C-terminal polymerase domains, held
occurs. This syndrome is defined by the together by a linker region. Mutations in the
triad of progressive neurological degenera- two most common “hot spots,” c.467A>T
tion; explosive onset of seizures, often pre- and c.848G>T, are found in approximately
senting as status epilepticus or epilepticus 1% of the northern European population
partialis continua; and liver failure (Naviaux (Hakonen et al., 2007). It is estimated that
et al., 1999). Liver failure is almost univer- POLG mutations occur in 0.05% of other
sally induced by exposure to valproic acid. ethnic groups. In the most recent consor-
Death usually occurs during childhood, but tium meeting concerning POLG diseases, it
it can occur as late as in the second decade, was estimated that these diseases account for
depending on mutation and other unclear 25% of all mitochondrial diseases, reflecting
factors (Stewart et al., 2009). In all cases, the high POLG mutation rate (Chinnery &
the POLG mutations in Alpers syndrome are Zeviani, 2008).
recessive. Multiple combinations of muta-
tions within POLG have been reported to
Barth Syndrome
induce Alpers syndrome (dir-apps.niehs.
nih.gov/polg). Interestingly, the same muta- Barth syndrome is an X-linked recessive dis-
tions that induce an Alpers phenotype can order caused by mutations in the tafazzin
also be responsible for autosomal recessive gene, located at Xq28 (Bione et al., 1996).
PEO or the syndrome of ataxia–neuropathy Tafazzin is responsible for remodeling of
described next (Copeland, 2008; Weiss & cardiolipins in the mitochondrial inner
Saneto, 2010; Wong et al., 2008). The rea- membrane. Cardiolipins play a modulatory
son for this remains unknown. role in the activities of several electron trans-
In the phenotypic continuum of POLG port chain complexes, suggesting alterations
disorders, a syndrome of ataxia–neuropathy of electron transport chain activities as the
with its onset in the early teenage years has etiology of disease (Valianpour et al., 2002).
been described. This disorder has many The cardinal features of this syndrome are
names: mitochondrial–ataxic syndrome; spi- cardiac and skeletal myopathy with neutro-
nocerebellar ataxia–epilepsy syndrome; and penia, and short stature (Barth et al., 1983).
sensory neuropathy, ataxia, dysarthria, oph- The cardiomyopathy is classically a dilated
thalmoplegia syndrome. Clinical symptoms cardiomyopathy with endocardial fibroelas-
occur in various combinations of peripheral tosis. Isolated left ventricular noncompac-
neuropathy, ataxia, cognitive impairment, tion can also be found. Barth syndrome usu-
dysarthria, involuntary movements, psychi- ally occurs during infancy, but can present
atric abnormalities, myoclonus, and epilep- at any time during the first decade of life.
tic seizures. Various mutations in POLG can The cardiomyopathy may improve with age,
give rise to this group of disorders but most if it does not prove fatal during early child-
contain the mutation c.467A>T in one allele hood. However, its severity can fluctuate
(reviewed in Copeland, 2008). This spec- and worsen again in adolescence.
trum of symptoms typlify the difficulties in Not reported in the cohort studies above
correlation of phenotype and genotype in are mutations in the C10orf2 gene or the
mtDNA helicase Twinkle (Lonnqvist, Pae- the disorder, the earlier the mortality of the
tau, Valanne, & Pihko, 2009). I add this infant or child. Earlier onset usually means
because of the early onset of disorders due that a nuclear mutation is responsible for a
to these mutations and their similarity to disorder. Within a particular family, nuclear
POLG disease. Initial symptoms of ataxia, mutations usually give rise to similar symp-
muscle hypotonia, athetoid movements, and toms, time of onset, and outcome, whereas
loss of deep tendon reflexes occur at about pathological mutations in mtDNA usually
1 year of age in patients with homozygote give rise to onset of disease later in life and
mutations and 6 months of age in patients to milder symptoms. Furthermore, a range
with compound heterozygote mutations. of symptoms can be found within families
Around the teenage years, sensory axonal with a pathological mtDNA mutation, from
neuropathy and female hypergonadotro- no symptoms to complete manifestation of
phic hypogonadism occur. There is a range the disorder. However, there are some ex-
of learning difficulties from moderate to ceptions even to these patterns, as described
severe. Type of mutation is associated with above.
morbidity; in the compound heterozy-
gote type, death occurs before 5 years of
age. Thus far, only the 23 children in the Biological and Neuropsychological
Lonnquist and colleagues cohort have been Markers
described, and these mutations may thus be
due to a founder effect. Although most large cohort studies (see
above) have indicated that the majority of
patients have neurological involvement, the
Genetic and Family Patterns true prevalence of cognitive defects in mito-
chondrial disorders remains unknown. CNS
Inheritance of mitochondrial diseases fol- involvement varied from 70% to 90% in
lows the rules of Mendelian inheritance of cohort studies. Patients expressing primar-
autosomal recessive, autosomal dominant, ily cardiomyopathy may have less promi-
or X-linked recessive disorders. In addition, nent cognitive delays; in one study, only
mitochondrial disease can be inherited by the 20% had delays (Scaglia et al., 2004). Defi-
unique pattern of maternal inheritance. The cits in the overall group included decreased
range of inheritance patterns, together with Performance IQ and short-term memory
the variability in disease expression, makes deficits. One study demonstrated higher
disease patterns unpredictable and hard to rates of cerebral dysfunction and intellec-
recognize. For example, a single disorder tual deterioration (Kartsounis, Truong,
such as Leigh syndrome can result from mul- Morgan-Hughes, & Harding, 1992). In
tiple genetic abnormalities. As noted earlier, another group of children, Performance IQ
over 26 pathological mutations in mtDNA was found to be lower than Verbal IQ, with
and over 22 nuclear gene mutations can give nonverbal cognitive impairment and com-
rise to Leigh syndrome. In contrast, multiple promised visual–spatial abilities (Turconi
phenotypes may arise from mutations in a et al., 1999). Further studies on this aspect
single gene. For example, mutations in the of mitochondrial disease, in a larger group
single gene POLG can give rise to at least of patients with defined mitochondrial dis-
eight syndromes that are expressed from in- orders, is needed.
fancy to old age (>75 years). This variability There are no highly specific and sensitive
in both phenotype and genotype creates a biological markers in mitochondrial disease.
spectrum of disorders that are often difficult Historically, elevated lactate and the pres-
to diagnose and limits specific recognition of ence of ragged red fibers have been used as
disease patterns. markers for mitochondrial disease; however,
However, there are some patterns that both of these can occur in other disorders,
seem to hold true, at least in the data we and thus their specificity and sensitivity for
have to date. As in so many metabolic dis- mitochondrial disease are limited. Neverthe-
orders, the earlier the onset of the disease, less, in the correct clinical context, elevated
the more involved the disease. In the case lactate and/or pyruvate can be an important
of mitochondrial disease, the more severe biological indicator of mitochondrial dis-
ease, so such elevations must be considered Treatment

in the context of other signs and symptoms.
An excellent explanation of lactate and pyru- Treatment of mitochondrial disorders has
vate in mitochondrial disease can be found been limited for a variety of reasons, one of
in the article by Haas and colleagues (2007). which is that the lack of diagnostic consen-
By contrast, ragged red fibers have not been sus has made it difficult to create a standard-
shown to be sensitive for mitochondrial dis- ized pool of patients for clinical trials. How-
ease in the neonatal to young adult popula- ever, there are other reasons why treatment
tions (Vogel, 2001). So, although many pa- remains in its infancy. These diseases have
tients with mitochondrial disease may have been only been widely described since the
specific biological abnormalities, there are late 1980s; research dollars have been lim-
no highly specific markers of such disease. ited; most current treatments are considered
The constellation of findings—clinical, biomedical foods, and therefore the incentive
chemical, and neuroimaging—is what leads for clinical trials is small; and the mitochon-
the clinician to an appropriate diagnosis drial disease spectrum is broad.
(Haas et al., 2007, 2008). Currently, most mitochondrial medicine
physicians use a combination of vitamins
and cofactors to optimize nutrition and gen-
Assessment eral health, and to prevent worsening (catab-
olism) of symptoms during times of illness
Over the years, there have been multiple ap- and physiological stress. The current goals
proaches to the diagnosis of mitochondrial for medical intervention are to increase en-
disease (Bernier et al., 2002; Nissenkorn et ergy production (ATP) and reduce abnormal
al., 1999; Nonaka, 2002; Taylor, Schaefer, free-radical production. A review of this
Barron, McFarland, & Turnbull, 2004; Wolf subject has recently been published by the
& Smeitink, 2002). These systematic ap- Mitochondrial Medicine Society (Parikh et
proaches use a combination of clinical, bio- al., 2009).
chemical, and morphological criteria. None
of these systems are perfect; the certainty
Organ Transplantation
of diagnosis is stratified into “definite,”
“probable,” “possible,” and “unlikely.” A The multiorgan involvement of most mito-
nice summary of the limitations to these chondrial diseases would preclude the trans-
approaches has been published (Naviaux, plant of single organs. However, there are
2004). In this summary, Naviaux makes the three circumstances in which specific organ
astute statement that “none of these systems transplantation may be considered. Two
has yet been applied to a mixed population involve mtDNA depletion syndromes, one
of patients with mitochondrial disease and causing gastrointenstinal dysfunction and
similar, but non-mitochondrial disease” the other liver dysfunction. The third situta-
(p. 354). Although this is true, most in the tion involves isolated cardiomyopathy.
field have selected their “favorite” diagnostic MNGIE may be the single mitochondri-
paradigm and adhere to this system as their al disease for which organ transplant may
diagnostic tool. Two helpful review articles be the “cure.” This disorder, as described
on the diagnosis of mitochondrial disorders above, is a disorder of nucleotide utilization
have been published by a collaborative ef- that results in severe gastrointestinal mal-
fort of the Mitochondrial Medicine Society absorption, encephalopathy, leukodystro-
(Haas et al., 2007, 2008). Because several phy, and myopathy. Stem cell transplant
databases now exist, the rigorous testing of has proven to be efficacious in the long-
systems across patient populations should term reversal of symptoms (Hirano et al.,
allow investigators to become more precise 2006). At this writing, the initial stem cell
in diagnosing mitochondrial diseases and in transplant patient is demonstrating clinical
differentiating these from nonmitochondrial improvements about 60 months after trans-
diseases. Ideally, the eventual results will be plant (M. Hirano, personal communication,
more precise definitions of mitochondrial April 2009). A total of nine patients with
diseases and refined criteria for their diag- MNGIE have undergone stem cell trans-
nosis. plant, with some mixed results (Schupbach
et al., 2009). Two of the patients have shown produce a wide spectrum of diseases, usu-
significant clinical improvement. Three pa- ally with multiple organ involvement. As in
tients were showing some improvement less many other metabolic disorders, the more
than 2 years after transplant. The other severe the disease, the earlier the presenta-
four patients suffered transplant complication and the more devastating the disorder.
tions and expired. Multiple factors need to Neonatal onset usually confers high morbid-
be considered in severely compromised pa- ity with early mortality; patients typically die
tients with MNGIE. Optimizing treatment, within 3 years of diagnosis. The mortality
such as timing transplantation to occur and morbidity caused by infancy/childhood-
when patients are relatively healthy, may onset disorders are also high, but lower than
improve outcome. those of the neonatal-onset disorders. Due to
Patients with the hepatocerebral depletion the high energy demand, the CNS and mus-
syndrome caused by DGUOK mutations cular system are usually involved, with high
may represent candidates for liver transplan- morbidity. The most common neurological
tation. In a meta-analysis, a Kaplan–Meier dysfunction is cognitive delay, and most pa-
analysis showed that the lack of neurologi- tients have some compromise in cognitive
cal involvement is associated with long-term functioning. Only limited neuropsychologi-
survival (Dimmock et al., 2007). Neurologi- cal testing has been performed in this popu-
cal involvement was defined in this review lation. The extent of cognitive involvement
as profound hypotonia, significant psycho- within mitochondrial disease in general, and
motor retardation, and mystagmus. In this specific syndromes in particular, remains to
meta-analysis, liver transplant in patients be better studied.
with neurological symptoms was not as- Unfortunately, there is no single test that
sociated with improved survival. However, is sensitive or specific for any mitochon-
of the three patients with no neurological drial disease; therefore, diagnosis remains
symptoms, one patient had died but two dependent on a combination of biochemi-
others were still alive. The numbers are too cal, structural, and neuroimaging testing,
small to permit any judgments on trans- together with clinical exam and history. As
plantation, and caution should be used at genetic testing becomes more readily avail-
this time. Dimmock and colleagues (2007) able, diagnosis should become more precise.
strongly suggest that neurological involve- However, given the possible combinations of
ment should preclude transplant, and this genetic and physiological interactions, these
has been echoed in the literature by others. diseases are likely to remain spectrum dis-
The third possible clinical scenario in orders. The multiplicity of symptoms within
which transplantation may be considered is varying disease presentations makes clinicial
isolated cardiomyopathy. As noted above, acumen essential in diagnosis.
these patients seem to have limited neurolog- The most pressing needs in mitochondrial
ical involvement, and patients with isolated medicine are to stratify various diseases into
myopathy (noncardiac) have long-term sur- a classification scheme based on phenotype
vival compared to those with other types of and genetics, to uncover the natural history
mitochondrial disease. My colleagues and I of these diseases, and to develop treatment
have transplanted four patients with isolated strategies for specific disease types. I think
cardiomyopathy who had developed cardiac that this is the right time for these possibili-
failure (Saneto, 2010). All of these patients ties to begin becoming realities. The next
had electron transport chain defects. Each of few years will be an exciting adventure for
these patients is currently alive and thriving the development of mitochondrial medi-
4–9 years after transplant. cine.
Concluding Remarks Acknowledgments
I wish to thank the families of my patients who have

Mitochondrial disorders are relatively com- allowed me to care for their loved ones. In addition,
mon and can present at any time throughout I thank the Mitochondrial Research Guild at Seattle
the lifespan. The expression of dual genomes Children’s Hospital for donating its time and funds
and the unique physiology of mitochondria to help me care better for my patients.
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Chapter 27
Major Structural Anomalies

of the Neocortex
Nancy L. Nussbaum
Gina B. Christopher
Valerie Van Horn Kerne
The pace and complexity of the human Normal Development

brain’s development is nothing short of as- of the Cerebral Cortex
tounding; the invariable progression follows
a blueprint programmed into every human Development of the nervous system begins
being for millennia, with no intention re- with the development of the neural tube,
quired. When the progression is varied, it commencing near the 18th day of gestation.
often comes at a very high cost to the in- Early in embryonic development, the ecto-
dividual, and the outcome can be devas- dermal tissue thickens and forms the neural
tating and tragic. Abnormalities in brain plate. The edges of the neural plate then form
development may lead to a wide variety of ridges (often referred to as neural folds) that
clinical outcomes—from relatively minor curl toward each other until they fuse, form-
consequences, such as a mild microgyria or ing the neural tube (see Figure 27.1).
ectopias possibly leading to subtle cognitive Near 24 days’ gestation, the anterior neu-
deficits, to the inevitable fatal outcome as- ral tube closes and serves as the foundation
sociated with anencephaly. In this chapter, for future brain development (Clark, 2004).
we focus primarily on the major cortical When the neural tube is closed, develop-
anomalies found in the development of the ment progresses and the lateral, third, and
human brain. fourth ventricles are formed. The tissue
To begin, we briefly discuss the typical de- that surrounds these ventricles becomes the
velopment of the human nervous system. It is forebrain, the midbrain, and the hindbrain,
helpful to have a basic grasp of the ontogen-
esis of the brain in general and the cerebral
cortex in particular before further exploring Neural Crest
structural abnormalities in development. Neural Groove Neural Tube
Following this discussion, we describe a
number of major structural anomalies, in-
cluding schizencephaly, anencephaly, and
lissencephaly. The relevant history, etiology,
developmental course, prevalence, genetic Neural Plate Ectoderm
and family patterns, biological and neurop-
sychological factors, risk factors for pheno- FIGURE 27.1. Neural tube development. From
typic expression, assessment, and treatment Chudler (2009). Used by permission of Eric H.
are covered for these cephalic disorders. Chudler, PhD.
539
respectively (Carlson, 2007). The posterior Barkovich et al., 2001) and is now based on
neural tube closes at approximately the 26th the identified gene whenever possible, rather
day of gestation and serves as the foundation than on the clinical features associated with
for spinal cord development (Clark, 2004). the disorder (Barkovich et al., 2005). Still, it
Cell proliferation, cell migration, and is suggested that the clinical manifestations
cortical organization are three stages of and severity of the disorders depend largely
cerebral cortex development. Although de- on the stage of cortical development.
scribed as discrete steps, these stages often Malformations due to abnormal neuronal
occur simultaneously, since cell proliferation and radial glial proliferation may result in
continues after neuronal migration begins conditions that are characterized by too
(Abdel Razek, Kandell, Elsorogy, Elmongy, many, too few, or malformed cells (Barkovich
& Basett, 2009). Cell proliferation begins & Kuzniecky, 1996). Several conditions be-
with the layer of cells that line the inside of lieved to result from a primary defect in cell
the neural tube, referred to as the ventricular proliferation include microlissencephaly,
zone (VZ) (Guerrini & Marini, 2006). The hemimegalencephaly, and focal cortical dys-
VZ contains the founder cells that divide plasias (Abdel Razek et al., 2009). Disorders
and give rise to the cells of the central ner- of cellular migration develop when neurons
vous system (Carlson, 2007). Each founder fail to reach their intended destination in the
cell first undergoes symmetrical division, cerebral cortex early in the development of
producing two identical cells and thus in- the fetal nervous system. Impairments may
creasing the size of the VZ. Each founder cell occur at the beginning of migration, during
then undergoes asymmetrical division, pro- the ongoing process, or at the completion of
ducing a founder cell that remains in the VZ migration (Gleeson & Walsh, 2000). This
and another cell that is guided outward into results in structural deformities of the cere-
the cerebral cortex by radial glial cell fibers. bral hemispheres that result from undermi-
Radial glial cells were discovered by Rakic gration, overmigration, or ectopic migration
(1972, 1988), and their fibers provide the of the neurons (Menkes & Sarnat, 2000).
pathways for neurons to follow during their The classic lissencephalies and heterotopias
migration into the cerebral cortex (Carlson, are thought to result from defects in cell mi-
2007). Studies of brain development have gration (Abdel Razek et al., 2009). Golden
shown that the cerebral cortex develops from (2001) reported that pachygyria (i.e., few
the inside out. The earliest-migrating cells course and wide gyri) and polymicrogyrias
occupy the deepest layer of the cortex, with (i.e., many small gyri crowded in an irregular
subsequent migrations passing through pre- pattern) are additional neuronal migration
viously formed layers (Carlson, 2007). Cor- disorders (see Figure 27.2). Malformations
tical organization, the third stage of cerebral due to cortical organization are character-
cortex development, involves formation of ized by abnormalities in gyral formation and
the cellular network and includes neuronal commonly result from prenatal ischemia or
extensions, synaptogenesis, and maturation infection. Some of the associated conditions
(Barkovich, Kuzniecky, Jackson, Guerrini, include polymicrogyrias and schizencephaly
& Dobyns, 2001). (Abdel Razek et al., 2009). Table 27.1 sum-
Structural anomalies of the neocortex are marizes the structural anomalies of the neo-
a heterogeneous group of disorders (Abdel cortex.
Razek et al., 2009). Their numerous causes
include chromosomal and genetic diseases,
environmental factors, and traumas that Schizencephaly
occur at critical developmental periods.
Barkovich, Kuzniecky, Jackson, Guerrini, Schizencephaly occurs between the end of
and Dobyns (2005) proposed a classification the neuronal migration period and the early
scheme of structural anomalies of the cortex phase of cortical organization (Iannetti,
based on the stage of cerebral cortical devel- Spalice, Atzei, Boemi, & Trasimeni, 1996).
opment at which each anomaly occurs (i.e., It is a structural anomaly of the brain char-
cell proliferation, cell migration, or corti- acterized by the presence of abnormal clefts
cal organization). The classification scheme in the cerebral hemispheres. The clefts ex-
has evolved (Barkovich & Kuzniecky, 1996; tend from the cortical surface to the underly-
Major Structural Anomalies of the Neocortex 541
ing ventricular cavity, often resulting in the

replacement of large portions of the cerebral
hemispheres with cerebrospinal fluid (CSF)
(Menkes & Sarnat, 2000). The classification
of schizencephaly is based on the presence
of bilateral clefts (i.e., clefts in both hemi-
spheres) or unilateral clefts (i.e., a cleft or
clefts in one hemisphere). Bilateral clefts are
usually symmetrical, affecting both hemi-
spheres of the brain (Ferrer, 1984). Schizen-
cephaly clefts are further described as type
I or closed-lipped when the cleft walls are
fused, eliminating any space within the cleft
for CSF; they are described as type II or
open-lipped when the cleft walls are separat-
ed and filled with CSF (Clark, 2004). Type II
schizencephaly is more common than type I
(Guerrini, 2005), and in 70% of cases, clefts
FIGURE 27.2. T2-weighted image shows mi- are located most frequently in the frontal
grational anomaly in a 41-year-old male with
seizures. Abnormal gray matter extends from the
and parietal lobes, typically around the syl-
cortex to the ventricular surface. (Courtesy of vian fissures (Arantes, Perdigao, Pereira, &
David Leake, MD, Austin, Texas.) Costa, 2007; Barkovich, 1995) (see Figure
27.3).
TABLE 27.1. Structural Anomalies of the Neocortex

Structural
anomaly Pathogenesis Characteristics Associated anomalies disorders
Schizencephaly Neuronal migration Abnormal clefts Agenesis of septum pellucidum
Cortical organization Bilateral clefts Agenesis of corpus callosum
Unilateral clefts Cortical dysgenesis
Type I: Closed-lipped—cleft Hydrocephalus
walls are fused Polymicrogyria
Type II: Open lipped—cleft
walls are separated and
filled with cerebrospinal
fluid
Anencephaly Failure of neural tube Partial or total absence of Abnormal development of

formation cerebral structures skull base
Exencephaly
Lissencephaly Neuronal migration Deficient gyration Miller–Dieker syndrome

Cortical organization Agyria (lack of gyri) Isolated lissencephaly sequence
Pachygyria (broad gyri) X-linked lissencephaly with
Type I: Classical—poorly abnormal genitalia
defined sylvian and rolandic Cerebellar hypoplasia
fissures, thickening of Microlissencephaly
cerebral cortex, increased Agenesis of corpus callosum
gray matter Eye abnormalities
Type II: Cobblestone—agyria, Muscular dystrophy
pachygyria; abnormal Walker–Warberg syndrome
migration of gray matter to Muscle–eye–brain syndrome
cortical surface Fukuyama syndrome
Hydrocephalus
Encephaloceles
FIGURE 27.3. Schizencephaly. (A) Coronal T2-weighted image shows a closed-lipped right-sided
schizencephalic defect lined by pachygyria. (Courtesy of R. Zimmerman, MD, Philadelphia, Pennsyl-
vania.) (B) Axial T2-weighted image shows a wide CSF-filled cleft connecting the left lateral ventricle
with the subarachnoid space, which is lined with gray matter parenchyma. From Abdel Rasek, Kandell,
Elsorogy, Elmongy, and Bassett (2009). Copyright 2009 by the American Society of Neuroradiology.
Reprinted by permission.
Schizencephaly is considered a disorder Developmental Course

of cortical organization, since the cortex
The etiology of schizencephaly is still much
surrounding a cleft is typically polymicro-
debated; however, the most widely accepted
gyric (Barkovich et al., 2001). In 50–90%
of cases, it is associated with other brain hypothesis is that it involves both environ-
abnormalities—agenesis of the septum pel- mental and genetic risk factors (Abdel Razek
lucidum, agenesis or thinness of the cor- et al., 2009; Arantes et al., 2007; Granata &
pus callosum, cortical dysgenesis, and hy- Battaglia, 2008). Schizencephaly may occur
drocephalus, among others (Arantes et al., as a result of prenatal ischemia, exposure
2007; Komarniski, Cyr, Mack, & Weinberg- to toxins, viral infections, or genetic errors
er, 1990). that occur during the cortical organization
stage (Granata, Freri, Caccia, Setola, Taro-
ni, & Battaglia, 2005). A theory suggesting
History that schizencephaly results from inadequate
Although the first reported case of a schi- blood flow and subsequent ischemic damage
zencephaly cleft was identified by Kundrat to the developing cortex is supported by the
in 1882 (as cited in Granata & Battaglia, frequent co-occurrence of schizencephaly
2008), the term schizencephaly was origi- with polymicrogyria. Barkovich and col-
nated by Yakovlev and Wadsworth (1946a, leagues (2005) reported no known cases of
1946b). They presented case studies of five schizencephaly without accompanying poly-
autopsied patients with severe cognitive and microgyria. Still, in utero infections, toxic
motor deficits, and described their morpho- agents, and trauma are also implicated in
logical features (e.g., unilateral vs. bilateral the development of schizencephaly. Specifi-
and open-lipped vs. closed-lipped clefts). cally, schizencephaly may occur with a pre-
Prior to Yakovlev and Wadsworth’s identifi- natal cytomegalovirus infection (Iannetti
cation of the syndrome, schizencephaly had et al., 1996). Data obtained from a study
been included in the category of porenceph- utilizing experimental animals supports the
alies (Granata & Battaglia, 2008). In 1859, theory that clefts may be produced following
Heschl coined the term porencephaly and in utero viral exposure. Specifically, the in-
used it to describe any defect that extended oculation of a mumps virus strain impaired
through the full thickness of the cerebral neuronal migration and produced a cleft
hemispheres (as cited in Raybaud, 1983). and other brain malformations in hamsters
The term porencephaly is now commonly (Takano, Takikita, & Shimada, 1999).
used to describe any congenital focal lesion An alternative theory hypothesizes that
or cavity in the brain (Raybaud, 1983). schizencephaly is genetically determined. The
EMX2 gene mutation has been implicated in ment, seizures, blindness, microcephaly, and
a minority of familial cases of schizenceph- emotional/behavioral disorders (Arantes et
aly (Granata et al., 1997), and according to al., 2007; Packard et al., 1997). A negative
Verrotti and colleagues (2010), the EMX2 prognosis is suggested when the anomaly
gene is probably involved in controlling cor- is characterized by a large, open-lipped, bi-
tical migration and structural patterning of lateral cleft. There is a better prognosis in
the developing brain. In recent studies, how- persons with unilateral forms, since cere-
ever, the EMX2 gene has not accounted for bral plasticity may allow for reorganization
all cases (Menkes & Sarnat, 2000), and it of cognitive functions in the contralateral
has not been confirmed in follow-up stud- hemisphere (Al-Alawi, Al-Tawil, Al-Hathal,
ies by other researchers (Barkovich et al., & Amir, 2001; Garel, 2004). Persons with
2001) or in experimental models (Granata small, unilateral, closed-lipped clefts have
& Battaglia, 2008). Therefore, genetic test- the mildest clinical features. They typically
ing protocols are not currently recommend- present with mild hemiparesis and seizures,
ed (Innes, 2008). but no other impairments or delays in typi-
cal developmental milestones are usually
noted (Barkovich & Kjos, 1992; Barkovich
Prevalence
& Kuzniecky, 1996; Verrotti et al., 2009).
Prevalence rates for schizencephaly are not In contrast, large, bilateral, open-lipped
reported in the scientific literature; however, clefts have the most severe features and typi-
a recent epidemiological study tracing 4 mil- cally present in early infancy (Granata et
lion births in California from 1985 to 1991 al., 2005). Bilateral clefts are typically as-
reported that 1.54 in 100,000 births resulted sociated with microcephaly, severe cognitive
in a schizencephaly diagnosis (Curry, Lam- delays, and severe motor abnormalities (in-
mer, Nelson, & Shaw, 2005). Therefore, cluding spastic quadriparesis). Blindness as
schizencephaly is a rare structural anoma- the result of optic nerve hypoplasia can also
ly, and it has been reported to affect males be common (Verrotti et al., 2009).
and females equally (Granata & Battaglia,
2008).
Motor Deficits
Overall, motor deficits are almost invariably
Biological and Neuropsychological
present in children with schizencephaly, as
Markers
would be expected with clefts located in the
The clinical picture of schizencephaly is frontoparietal lobes (Granata et al., 2005;
characterized by a range of neurological Packard et al., 1997). As mentioned previ-
and developmental impairments, which will ously, the severity of motor impairment will
depend on size, location, and the unilateral vary from apparently normal health or mild
or bilateral nature of the clefts. Studies by asymmetry of motor skills characteristic of
Barkovich and Kjos (1992) and Packard, unilateral clefts to spastic quadriparesis,
Miller, and Delgado (1997) indicated that which is often seen in patients with bilat-
the number of lobes affected by clefts has an eral schizencephaly (Al-Alawi et al., 2001;
impact on the severity of outcome. Several Granata et al., 2005). Hypotonia (deficient
studies have reported that schizencephaly muscular tone) or hemiparesis (muscular
clefts more often affect the frontal lobes, weakness or partial paralysis restricted to
followed by the frontoparietal regions, and one side of the body) may be present (Men-
then the parietal and occipital lobes (Bark- kes & Sarnat, 2000), and both are typically
ovich & Kuzniecky, 1996). The presence associated with a contralateral cortical cleft
of associated cerebral malformations (e.g., (Packard et al., 1997).
agenesis of the septum pellucidum, agenesis
of the corpus callosum, hydrocephalus) also
Cognitive Delays
influences developmental outcome (Arantes
et al., 2007). Symptoms of schizencephaly The severity of cognitive and language im-
may include developmental delay, mental pairments associated with schizencephaly
retardation, speech delay, muscle weak- also depends in large part on the unilateral
ness or paralysis, difficulties with move- or bilateral nature of the clefts (Granata et
al., 2005). Cognitive impairments are present with seizures, it is not surprising that
ent in approximately 50% of cases with seizures often accompany schizencephaly.
unilateral clefts, and they are almost invari- Despite the high prevalence of seizures, the
ably present with bilateral clefts. Persons association between size, location, and the
diagnosed with schizencephaly may display uni- or bilateral nature of the schizenceph-
major language impairments, including a aly clefts on the one hand and the severity
lack of speech (Verrotti et al., 2009); how- of the epilepsy on the other is still unclear
ever, the language impairments are some- (Seguti, Schappo, Sobrinho, & Ferreira,
what less severe than the motor deficits 2006). Some patients with schizencephaly
and possible seizure complications (Pack- present with seizures while others do not.
ard et al., 1997). Patients with unilateral, Barkovich and Kuzniecky (1996) found that
closed-lipped (type I) clefts typically have patients with unilateral schizencephaly typi-
better language development than patients cally have epilepsy with partial simple or
with bilateral, open-lipped (type II) clefts complex seizures, whereas patients with bi-
(Packard et al., 1997). In cases with unilat- lateral schizencephaly typically present with
eral clefts, the unaffected hemisphere may mixed seizure disorders. In addition, Pack-
compensate, and cognitive functions may be ard and colleagues (1997) reported that pa-
completely normal. Brown, Levin, Ramsay, tients with open-lipped clefts had an earlier
and Landy (1993) presented a case study age of onset and less seizure control than pa-
of a 32-year-old, left-handed male with tients with closed-lipped clefts had. Overall,
unilateral left-hemisphere type I (closed- various types of seizures have been reported,
lipped) schizencephaly. According to his including generalized, tonic–clonic, partial
neuropsychological test findings, the patient motor, and sensory (Arantes et al., 2007).
demonstrated average to above-average per- However, the seizures are mostly focal, and
formance on all measures of language, judg- a single patient will typically present with
ment and reasoning, visual–spatial abilities, a single seizure type (Granata & Battaglia,
and memory function. He had completed 2 2008). The onset of seizures occurs most fre-
years of college education, earned an associ- quently in early or late childhood, although
ate’s degree, and managed a successful land- many cases have had onset in either early
surveying business. He showed no evidence infancy or adulthood. Patients diagnosed
of cognitive or emotional dysfunction, and with bilateral clefts typically have an onset
his only reason for seeking treatment was of seizures before 3 years of age (Guerrini
the onset of seizures at 26 years of age. This & Marini, 2006). According to Packard
case example provides evidence for the com- and colleagues, good seizure control can be
pensatory mechanisms of the unaffected achieved in many cases.
hemisphere in some cases of schizenceph-
aly. Brown and colleagues raise the question
Assessment
about undetected cases of schizencephaly as
a result of apparently normal functioning in According to guidelines published by the
some individuals. American Academy of Neurology and Child
Neurology Society (Shevell et al., 2003),
evaluation of children who display develop-
Epileptic Seizures
mental delays should include various forms
Epilepsy may be the most serious compli- of assessment. The consensus-based recom-
cation associated with schizencephaly, and mendations include obtaining a detailed
seizures are often the presenting symptoms family and medical history to assess for
(Granata et al., 2005; Menkes & Sarnat, familial and prenatal risk factors; conduct-
2000). They occur in 40–65% of cases ing a comprehensive physical exam; screen-
(Granata et al., 2005), and in one large re- ing for auditory and/or visual impairments;
view conducted by Granata and colleagues and metabolic and electroencephalographic
(1997), 80% of participants reported sei- monitoring for individuals who present with
zures. According to Golden (2001), schizen- suspected seizure activity. When assessment
cephaly frequently co-occurs with polymicr- protocols reveal physical complications, such
ogyria, and since most infants and children as motor impairments or seizures, neuroim-
with different forms of polymicrogyria pres- aging is strongly recommended to rule out
an underlying cortical malformation (Shev- be used as a first-line neuroimaging tech-

ell et al., 2003). nique for patients who have seizures (Bark-
In addition, a full neuropsychological ovich & Kuzniecky, 1996).
evaluation is a valuable resource for obtain- The use of positron emission tomography
ing information about a patient’s cognitive, (PET) and single-photon emission computed
motor, behavioral, language, and executive tomography (SPECT) to detect seizures has
functioning abilities. Developmental disor- proven helpful, but because these function-
ders require detailed assessment of cogni- al imaging techniques lack specificity, they
tion, academic achievement, and psychoso- have not been sufficient in determining the
cial adjustment for proper identification and exact location of the malformation of cor-
as a guide to their management. Academic tical development (Barkovich & Kuzniecky,
placement in special education and resource 1996). Typically, PET and SPECT may be
classrooms may be needed. utilized as additional resources when pos-
sible treatments for associated seizures are
being evaluated.
Neuroimaging
Prenatal ultrasound can be utilized as an
Treatment
initial screening exam, and one of the ad-
vantages of brain ultrasonography is that it Treatment for schizencephaly is primar-
can be used for the detection and manage- ily determined by the level of impairment
ment of neonatal disease in the preterm in- caused by commonly associated conditions,
fant. It is a noninvasive and radiation-free such as seizures, cognitive delays, and motor
procedure, and scanning technology has deficits. The involvement of various medical
improved the ability to visualize cortical and rehabilitative specialists in providing
dysplasias in the neonatal brain (Rodriguez treatment and care is essential for improving
& Poussaint, 2007). According to Brant and a person’s overall development. Occupation-
Helms (2006), prenatal ultrasounds may deal and physical therapy services may pro-
tect only large, open-lipped schizencephaly vide individuals with interventions focused
clefts; therefore, multiple imaging planes are on improving fine and gross motor skills,
often necessary to optimally visualize the or assistance and training in the use of mo-
clefts and migrational anomalies. bility devices. Speech therapy services may
Neuroimaging advancements have en- also be necessary when someone presents
hanced the ability to detect schizencephaly with a language delay. The implementation
clefts (Clark, 2004). Magnetic resonance im- of an individualized educational program
aging (MRI) is preferred over x-ray comput- may be necessary for those individuals with
ed tomography (CT), since the low-contrast language or cognitive deficits (Granata &
resolution of the CT makes it difficult to Battaglia, 2008).
differentiate between the gray matter of the Treatment for seizures depends largely on
cortex and white brain matter (Barkovich & their severity and responsiveness to medica-
Kuzniecky, 1996). Overall, MRI is consid- tion or surgical interventions. According to
ered superior to other imaging techniques Granata and Battaglia (2008), some individ-
because it provides excellent cortical detail, uals’ seizures are unresponsive to antiepilep-
and it can detect with higher quality associ- tic drugs, and surgery should be considered.
ated features such as absence of the sylvian Hydrocephalus is a common condition in
vasculature, thinning of the corpus callo- children who have open-lipped clefts; there-
sum, and absence of the septum pellucidum fore, treatment may require the use of ven-
(Arantes et al., 2007). MRI is also preferred tricular shunts to reduce the abnormal CSF
since it can provide contrast detail between pressure (Packard et al., 1997).
different tissues with very similar densities,
such as that between gray and white brain
matter. It is the preferred imaging modality Anencephaly
for patients with epilepsy who are suspected
of having a disorder of cortical development Anencephaly is a malformation that is char-
(Barkovich & Kuzniecky, 1996). Further- acterized by partial or total absence of the
more, it has been recommended that CT not cerebral structures and of the cranial vault.
It is also characterized by abnormal devel- the sample had children who died within an
opment of the skull base (Calzolari, Gambi, hour of birth, and that by 24 hours the per-
Garani, & Tamisari, 2004). centage increased to 67%. The longest sur-
vivals reported in this sample were 10, 18,
and 28 days (Jaquier et al., 2006).
History
Anencephaly was first described by E. Geof-
Risk Factors
froy Saint-Hillare in the paleopathological
for Phenotypic Expression
literature in his descriptions of an anen-
cephalic infant mummy (cited in Miller & The etiology of anencephaly remains unclear.
Simon, 2001). Causes that have been suggested include an-
tiepileptic drugs, mechanical insult, environ-
mental factors, radiation, and chromosomal
Developmental Course
abnormalities (Arnold et al., 2001; Calzolari
Anencephaly is the most severe form of a et al., 2004; Lewis, Van Dyke, Stumbo, &
neural tube disorder. It is also one of the Berg, 1998; Volpe, 1995; Winsor, McGrath,
most lethal congenital defects, as it comes Khalifa, & Duncan, 1997). Anencephaly is
with a 100% mortality rate in the neonatal more common in whites than blacks, and is
period (Forrester & Merz, 2003). Also asso- more often seen in families of lower socio-
ciated with this condition is the malforma- economic status (Volpe, 1995). The risk for
tion of other organs (Calzolari et al., 2004). anencephaly increases when the mother is
Studies of the pathogenesis of anencephaly either especially old or young (Arnold et al.,
suggest that the condition arises from a fail- 2001; Volpe, 1995). In addition, the risk is
ure of the neural tube to close or a reopen- higher for mothers with diabetes (Naidich et
ing of the neural tube after original closure al., 1992).
(Arnold, Lang, & Sperber, 2001; Kashani Research has demonstrated that women
& Hutchins, 2001; Matsumoto, Hatta, with a history of miscarriage in previous
Moriyama, & Otani, 2002). Others suggest pregnancies were 4.58 times more likely to
that the condition arises from exancephaly, have a child with anencephaly than women
a condition where the cerebral tissue is de- who did not have this history, and this find-
stroyed in utero (Cox, Rosenthal, & Hol- ing was independent of a mother’s age and
sapple, 1985; Kashani & Hutchins, 2001; number of pregnancies (Blanco-Muñoz, Lac-
Matusmoto et al., 2002). asaña, & Borja-Aburto, 2006). This finding
does not necessarily mean that miscarriage
itself is the cause, but it suggests that com-
Prevalence
mon mechanisms could be involved in both
The frequency of anencephaly is approxi- events. Researchers suggest that environ-
mately 0.5–2 births per every 1,000 live mental factors present during the multiple
births (Calzolari et al., 2004; Naidich, Alt- pregnancies, genetic factors, or a combina-
man, Braffman, McLone, Zimmerman, tion of both could be involved in the etiology
1992). Females seem to be more susceptible, of both events (Blanco-Muñoz et al., 2006).
as they are affected more frequently, at a rate They additionally hypothesize that the pre-
of 3–4:1 (Calzolari et al., 2004; Naidich et vious miscarriages could also have involved
al., 1992). Survey data of parents with a pre- some type of neural tube disorder, as the
natal diagnosis of anencephaly revealed that frequency of congenital malformations is
approximately 5% of the families affected greater in miscarriages than in live births
had a family history of neural tube disorders (Blanco-Muñoz et al., 2006; Nishimura,
(Jaquier, Klein, & Bolthauser, 2006). Uwabe, & Shiota, 1987).
Finally, a lack of folic acid in the mother’s
diet is a risk factor that has been well docu-
Biological and Neuropsychological
mented. Folic acid assists with neural tube
Factors
closure, and the U.S. government began for-
Infants born with anencephaly die quickly. tification of foods with folic acid in 1998.
Survey data of 211 pregnancies with prenatal Since this fortification process began, re-
diagnoses of anencephaly found that 28% of searchers have found an 18–30% drop in
malformations of the neural tube, which

include both anencephaly and spina bifida
(Robbins et al., 2006).
In 1991, there was a large cluster of an-
encephalic births in Brownsville, Texas. In
response to this event, the state of Texas es-
tablished the Texas Birth Defects Registry
in 1993 (Canfield et al., 2009). This has al-
lowed for more detailed study of anenceph-
aly in Texas. Analysis of this data suggests
that prevalence is higher in Hispanics, in
those who live on the Texas–Mexico border,
in women with a larger number of previous
live births, in women pregnant with female
infants, in mothers older than 40, in women
with no record of prenatal care, and among
women with less than 7 years of education
(Canfield et al., 2009).
Assessment
As discussed above, the mortality rate for
anencephaly is high, and death occurs rapid-
ly; therefore, there are few to no assessment
data for this disorder. What data do exist
come from case studies. Calzolari and col-
leagues (2004) completed an MRI case study
of a male infant 8 hours after his birth. They
found the presence of the brainstem and cer-
ebellum, with normal development of the
eyes. They suggest that these results support
the theory of anencephaly as a transforma-
tion from exancephaly. MRI assessment can
be helpful in distinguishing anencephaly
from other disorders, as some disorders that
may appear similar have anatomical condi- FIGURE 27.4. T2-weighted images of a 4-year-
tions that are compatible with survival (Cal- old male with lissencephaly and cerebellar hyp-
zolari et al., 2004). oplasia (note diffuse pachygyria). (Courtesy of
David Leake, MD, Austin, Texas.)
Treatment
With a 100% mortality rate and a short
lifespan, treatment for anencephaly is medi- (lack of gyri) to pachygyria (broad gyri) (Ta-
cal and palliative in nature. kanashi, Tada, Fujii, & Barkovich, 2007).
Most patients with this disorder have a com-
bination of areas of agyria and pachygyria
Lissencephaly (Leventer, 2008). Agyria is considered more
severe than pachygyria, which tends to be
General History and Description associated with a broader spectrum of clini-
Owen originally used the term lissenceph- cal features (Liang, Lee, Young, Peng, &
aly in 1868 (cited in Hynd, Morgan, & Shen, 2002).
Vaughn, 2009). Generally, the term is used There are two types of lissencephaly.
to describe a brain that is deficient in gyra- Dambska, Wisniewski, and Sher (1983)
tion (Leventer, 2008) (see Figure 27.4). This were the first to divide it into type I and type
deficiency can range from complete agyria II lissencephaly. Type I lissencephaly is also
referred to as classical lissencephaly; type can also present with feeding problems (Lev-
II lissencephaly is sometimes referred to as enter, 2008). Finally, acquired microcephaly
cobblestone lissencephaly. The type I–type can also be present (Gleeson, 2001).
II and classical–cobblestone distinctions are Seizures typically begin in the first year of
both used in current literature (Leventer, life and progress into intractable mixed sei-
2008). For the purposes of this chapter, the zure disorder as the patients grow older (de
remainder of the information is presented Rijk-van Andel et al., 1992; Gleeson, 2001;
separately for classical and cobblestone lis- Leventer, 2008). There are some reports of
sencephaly. Both classical and cobblestone fetal-onset seizures as well (Patante & Ghi-
lissencephaly are migration disorders. dini, 2001). Different forms of classic lissen-
cephaly are more severe and can contribute
Classical Lissencephaly to a shorter lifespan. These forms include
Miller–Dieker, X-linked lissencephaly with
History abnormal genitalia, lissencephaly with com-
As mentioned above, lissencephaly was first plete agenesis of the corpus callosum, and
described as such in 1868 by Owen. It was lissencephaly with extreme cerebellar hyp-
also the first of the human cortical mal- oplasia (Leventer, 2008).
formations for which the genetic basis was
identified (Leventer, 2008). In classical lis- Genetic and Family Patterns
sencephaly, the brain shows poorly defined
sylvian and rolandic fissures and thickening The primary genes that have been identified
of the cerebral cortex (Harding & Copp, in classical lissencephaly are the L1S1 gene
2002; Leventer, 2008). Severe cases can and Doublecortin (Clark, 2004, Gleeson,
present with failure to develop the primary 2001; Leventer, 2008). Within X-linked lis-
sulci (Harding & Copp, 2002). In addition, sencephaly, the abnormalities in these genes
some areas of the brain may appear more se- give rise to differences in the localization
verely affected than others, which could be of the severity of gyral abnormalities: Dou-
due to the type of gene mutation (Dobyns et blecortin mutations result in greater anterior
al., 1999). That is, depending on the type of than posterior severity, and L1S1 mutations
gene mutation, there may be increased sever- result in the opposite pattern (Clark, 2004;
ity in the posterior or anterior portions of Dobyns et al., 1999). Because it is X-linked,
the cortex. Increased gray matter is present this subtype of lissencephaly occurs mostly
at a rate of 1–4 cm versus a typical 0.5 cm in boys, with girls often expressing band
(Gleeson, 2001; Kuchelmeister, Bergmann, heterotopia (Gleeson et al., 1998, 2000; Pilz
& Gullotta, 1993). Classical lissencephaly et al., 1998). Women with band heterotopia
includes a range of disorders that differ in are at risk for giving birth to boys with lis-
severity. These disorders include Miller– sencephaly (Clark, 2004). Lissencephaly
Dieker syndrome, isolated lissencephaly se- with cerebellar hypoplasia has been shown
quence, X-linked lissencephaly with abnor- to be related to mutations in RELN, an
mal genitalia, lissencephaly with cerebellar important secretory extracellular protein
hypoplasia, and microlissencephaly (Clark, (Hong et al., 2000). Some types of lissen-
2004; Gleeson, 2001; Leventer, 2008). cephaly are passed in an autosomal recessive
fashion (Clark, 2004). Other genes implicat-
ed in various types of classical lissencephaly
Developmental Course include the 14-3-3€ gene and the ARX gene
Children born with lissencephaly tend to (see Leventer, 2008, for a review of gene im-
have a shortened lifespan, but the exact de- plications).
gree can vary by subtype (Garg, Sridhar, &
Gulati, 2007; Leventer, 2008). These pa- Biological and Neuropsychological Markers
tients also present with severe to profound
mental retardation (de Rijk-van Andel, Arts, These patients present with severe to pro-
& de Weerd, 1992; Gleeson, 2001; Leventer, found mental retardation (de Rijk-van Andel
2008). They often have early hypotonia that et al., 1992; Gleeson, 2001; Leventer, 2008).
can persist or evolve (Leventer, 2008); they The Miller–Dieker subtype also includes
facial dysmorphism, which can consist of sessed neurophysiologically, this same child
bitemporal hollowing, upturned nares, and was shown to have a lack of somatosensory-
burying of the upper lip by the lower lip at evoked potentials. The researchers argue
the corners of the mouth (Clark, 2004; Lev- that the results of the evoked potential study
enter, 2008). might explain the worse clinical outcome
for this child, and suggest that this type of
evaluation should be used in the future to
Risk Factors for Phenotypic Expression
help supplement more standard neuroimag-
Some research has examined group differing evaluations.
ences in clinical features. Kurul, Çakmakçi
and Dirik (2004) separated patients with lis- Assessment
sencephaly into two groups; one group had
bilateral or generalized gyral malformations, Classical lissencephaly tends to be assessed
and the other group had manifested local or through neuroimaging. The images can be
unilateral malformations. In this study, the classified by severity on a grading system
group with the generalized gyral malforma- such as that of de Rijk-van Andel and col-
tions demonstrated a higher ratio of seizures leagues (1990). In addition, evaluations of
and more frequent seizures than the other cognitive and adaptive functioning are used
group. These patients also became symp- to classify the levels of mental retardation
tomatic earlier than the patients with local and developmental functioning.
or unilateral malformations. Moreover, this
study found a high rate of family history for Treatment
neurological diseases (e.g., seizure disorders
and mental retardation). With the high degree of medical complica-
Liang and colleagues (2002) found that tions in patients with lissencephaly, such as
patients in their sample with agyria, as op- intractable seizures, the treatment is gener-
posed to pachygyria, tended to have worse ally medical in nature. There is the oppor-
outcomes. They also found that patients tunity for appropriate developmental treat-
with earlier onset of seizures had worse out- ments as warranted by specific deficits in
comes. These researchers classified the de- motor, sensory, communicative, and cogni-
gree of lissencephaly according to neuroim- tive functioning.
aging findings, using a system modified from
de Rijk-van Andel, Arts, Barth and Loonen Cobblestone Lissencephaly
(1990). The system Liang and colleagues uti-
lized ranked the patients from grade 1, which History
would indicate complete agyria, to grade 6, Cobblestone lissencephaly was first described
which would indicate focal pachygyria in by Walker (1942). This disorder is associ-
less than 50% of the cortex. Intermediate ated with eye abnormalities, muscle disease,
gradations included agyria with some sulci, and progressive hydrocephalus, all of which
a mixture of agyria and pachygiria, com- help distinguish this disorder from classi-
plete pachygyria, and focal pachygyria in cal lissencephaly (Clark, 2004; Topaloglu
more than 50% of the cortex. Liang and col- & Taim, 2008). Krijgsman and colleagues
leagues also used neurophysiological studies (1980) first reported the muscular dystrophy
to predict the neurological outcome of these associated with cobblestone lissencephaly.
patients. They found that somatosensory- Cobblestone lissencephaly is part of a com-
evoked potential evaluation was helpful be- plex of symptoms that constitute muscle–
yond neuroimaging in predicting the clini- eye–brain disease (Gleeson, 2001). Patients
cal outcome of the patients. Specifically, one with cobblestone lissencephaly have deficient
child in their study was classified as having gyration and sulci, similar to those in classi-
a less severe outcome based on neuroimag- cal lissencephaly; in addition, the cortex has
ing alone; however, he was shown to have a a pebbled or “cobblestone” appearance, due
worse clinical outcome than those classified to an abnormal migration of gray matter to
by neuroimaging methods as having more the cortical surface (Clark, 2004; Gleeson,
severe outcomes. When the children were as- 2001; Topaloglu & Taim, 2008).
Developmental Course sical lissencephaly, evaluations of cognitive

and adaptive functioning are used to classify
Cobblestone lissencephaly is due to a defect
the levels of mental retardation and develop-
in neuronal migration in which neurons pass
mental functioning.
their normal stopping point and erupt over
the surface of the cortex into the subarach-
noid spaces and the pia, causing the cobble- Treatment
stone appearance (Clark, 2004; Gleeson, The treatment for patients with cobblestone
2001; Topaloglu & Taim, 2008). Similar lissencephaly is often medical in nature,
to classical lissencephaly, cobblestone lis- with physical therapy as needed to address
sencephaly also has various subtypes; in the motor concerns. There is also the op-
this case, they include Walker–Warburg portunity for developmental treatments as
syndrome, muscle–eye–brain syndrome, needed.
and Fukuyama muscular dystrophy (Clark,
2004; Gleeson, 2001; Topaloglu & Taim,
2008). Fukuyama is distinguished from the Case Example
other types by the severity of the muscular
dystrophy associated with the condition Because the clinical features of these dis-
(Clark, 2004; Fukuyama, Ohsawa, & Su- orders can vary widely, we present a case
zuki, 1981) example of structural anomalies observed
in our clinic. This is not a straightforward
Genetic and Family Patterns case of lissencephaly or schizencephaly, but
rather an example of structural abnormali-
For the majority of these disorders, no genes ties with a typical range of clinical features.
have been isolated. The Fukuyama subtype The patient was a European American fe-
is seen more often in Japan, and is thought male who was 10 years old at the time of
to be related to a founder mutation in fami- the assessment. She had multiple congenital
lies of those affected (Clark, 2004). Recent- abnormalities, including congenital deafness
ly, researchers identified Fukutin as a caus- that was not conducive to cochlear implant,
ative gene in this disorder (Kobayashi et al., due to dysgenesis of the cranial nerve. She
1998). It is inherited in an autosomal reces- also presented with a malformed right ear,
sive fashion (Clark, 2004). submucosal cleft palate, bifid uvula, dislo-
cated left hip, small retinal coloboma, and
Biological and Neuropsychological Markers plagocephaly. A genetic study had been per-
formed, and no clear genetic causative fac-
The aforementioned muscular dystrophy tors were found. MRI showed smaller pos-
is one of the main biological markers for terior frontal and anterior temporal lobes on
this set of disorders (Clark, 2004; Gleeson, the left side than on the right. In addition,
2001; Topaloglu & Taim, 2008). Other ab- there was evidence of mild pachygyria in
normalities that can be seen in cobblestone the left frontal temporal cortex. The patient
lissencephaly include ocular anterior cham- had also developed feeding problems that re-
ber abnormalities, retinal dysplasias, hydro- quired the insertion of a G peg; she was still
cephalus, and encephaloceles (Clark, 2004). using this at the time of the assessment for
As in classic lissencephaly, mental retarda- fluid and nutrient intake.
tion and epilepsy are commonly seen in these Neuropsychological testing results
patients (Gleeson, 2001). In the Fukuyama showed weaknesses in academic function-
type, there is more severe muscular dystro- ing, fine motor functioning, and executive
phy, and patients can present with evidence functioning. Cognitive functioning was in
of hypotonia and depressed reflexes (Clark, the low-average range, as measured by the
2004). Test of Nonverbal Intelligence—Third Edi-
tion. These results were consistent with her
frontal lobe abnormalities as seen on MRI.
Assessment
She had particular difficulty with language-
Cobblestone lissencephaly also tends to be related academic skills, including reading
assessed through neuroimaging. As in clas- and written expression. These difficulties
were consistent with her temporal lobe mations of cortical development. Neurology, 65,
abnormalities. There was some evidence of 1873–1887.
a left-sided visual field deficit or visual ne- Blanco-Muñoz, J., Lacasaña, M., & Borja-Aburto,
glect; there was also some evidence of stra- V. (2006). Maternal miscarriage history and risk
of anencephaly. Paediatric and Perinatal Epide-
bismus. miology, 20(3), 210–218.
Brant, W. E., & Helms, C.A. (2006). Fundamentals
of diagnostic radiology. Philadelphia: Lippincott
Conclusion Williams & Wilkins.
Brown, M. C., Levin, B. E., Ramsay, R. E., &
Many well-deserved superlatives have been Landy, H. J. (1993). Comprehensive evaluation of
used to describe the development and func- left hemisphere type I schizencephaly. Archives of
tioning of the human brain. As described by Neurology, 50, 667–669.
Nobel laureate Eric Kandel (2007), “The Calzolari, F., Gambi, B., Garani, G., & Tamisari,
brain is a complex biological organ of great L. (2004). Anencephaly: MRI findings and patho-
genetic theories. Pediatric Radiology, 34(12),
computational capability that constructs our
1012–1016.
sensory experiences, regulates our thoughts Canfield, M., Marengo, L., Ramadhani, T., Suarez,
and emotions, and controls our actions.” L., Brender, J., & Scheuerle, A. (2009). The prev-
Lest we take this for granted, the structural alence and predictors of anencephaly and spina
anomalies that we have discussed illustrate bifida in Texas. Paediatric and Perinatal Epide-
the complexity of this 3-pound organ that miology, 23(1), 41–50.
is at the center of who we are as human be- Carlson, N. R. (2007). Physiology of behavior (9th
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Chudler, E. H. (2009). Brain development. In Neu-
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Chapter 28
Spina Bifida Myelomeningocele
Angela Giacoletti Argento

Seth A. Warschausky
Laura Shank
Joseph E. Hornyak
This chapter is an overview of the phenotyp- only about 10%. Improved management (es-
ic physical and neurocognitive profile found pecially improvements in surgical repair and
among children and adolescents with spina antibiotics) has dramatically decreased mor-
bifida myelomeningocele (SBM). Spina bi- bidity and mortality (Bowman, Boshnjaku,
fida (SB) refers to a subgroup of neural tube & McLone, 2009). The present chapter fo-
defects (NTDs) in which there is incomplete cuses exclusively on SBM and its etiology, ef-
closure of the spinal component of the neu- fects, and neurological expression.
ral tube. SB can be categorized as spina bi- NTDs are relatively common congenital
fida occulta (SBO) and spina bifida cystica malformations, occurring at a rate of 1–2
(SBC). SBO is a common disorder, reported
at rates as high as 5–36% in an asymptom-
atic population. It is the result of a failure of
the posterior elements of the spinal column
to close completely, with no abnormalities
to the neural elements. A birthmark, tuft
of hair, or dimple may overlie the defect.
SBC involves a cystic structure overlying the
bony defect, which may be noted intrauter-
ine or at the time of birth. The makeup of
the cystic structure may or may not cause
neurological effects. A meningocele is a her-
niation of the meninges through the defect,
with no neural elements. A lipomeningocele
includes a herniation of the meninges with
an accompanying lipoma, but again no neu-
ral elements. A myelomeningocele is the
most serious form, with neural elements of FIGURE 28.1. Spina bifida myelomeningocele
the spinal cord herniating through the defect (SBM). From Centers for Disease Control and
within the meningeal sac (see Figure 28.1). Prevention, National Center on Birth Defects
Prior to the 1950s, survival for SBM was and Developmental Disabilities.
554
Spina Bifida Myelomeningocele 555
per 1,000 births (Copp, Greene, & Mur- larity, signaling. Core PCP genes have been
doch, 2003; Kibar, Capra, & Gros, 2007). identified in animal models, and disruption
There is significant temporal, geographic, of those genes in turn disrupts neurulation.
and ethnic variation in prevalence. For ex- However, there is not yet a precise under-
ample, there is very low prevalence among standing of PCP regulation of CE.
African Americans, but not among sub- NTDs are not simple Mendelian traits—
Saharan Africans (Njamnshi et al., 2008). the results of a single, pathogenic dominant
There is low prevalence among the Japanese, or recessive gene—but polygenic disorders
but very high prevalence in Shanxi Province resulting from the interaction of a number
in China (Li et al., 2006). Individuals of of genes with each other, as well as with
Celtic origin are at particularly high risk for environmental factors (Carter, 1969). Over
NTDs (Gordon, 1995). the last few decades, a great deal of research
Evidence of NTDs in humans predates has gone into trying to understand both the
written history. Skeletons discovered in a genetic and the environmental factors that
cave in Morocco from 10,000 B.C.E. includ- lead to NTDs. From a genetic standpoint,
ed split sacral vertebra (Smith, 2001). After the mouse has been a convenient animal
5000 B.C.E., skeletal evidence of SB was to look for candidate genes. Almost 200
more common. In the 17th century, descrip- mutant mouse models of NTDs have been
tions of SB include those of Nicolas Tulp developed, with known genes in 155 mod-
(1593–1674) in his most prominent book, els, 33 with unidentified genes, and 8 being
Observationes Medicae (1641); this vol- considered multifactorial strains (Harris
ume included a detailed sketch, possibly by & Juriloff, 2007). Many of these models
Rembrandt (Simpson, 2007). Yet SB was not are knockouts, in which a single gene is
widely known until the 19th century, when switched off. Although knockouts are com-
von Recklinghausen published a classic de- monly used, they represent models of a sin-
scription of SB in 1886. gle gene disorder, which seems to be similar
NTDs stem from partial or complete fail- to a known disease. If the disease in question
ure of neural tube closure during primary is monogenic in nature, the knockout may
neurulation. The most common forms of provide an accurate model, but for polygenic
NTDs are anencephaly and myelomenin- traits, they may be of limited value (Koch &
gocele. Etiology appears to involve environ- Britton, 2007, 2008). Currently, none of the
mental factors, such as geography; demo- genes identified in mouse models have been
graphics, including socioeconomic status, correlated with human NTDs. The mouse
maternal age, and maternal health; and model genes have a high level of penetrance,
teratogens. Increasing evidence of genetic while that is not the case in human NTDs.
influences include associations with chro- This may suggest that if any of these candi-
mosomal abnormalities, genetic syndromes, date genes are involved, that it may not be
ethnicity/race, and familial distributions directly, but possibly through regulation of
(Kibar et al., 2007). Heritability is estimated expression of these genes (Harris & Juriloff,
at 60%. 2007).
These unknown genetic factors result in
an increased familial incidence. After a single
Genetic and Environmental Causes NTD, the recurrence rate is reported as 2.4–
of NTDs 5%; after a second NTD, this risk doubles
(Cowchock et al., 1980). This also increases
Recent increased understanding of the com- the risk in other relatives, most significantly
plex processes involved in neurulation has in siblings, less so in second- and third-degree
informed the search for genetic influences relatives (Toriello & Higgins, 1983).
on NTDs. Initial steps in neurulation in- A number of environmental factors have
clude formation and shaping of the neural been identified that increase the risk of
plate. Initial elongation of the neural plate is NTDs. These environmental factors do not
driven by a complex process called conver- always cause NTDs, but most likely are in-
gent extension (CE). CE movements during volved as the result of a susceptible genome.
neural tube closure are mediated by planar These include low socioeconomic class, mid-
cell polarity pathway (PCP), or tissue po- spring conception, maternal obesity, and in-
creased intrauterine temperatures (Milunsky MTHFR mutations have been associated

et al., 1992; Nevin, Johnston, & Merrett, with increased risk for NTDs. Other folate-
1981; Sandford, Kissling, & Joubert, 1992; related genes have also been implicated.
Watkins, Scanlon, Mulinare, & Khoury, In summary, NTDs are disorders result-
1996). A number of medications such as the ing from the interaction of a susceptible
antiepileptic medications carbamazepine genome (polygenic trait) with one or more
and valproic acid have been identified as environmental factors. The risk for NTDs
teratogenic, increasing risk for NTDs (Lind- may be associated with maternal or embry-
hout, Omtzigt, & Cornel, 1992; Weinbaum onic gene–gene and/or gene–environment
et al., 1986). interactions. The genetics of NTD risks have
Perhaps the most significant environmen- been studied in animal models with natural
tal factor relating to NTD has been folate and or experimentally induced mutations. To
folic acid. Folic acid (pteryolmonoglatamic date, scores of candidate genes have been
acid) is a synthetic vitamin, B9, with folate identified, typically affecting fundamental
being its naturally occurring analog. Meta- processes of neurulation, but none has been
bolically, folic acid plays an essential role in shown conclusively to play a major role in
the transfer of single carbon units for DNA the etiology of the NTDs. Folic acid is an
synthesis, and thus important for cell multi- important environmental agent, with supple-
plication and fetal development. In addition, mentation resulting in a markedly decreased
folic acid serves as a methyl group donor for risk of NTDs.
protein methylation of some cytoskeletal
proteins that are highly expressed in neural
ectoderm, which eventually forms the brain Physical Aspects of SBM
and spinal cord (Moephuli, Klein, Baldwin,
Sensory–Motor Effects
& Krider, 1997). A possible link between
folate and NTDs was first proposed in 1976 Myelomeningoceles are typically seen at the
by Richard Smithells (Smithells, Sheppard, thoracic and lumbosacral levels, as cervical
& Schorah, 1976). This has led to numerous lesions are usually incompatible with life.
studies that have demonstrated the effective- These lesions will result in motor (volun-
ness of folic acid supplementation on de- tary and autonomic) and sensory deficits at
creasing the incidence of NTDs by 50–70% and below the level of the lesions. With the
(Botto et al., 2005; Eskes, 2000; Habibza- sparing of the upper extremities, this is de-
deh, Schorah, Seller, Smithells, & Levene, fined as paraparesis. Paraparesis in SBM is
1993; Schorah, Habibzadeh, Wild, Smith- most consistent with a lower-motor-neuron
ells, & Seller, 1993; Schorah & Smithells, (LMN) syndrome, with occasional upper-
1993; Schorah, Wild, Hartley, Sheppard, motor-neuron (UMN) syndrome features.
& Smithells, 1983; Smithells, 1982, 1989; This is in contrast to most traumatic spinal
Smithells et al., 1981a, 1981b, 1983, 1985; cord injuries, which are primarily UMN
Smithells, Sheppard, & Wild, 1989; Smith- syndromes. Individuals with SBM will typi-
ells, Sheppard, Wild, & Schorah, 1989; Wild cally have a flaccid paralysis, decreased
et al., 1986). muscle tone, areflexia, and marked muscle
Thus the study of genes that predispose atrophy. UMN signs (especially spasticity)
humans to NTDs has focused on folate- may be present with higher lesions, if there
related genes, given the efficacy of prenatal is sparing of some LMNs and sensory sys-
folic acid in reducing incidence of NTDs. The tems. New findings of UMN signs suggest
folate-related genes of interest include those a possible new pathological event (e.g., cord
involved in transport mechanisms and those tethering, tumor), which may require further
involved in metabolism. There is evidence medical evaluation. Table 28.1 lists features
that some mothers of children with NTDs of the UMN and LMN syndromes.
have autoimmune responses that block up- The higher the level of the lesion, the
take of folate. The most extensively studied more proximal the involved muscle group
gene involved in metabolism of folate is the will be, causing more impairment of func-
MTHFR gene, which regulates the extent to tion. Thoracic lesions will affect trunk and
which folate is available as a methyl donor all muscles of legs, while low sacral lesions
for methylation of DNA and transfer RNA. may only affect urinary and anal sphincters.
TABLE 28.1. Comparison of Lower-Motor-Neuron (LMN) and Upper-Motor-Neuron (UMN)

Syndromes
LMN syndromes UMN syndromes
Weakness Yes Yes
Tone Decreased (hypotonic or flaccid) Increased (spasticity)
Tendon reflexes Diminished or absent Increased
Cutaneous reflexes (e.g., Babinski) Normal or no response Abnormal response present
Contractures Yes, tend to be positional Yes, tend to reflect tone patterns
It is common for there to be some asymme- Orthopedic Complications

try in the motor and sensory involvement
Contractures are very common in SBM,
between the two sides, as the malformation
due to a lack of innervation to the muscles
is a bit haphazard. Sensory loss is in a rough
surrounding a joint. Contractures may
dermatomal pattern, again with variation
based on the disorganization of the spinal be present at birth or may develop later in
cord. This loss of sensation puts a patient life. Stretching is the primary treatment for
with SBM at risk for injuries. Pressure sores contractures, although surgical procedures
are very common in asensate areas that are may be necessary when these are severe.
exposed to pressure (e.g., buttocks, heels). Kyphoscoliosis in SBM results from a num-
Fractures can occur in the lower extremi- ber of factors. It may be present at birth or
ties with no pain. Individuals with SBM are may develop later in childhood. The under-
also at higher risk for associated local os- lying spinal deformity provides a poor base
teopenia from poor innervation and lack of of support for the spine above it, causing
weightbearing. the generation of abnormal spinal curves.
Abnormal curves may also develop as a re-
sult of weakness and strength imbalance of
Neurogenic Bowel and Bladder paraspinal muscles. Treatment may be ob-
Bowel and bladder control is located primar- servation, bracing, or surgical fusion, de-
ily at the sacral levels, and thus is affected pending on the extent of the scoliosis and its
in almost all cases of SBM. The bladder is impact on functioning (Brown, 2001).
typically flaccid, with relaxed sphincters.
This leads to a high-capacity, low-pressure Latex Allergy
bladder, often with spontaneous leakage. If
the bladder does not empty well, there may Allergic reactions to latex and related aller-
be ureteral reflux, eventually leading to hy- genic substances (e.g., tomatoes, bananas)
dronephrosis (dilation of the more proximal are very common in SBM. The cause for this
urine-collecting system) with kidney dam- is unknown; perhaps such allergies are relat-
age. At a young age, children may just use ed to early exposure to surgical procedures,
diapers. At about the time typical children though they are not as common in other
are being toilet-trained, bladder catheteriza- disorders having similar early exposure. Re-
tion via the urethra can result in adapted actions vary from contact dermatitis to risk
urinary continence. Urological surgical pro- of anaphylaxis. Latex and cross-reacting
cedures are available to augment bladder substances need to be avoided, though this
size and create a diversionary stoma on the can be quite difficult, as latex is a very com-
abdominal wall to ease self-catheterization monly used substance (Eustachio, Cristina,
(de Jong, Chrzan, Klijn, & Dik, 2008; Jo- Antonio, & Alfredo, 2003).
seph, 2008). Bowel continence is also an
issue. As a child approaches toilet-training
Sleep-Disordered Breathing
age, a bowel program can be implemented
to achieve adapted continence (King, Currie, There is a 20% prevalence of moderate to
& Wright, 1994; Leibold, 1991). severe sleep-disordered breathing (SDB)
in children with SBM (Kirk, Morielli, & SBM and their implications. Bannister and
Brouillette, 1999). Up to 50% of individuals colleagues (2005) provide evidence from rat
with the Arnold–Chiari type II malforma- and human studies of the importance of ce-
tion (see below) evidence sleep apnea, and rebrospinal fluid (CSF) in neuronal develop-
the majority of these are children (Dauvil- ment and migration. In SBM, the lack or re-
liers et al., 2007). Unfortunately, only a duction of CSF, which contains growth and
small proportion of children receive a sleep signaling factors, within the subarachnoid
study. SDB can be associated with sudden, spaces of the developing brain is proposed to
unexplained death during sleep, as well as lead to the observed abnormalities in corti-
cognitive impairments (e.g., in attention and cal formation.
memory) and mood/behavior disturbances.
Thus screening for symptoms of SDB and
providing appropriate treatment as indicat- Risk Factors
ed are important aspects of care. for Phenotypic Expression
A number of risk factors for the phenotyp-

Neuropathology in SBM ic expression in SBM have been identified,
including primary and secondary effects
In addition to the physical effects related (Dennis, Landry, Barnes, & Fletcher, 2006).
to the spinal malformation and spinal cord These effects are associated with a pheno-
injury, SBM is associated with characteris- typic neurocognitive profile that ranges from
tic malformations of key brain structures, mild to severe impairment, depending on the
as well as delayed maturation of gray and number and extent of risk factors present
white matter. Ultrasound studies typically for a particular individual. Risk factors in-
conducted by the 18th to 20th week of ges- clude lesion level (thoracic, lumbar, sacral);
tation show a characteristic “lemon-shaped” shunting for hydrocephalus and number of
skull development. Frontally, there is a bi- infections or shunt revisions; seizures (see
lateral narrowing of the frontal lobes, with Yoshida et al., 2006); and the presence and
an associated enlargement of the ventricular number of oculomotor/visual deficits, such
atrium where the frontal, temporal, and oc- as strabismus, nystagmus, papilledema, and
cipital lobes converge at the lateral ventricles optic atrophy. Of particular significance are
(Bannister, Nabiuni, Zendah, Mashayekhi, the presence and extent of characteristic cen-
& Miyan, 2005). Posteriorally, the pons and tral nervous system (CNS) anomalies associ-
medulla are elongated, with an accompany- ated with SBM.
ing deformation of the cerebellar tonsils into
the cervical spinal canal and abnormalities
Primary CNS Risk Factors
of the fourth ventricle. Midbrain anomalies
include a beaked appearance of the mesen- Higher lesion levels are associated with
cephalic tectum. These posterior anomalies greater cognitive and motor impairment
are collectively referred to as the Arnold– (Fletcher et al., 2005; Wills, 1993), and
Chiari type II malformation (ACM). Con- with more extensive anomalies within the
genital abnormalities of the corpus callosum, cerebellum and midbrain structures, than
including the rostrum and/or splenium, are those seen with lower lesion levels (Fletcher
observed in over half of children with SBM. et al., 2005). Dennis, Landry, and colleagues
These abnormalities result from disruption (2006) found that children with lower lesion
of neuroembryogenesis early in gestation levels had greater gray matter volumes in the
(approximately 7–20 weeks), during a period medial cerebellum, and white and gray mat-
of rapid development of the corpus callosum ter volumes in the lateral hemispheres, than
(Barkovich, 2000; Hannay, 2000). The read- those with upper lesion levels.
er is referred to other sources (Bannister et The ACM, which (as noted above) includes
al., 2005; Dennis, Hetherington, & Spiegler, deformation of the brainstem and cerebel-
1999; Fletcher, Francis, Thompson, David- lum, is the most common congenital brain
son, & Miner, 1992; Juranek et al., 2008; anomaly in SBM, occurring in the major-
Stevenson, 2004) for more detailed explana- ity of cases (Barkovich, 2000). In SBM, the
tions of the brain anomalies associated with posterior fossa is small, and portions of the
medulla, fourth ventricle, and cerebellum normalities of the splenium and rostrum,
herniate through the foramen magnum. The with relative preservation of the genu, and
pons, cerebellar vermis, and fourth ventricle are related to prolonged disruption of neu-
thus are elongated. There is a “beaked” ap- roembryogenesis (Barkovich, 1995; Hannay,
pearance to the mesencephalic tectum (Ste- 2000). Anterior brain effects, including ab-
venson, 2004). normalities of the prefrontal and frontal re-
The cerebellum and basal ganglia and their gions, are less well studied but have received
interface with higher cortical systems play a increased attention recently.
role in the acquisition of motor skills, motor
timing, and control of motor performance.
Secondary CNS Risk Factors
These skills include the coordination of eye–
hand movements, as well as sequencing and A number of important secondary CNS ef-
accommodation in response to sensory feed- fects are common in SBM. In particular, the
back (Colvin, Yeates, Enrile, & Coury, 2003; presence of hydrocephalus has implications
Doyon & Benali, 2005; Doyon, Penhune, & for phenotypic expression in SBM. Hydro-
Ungerleider, 2003; Laforce & Doyon, 2001, cephalus is a common complication, affect-
2002; Miall & Reckess, 2002; Salman et al., ing approximately 80–90% of individuals
2005; Thach, 1998). The presence of tectal with SBM. It is caused by an obstruction in
beaking is associated with oculomotor im- the normal flow of CSF, typically as a di-
pairments, including nystagmus (Tubbs et rect result of the ACM. In the newborn, the
al., 2004). open sutures allow for the buildup of CSF,
Vinck, Maassen, Mullaart, and Rotteveel resulting in macrocephaly. In children, the
(2006) investigated the specific contribution ventricles become enlarged, which results in
of the ACM to the information processing increased intracranial pressures and second-
of children with SBM. In addition, differ- ary effects on the brain. Treatment involves
ences in phenotypic expression between placement of a shunt (most commonly ven-
children with a full range of intellect and triculoperitoneal) to remove excess CSF to
children with IQs above 70 were examined. the peritoneum, where it is reabsorbed. As
In the full-range group, the classic picture with any implant, there is a risk of failure
of deficits in perception, visual–motor inte- of the shunt, as well as infection. Failure of
gration, processing speed, verbal skills, se- the shunt results in increased intracranial
quential memory, and arithmetic emerged. pressure. Signs and symptoms of this include
The higher-functioning group demonstrated headache, visual changes, papilledema, in-
a different pattern of deficits in perception, creased motor impairments, somnolence,
verbal memory, and verbal fluency. Vinck and irritability, among others. Shunt failure
and colleagues conclude that the higher- can lead to herniation, so it requires prompt
functioning group of children with ACM medical attention, with magnetic resonance
demonstrated impairments in cognitive imaging (MRI) being the technology of
abilities hypothesized to be mediated by the choice to evaluate for hydrocephalus. Classi-
cerebellum (Leiner, Leiner, & Dow, 1993; cally, children with early hydrocephalus dem-
Schmahmann & Sherman, 1998). Thus, onstrate impairments in visual-perceptual
apart from the effects of hydrocephalus and and motor functions (Dennis et al., 1981;
increased cranial pressures, the cerebellar Donders, Rourke, & Canady, 1991; Fletcher
abnormalities appear to make a unique con- et al., 1992, 1996). The neurocognitive ef-
tribution to the pattern of neurocognitive fects associated with hydrocephalus are ob-
effects observed in SBM. Other CNS abnor- served even when shunting occurs very early
malities include selective thinning of the pos- in life (Donders et al., 1991; Rourke, 1995).
terior cerebral cortex (Dennis et al., 2004; That said, other research suggests that shunt
Salman, Blaser, Sharpe, & Dennis, 2006). placement can improve the neuropsycho-
More than half of children with SBM pres- logical functioning of young adults with as-
ent with agenesis or dysgenesis of the corpus sumed arrested hydrocephalus. Specifically,
callosum, which is associated with white improvements in verbal and visual memory,
matter dysfunction and decreased cross- attention, and cognitive flexibility are seen
hemispheric integration. Primary effects on (Mataro et al., 2000). Later-occurring
the corpus callosum typically result in ab- changes in white matter tracts, including
hypoplasia of the middle, posterior, or full Yeates and colleagues (2003) found NLD in
corpus callosum, are thought to be related to 45% of their sample of children with SBM
hydrocephalus (Hasan, Eluvathingal, et al., and shunted hydrocephalus, as compared
2008; Hasan, Sankar, et al., 2008). with 7% of their typically developing sib-
lings. However, a high degree of phenotypic
variability was observed among the children
Neuropsychological Phenotype with SBM; there were significant individu-
al differences in their pattern of assets and
Intelligence
deficits. These findings highlight the need
The majority of individuals with SBM have for caution against overgeneralization of the
low-average to average intellectual function- NLD model for children with SBM.
ing (Dennis et al., 1981; Mirzai, Ersahin, Deficits in fine motor skills include slowed
Mutluer, & Kayahan, 1998; Soare & Rai- speed and poor dexterity and graphomo-
mondi, 1977). Individuals with SBM and tor construction (Hetherington & Dennis,
hydrocephalus demonstrate lower overall 1999). Difficulties with eye–hand coordina-
cognitive ability than those without hydro- tion may be attributable to deficits in per-
cephalus, whereas individuals with SBO or ceptual and motor timing, which appear in
SBM but no hydrocephalus generally per- turn to be associated with reduced cerebel-
form similarly to typically developing peers. lar volumes (Dennis et al., 2004). Children
Thus the associated neuropathology (in this with SBM demonstrate severe deficits in vi-
case, hydrocephalus) is what largely affects sual planning and sequencing (Snow, 1999).
intelligence, rather than SBM per se (Barf et Consistent with the NLD profile, children
al., 2003; Vinck et al., 2006). with SBM demonstrate reading skills close
to age expectation, but mathematics skills
one standard deviation below expectation
Nonverbal Learning Disability
(Barnes et al., 2006). This profile persists
In efforts to organize the various neurocog- into adulthood (Hetherington, Dennis,
nitive impairments associated with SBM, Barnes, Drake, & Gentili, 2006). The motor
the construct of nonverbal learning disabil- deficits associated with SBM negatively af-
ity (NLD) has been widely proposed and has fect exploration and cognitive development
received some support (Fletcher, Brookshire, (Landry, Robinson, Copeland, & Garner,
Bohan, Brandt, & Davidson, 1995; Fletch- 1993; Thelen & Smith, 1994).
er, Dennis, & Northrup, 2000; Fletcher et More recent studies have sought to ex-
al., 1992; Rourke, 1995; Yeates, Loss, Col- amine the motor performance of children
vin, & Enrile, 2003), though the construct with SBM in more specific terms and have
remains controversial. Several methods of observed relatively intact motor learning in
classifying NLD have been proposed (Ris et children with SBM. Although children with
al., 2007; Rourke, 1995). Typically, NLD is SBM were initially slower and less accurate
understood in terms of the relative strengths than typically developing children in their
and weaknesses within a child’s neurocog- performance of a motor skill, with practice
nitive profile. NLD is largely characterized they were able to master this skill at a com-
by relative weaknesses in visual–spatial pro- parable performance level (Edelstein et al.,
cessing, motor coordination, arithmetic, and 2004). Preserved motor learning was found
interpersonal skills. in another study of children with SBM, de-
Risk factors for the phenotypic expression spite reduced cerebellar and pericallosal
of NLD in children with SBM include white gray matter volumes in these children (Den-
matter abnormalities such as dysgenesis of nis, Jewell, et al., 2006). These researchers
the corpus callosum (Rourke, 1995), as well distinguish between motor learning and
as early-shunted hydrocephalus (Donders et performance and conclude that motor learn-
al., 1991; Fletcher et al., 1995; Rourke, 1995); ing of nonreflexive tasks using hands, arms,
both of these are proposed to have negative or eyes is relatively preserved for children
effects on right-hemispheric functioning or with SBM, even when their motor perfor-
integration of the right hemisphere with mance is impaired. In addition, aspects of
more global brain systems (Rourke, 1995). spatial knowledge or way finding within a
computer-simulated or “virtual” environ- what they read or make inferences based

ment appear intact in children with SBM. on context is impaired (Fletcher, Barnes, &
Although route knowledge was impaired, Dennis, 2002). This reading pattern appears
landmark knowledge was comparable to to continue into adulthood (Barnes et al.,
that of typically developing children (Wie- 2004). Recent research indicates that diffi-
denbauer & Jansen-Osmann, 2006). These culties in speech and language can be found
researchers noted that behavioral measures in children as young as 3 years old (Lomax-
of spatial knowledge tend to overestimate Bream, Barnes, Copeland, Taylor, & Lan-
impairment in SBM because of the children’s dry, 2007).
decreased mobility. Most of the research regarding the devel-
opment of speech and language in children
with SBM focuses on the impact of hydro-
Language and Pragmatic
cephalus. However, it has been suggested
Impairments
that hydrocephalus alone cannot account
Although the concept of NLD suggests that for the speech and language impairments. In
the speech–language functioning of children a comparison of children with hydrocepha-
with SBM is relatively intact, specific areas lus of various etiologies, children with hy-
of weakness have been identified. The phrase drocephalus and SBM performed worse on
“cocktail party syndrome” has been used to measures of receptive and expressive lan-
describe the pragmatic language function- guage and on word generation tasks than
ing of children with SBM, particularly those children with hydrocephalus of different eti-
with hydrocephalus. It includes hyperverbos- ologies (Brookshire et al., 1995). Vinck and
ity; fluent, well-articulated speech containing colleagues (2006) found impairments in ver-
perseverations and stereotyped phrases; and bal fluency among children with ACM, com-
an overfamiliarity of manner (Tew, 1979). pared to children with SBM but no ACM.
Analysis of the speech samples from chil- These deficits were attributed to the cerebel-
dren with SBM suggests that although their lar dysfunction rather than the associated
discourse is fluent, it is not concise, fails to hydrocephalus. Higher-level language skills,
convey overall meaning, and lacks relevant such as comprehension of idioms, appear
content (Dennis & Barnes, 1993; Dennis, related to the corpus callosal abnormalities
Jacennik, & Barnes, 1994). Motor speech associated with SBM (Huber-Okrainec, Bla-
deficits are also apparent in many children ser, & Dennis, 2005)
with SBM, including slowed speech rate and
ataxic dysarthric features, which persist
Attention Deficits
into adulthood (Huber-Okrainec, Dennis,
and Executive Dysfunction
Brettschneider, & Spiegler, 2002).
Children with SBM also appear to have Attention deficits and impairments in other
difficulties understanding the meaning and aspects of executive functioning are robust
important content of others’ speech. Specifi- findings in populations of children and adults
cally, they are less able than their peers to with SBM. These have been associated with
understand the intended meaning of sen- anomalies in anterior brain (Anderson, Ja-
tences in a discourse, due to their difficul- cobs, & Harvey, 2005); midbrain, including
ties in making inferences and understand- the superior colliculus; and posterior brain
ing nonliteral language in the context of a regions (Dennis, Landry, et al., 2006; Den-
particular conversation (Barnes & Dennis, nis, Sinopoli, Fletcher, & Schachar, 2008).
1998). It has been suggested that these diffi- Previously, the attention deficits associated
culties are due to impairments in their online with SBM were likened to those in individu-
processing of word meanings, as well as dif- als diagnosed with attention-deficit/hyper-
ficulties suppressing irrelevant information activity disorder. However, recent research
(Barnes, Dennis, & Hetherington, 2004). by Dennis and colleagues suggests that at-
Similarly, with regard to reading, children tentional processes mediated by anterior
with SBM acquire typical word knowledge, brain regions tend to be relatively preserved
vocabulary, and decoding skills. However, in children with SBM, while those mediated
their ability to understand the meaning of by midbrain and posterior cortical regions
are deficient. Specifically, impairments are of the neuropsychological impairments as-

observed in covert orienting and inhibition sociated with SBM that provides a valuable
of return. In particular, the presence of tec- heuristic for future research. Impairments in
tal beaking, a characteristic midbrain anom- motor coordination and timing, covert and
aly in SBM, is associated with children’s re- voluntary attention, and perceptual process-
duced ability to orient themselves in their ing, and their association with abnormalities
environment—both overtly with eye move- of the cerebellar, midbrain, and parietal re-
ment, and covertly in the manner in which gions, are described. These authors posit ef-
they shift attention (Dennis et al., 2005a, fects of primary CNS insults on core deficits
2005b, 2008; Dennis, Landry, et al., 2006). (timing, attention orienting, and movement),
The deleterious effects of hydrocephalus in as well as effects of secondary CNS insults
particular on attention and other aspects of in mediating assembled and associative pro-
executive processes of children with SBM cesses. Deficits in assembled processing and
have been widely discussed (Boyer, Yeates, relative strengths in associative processing
& Enrile, 2006; Brown et al., 2008; Bur- yield the cognitive phenotype of functional
meister et al., 2005; Dennis, Landry, et al., deficits and assets that has been described
2006; English, Barnes, Taylor, & Landry, in the literature. These assets and deficits
2009; Heffelfinger et al., 2008; Iddon, Mor- may be seen both within and across cogni-
gan, Loveday, Sahakian, & Pickard, 2004; tive content domains (Dennis, Landry, et al.,
Matson, Mahone, & Zabel, 2005; Riddle, 2006).
Morton, Sampson, Vachha, & Adams, 2005;
Rose & Holmbeck, 2007; Swartwout et al.,
2008; Tarazi, Zabel, & Mahone, 2008). Assessment
Prenatal screening tests such as alpha-

Visual-Perceptual
fetoprotein and ultrasonography are com-
and Motor Functioning
monly used in diagnosing SBM. Increasingly,
Children with SBM show impairment in fast and ultrafast (to decrease movement ar-
both upper- and lower-extremity function- tifact, need for sedation, and imaging time)
ing (Dennis et al., 2004; Hetherington & MRI is being used to confirm abnormality
Dennis, 1999; Jansen et al., 1991), as well in equivocal cases and to identify specific
as in their quality of eye movements (Biglan, CNS abnormalities, including ventriculom-
1990, 1995; Salman et al., 2005). Recent re- egaly, agenesis of the corpus callosum, mi-
search regarding the visual-perceptual and gration abnormalities, and posterior fossa
motor functioning of children with SBM abnormalities; all of these can be important
suggests that, in part due to the effects of for management (Bekker & van Vugt, 2001;
hydrocephalus, such children demonstrate Levine, 2002; Mehta & Levine, 2005). As
impairments relative to typically developing a child develops, serial neuropsychologi-
peers on action-based tasks including mental cal evaluations are useful in identifying the
rotation, multistable figures, figure–ground child’s unique profile of neurocognitive
discrimination, and route planning. In con- strengths and weaknesses to aid treatment
trast, performance on spatial memory and planning. Neuropsychological testing can
object-based tasks such as object and face also identify changes in neurocognitive sta-
recognition, line orientation, and visual illu- tus that may signal shunt malfunction.
sions is comparable to that of typical peers
(Dennis, Fletcher, Rogers, Hetherington, &
Francis, 2002). Developmental Issues
The growth of children with SBM is marked

Alternative Models
by short stature. Prior to puberty, children
of Neurocognitive Deficits
with SBM and associated hydrocephalus
In response to this research describing a demonstrate slowed linear growth and bone
broadened range of more specific neurocog- age. However, even after the growth spurt
nitive variables, Dennis, Fletcher, and col- associated with puberty, stature is reduced.
leagues have proposed an alternative model Short stature in SBM has been attributed to
various factors, including shorter lower limbs SBM are mechanical obstruction and CSF
and various spine deformities. In addition, infection. Infection occurs in 12–18% of
it is possible that children with SBM have a individuals with SBM, although this rate is
growth hormone deficiency related to brain declining. Cognitive functioning is gener-
anomalies. Children with SBM are also at ally not related to the number of shunt revi-
risk for precocious puberty, with girls devel- sions during childhood; however, in adults
oping secondary sex characteristics as early the number of shunt revisions is related to
as age 8 and boys as early as age 9 (Greene, employment and independent living (Bow-
Frank, Zachmann, & Prader, 1985). man, McLone, Grant, Tomita, & Ito, 2001;
The rate of motor development in children Hunt, Oakeshott, & Kerry, 1999). The her-
with SBM is different from that in typically niation that characterizes the ACM may
developing children. Lomax-Bream and col- require surgical decompression. Although
leagues (2007) assessed the early cognitive, some patients are asymptomatic, nystagmus
motor, and language abilities of children related to lower cranial nerve nuclei com-
with SB at five points in their first 3 years. pression may be an early indicator. Surgical
Growth curve models were generated from treatment for spinal tethering and scoliosis
these data. The researchers found lower is also common. More than 90% of children
levels in functioning across all domains in with higher-level spinal lesions develop sco-
children with SB than in typically devel- liosis in early childhood, which can cause
oping controls. Motor skills were noted to pain, impair mobility, and affect respiratory
progress more quickly, while slower rates of functioning. Ongoing management of blad-
development in cognitive and language abili- der and bowel incontinence is critical. The
ties were observed. As noted earlier, speech importance of bowel and bladder control in
and language impairments were found in individuals with SBM goes beyond physical
children as young as 3 years old. The tether- needs. Incontinence and lack of sphincter
ing of the spinal cord can also slow down control are associated with less functional
motor development in children with SBM independence and greater social concerns
and eventually cause motor deterioration. (Lemelle et al., 2006; Verhoef et al., 2006).
Gross motor functioning typically deterio- Adolescents and adults with SBM consid-
rates in children with SBM as they age. The er incontinence and toileting as primary
majority of patients lose the ability to ambu- concerns (Malone, Wheeler, & Williams,
late by the age of 10–15 years due to weight 1994), and incontinence can be a barrier to
gain, making bracing difficult. employment (Leibold, Ekmark, & Adams,
2000).
Treatment
Rehabilitation Interventions
Medical Treatment
Early intervention is critical for optimal
Prevention efforts, including genetic coun- outcome in SBM. Services may be obtained
seling and folate supplementation, are criti- through a child’s school district or local hos-
cal to further reducing the incidence of pital. A multidisciplinary team approach—
SBM and other NTDs. The complex medi- including physical and occupational ther-
cal needs of a child with SBM are optimally apies, speech–language pathology, and
managed by a multidisciplinary team. New- rehabilitation psychology/neuropsychol-
borns with SBM frequently require one or ogy, as well as early education services—is
more surgeries within the first week of life. warranted. Fletcher, Ostermaier, Cirino,
Initial treatment typically includes the clo- and Dennis (2008) review neurobehavioral
sure of the open myelomeningocele. An ad- outcomes and recommended interventions
ditional surgery that may take place when a for use with children with SBM; they also
child with SBM is a newborn is placement provide a heuristic for organizing interven-
of a ventriculoperitoneal shunt if necessary tions targeting the cognitive and behavioral
to treat hydrocephalus. Additional surger- difficulties common among children with
ies may be needed to repair shunt malfunc- SBM on the basis of underlying neurocog-
tion or infection. The two most common nitive processes. Table 28.2 summarizes key
causes of shunt malfunction in patients with treatment targets by developmental stage
TABLE 28.2. Treatment Targets in SBM by Developmental Stage and Discipline

Stage Target Discipline
Infancy Feeding and swallowing (oral Speech–language therapy
hypersensitivity and gagging) Occupational therapy
Preschool Speech–language and pragmatic deficits Speech–language therapy

Independence for feeding and dressing Occupational therapy
Fine and gross motor impairments Physical therapy
Early childhood education services
School age Learning impairments Speech–language therapy

Social pragmatics Occupational therapy
Increased difficulties with mobility Physical therapy
(secondary to tethered cord and weight Rehabilitation psychology/neuropsychology
gain) Special education services
Precocious puberty Medical interventions
Change in mood (depression, social
isolation)
Adolescence Social pragmatics Speech–language therapy

Executive dysfunction as demands Rehabilitation psychology/neuropsychology
increase Occupational therapy
Change in mood, social status Special education services
(depression, social isolation) Medical/surgical intervention
Bowel and bladder
Precocious puberty
Early adulthood Transition issues Medical team

Independence (transportation, Rehabilitation psychology/neuropsychology
employment, cooking, etc.) Occupational therapy
and assumes a multidisciplinary treatment References

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Chapter 29
Inborn Errors of Metabolism

A Brief Overview
Robert T. Brown
The topic of inborn errors of metabolism is challenging for most physicians.

The number of known metabolic disorders is probably as large as the
number of presenting symptoms that may indicate metabolic disturbances. . . .
Furthermore, physicians know they may not encounter certain rare inborn
errors of metabolism during a lifetime of practice. Nonetheless, with a
collective incidence of one in 1,500 persons, at least one of these disorders
will be encountered by almost all practicing physicians.
—R aghuveer , Garg , and Graf (2006, p. 1981)
Inborn errors of metabolism (IEMs) are ge- disorders, but a few, such as Lesch–Nyhan
netically based disorders that interfere with syndrome (see Wodrich & Long, Chapter
normal metabolism. Metabolism occurs in 23, this volume), and adrenoleukodystro-
sequences of biochemical reactions, called phy, are X-linked recessive disorders. Some
metabolic pathways. Each pathway involves disorders known for hundreds or thousands
particular enzymes that break down in- of years have been identified as IEMs only
gested food into usable nutrients. An IEM relatively recently, gout being perhaps the
occurs when a defective gene results in an best-known and most common example.
absent or defective enzyme in one of these Many IEMs have been identified in the last
pathways, blocking normal metabolism and 40 years, and some, particularly new vari-
resulting in accumulation of an abnormal ants, are still being discovered.
substance in the body. In many cases, this This chapter is a brief general overview of
abnormal substance is toxic to developing IEMs; it focuses on those with neurological
neural tissue, resulting in varying degrees of consequences, including their characteris-
mental retardation, cerebral palsy, seizure tics, symptoms, diagnosis, and treatment.
disorders, and sensory and/or motor impair- Readers wanting detailed information on in-
ments, among other effects. Blocks of me- dividual IEMs other than PKU, Lesch–Ny-
tabolism of a given substance may occur at han syndrome, or the mucopolysaccharidos-
different points in the metabolic pathway, es (see M. Brown, Chapter 15, this volume)
leading to different disorders. IEMs are may wish to consult one of the recent books
single-gene disorders that follow principles on the topic (e.g., Fernandes, Saudubray, van
of Mendelian genetics. Most IEMs, such as den Berghe, & Walter, 2005; Mayatepek,
phenylketonuria (PKU; see Waisbren, Chap- 2008; Nyhan, Barshop, & Ozand, 2005;
ter 21, this volume), are autosomal recessive Sarafoglou, Hoffmann, & Roth, 2009); the
570
Inborn Errors of Metabolism 571
printed or online versions of Mendelian In- of the incidence of alkaptonuria and of con-
heritance in Man (McKusick, 1998; www. ditions which appear in a similar way are
ncbi.nlm.gov/omim); and a series of online best explained by supposing that, leaving
articles by Weiner (2009a, 2009b, 2009c, aside exceptional cases in which the charac-
2009d). Advanced pediatrics textbooks ter, usually recessive, assumes dominance, a
(e.g., Kliegman, Behrman, Jenson, & Stan- peculiarity of the gametes of both parents
ton, 2007) are also useful, as indicated by is necessary for its production.” Note that
citations in this chapter. In addition, the Garrod’s article appeared a few years before
National Institute of Neurological Disorders introduction of the terms genetics and genes
and Stroke (NINDS) provides routinely up- to the study of heredity.
dated webpages for many IEMs. Garrod subsequently presented his find-
IEMs can be difficult to identify because ings on alkaptonuria and other similar
they “can manifest at any time, can affect any rare disorders (albinism, cystinuria, por-
organ system, and can mimic many common phyrinuria [porphyria], and steatorrhea)
pediatric problems” (Thomas & Van Hove, in the Croonian Lectures (1908) and two
2007, p. 986). For many, even when accu- editions of his classic monograph (Gar-
rately diagnosed, no effective treatment is rod, 1909, 1923), all titled with his classic
currently available. Unfortunately, misdiag- phrase, Inborn Errors of Metabolism. Gar-
nosis, delayed diagnosis, or nondiagnosis of rod described the appearance of symptoms
IEMs can lead to devastating consequences. of some of these disorders in the newborn
In cases where effective treatment is avail- period; he also used his other classic phrase,
able, unnecessary death or severe permanent “one gene, one enzyme,” to account for the
organic damage may result. In cases where metabolic failures. Several involved unusual
treatment is not currently available, affected bodily odors or appearance of urine and/or
individuals may not be identified and thus feces. Of interest, some forms of porphyria
may be unable to participate in clinical trials but not others have significant nervous sys-
of experimental treatments; accurate family tem effects, including seizures and impaired
histories may not be compiled; and genetic mental functioning (depression, anxiety,
counseling may not be provided to parents. hallucinations). Unfortunately, the impor-
Furthermore, given that various IEMs can tance of Garrod’s findings was not appreci-
appear throughout infancy and into adult- ated for many years.
hood, an undiagnosed IEM may lead par- The first reported IEM associated with
ents to be charged with neglect, abuse, or mental retardation was PKU, detected on the
even Munchausen syndrome by proxy (see basis of mousy-smelling urine and reported
Pankratz, 2006). by Fölling in 1934 (see Waisbren, Chapter
21). Subsequent reports of new IEMs with
effects on the nervous system appeared regu-
Background larly; in 1970, O’Brien described 77 separate
disorders, some with numerous variants,
In the late 19th century, Archibald Edward that lead to various degrees of mental retar-
Garrod, an English physician, began to use dation. At this writing, approximately 300
urine with abnormal characteristics to study of the 1,000 or so known IEMs have been
metabolic processes. He first studied alkap- found to have nervous system effects, most
tonuria, a rare disorder whose most promi- commonly mental retardation. Many IEMs
nent symptom is darkening of urine after are also now known to have variant forms,
exposure to air. Affected adults typically owing to involvement of other genes or dif-
later develop a particular form of arthritis in ferent mutations on the same gene. Garrod’s
which brown pigment occurs in joint tissue. “one gene, one enzyme” concept is no longer
In his initial paper on the subject, Garrod applicable.
(1902/1996) described William Bateson’s
description of recently rediscovered Men-
delian principles of heredity and stated Classification
(p. 278): “Whether the Mendelian explana-
tion be the true one or no there seems to be Several ways of classifying IEMs are avail-
little room for doubt that the peculiarities able. Two quite different ones are described
here—one based on the type of metabolic Organic Acid Disorders

error, and the second based on the manner
The major and common effects of organic
and timing of symptom manifestation.
acid disorders are very similar to those of
amino acid metabolism disorders. Diagnosis
Type of Metabolic Error is generally made through testing for spe-
Several systems of classifying IEMs in terms cific abnormal substances in blood or urine.
of the type of metabolic error have been of- Methylmalonic aciduria is an organic acid
fered. Thomas and Van Hove (2007) divide disorder with a wide range of outcomes from
the entire group of IEMs into seven catego- benign to fatal in infancy. Severity depends
ries. The following material is based large- on the particular mutation present and on
ly on their description. For each category, the success of treatment. It may occur with
major general effects and a few examples are homocystinuria. Symptoms of propionic aci-
provided. duria, such as poor feeding, vomiting, dehy-
dration, acidosis, hypotonia, and seizures,
appear shortly after birth. Symptoms reflect,
Carbohydrate Metabolism Defects among other conditions, encephalopathy
Virtually all carbohydrate metabolism de- and hyperammonia. Progression to death is
fects are associated with mental retardation, often rapid. Treatment involves elimination
acute encephalopathy, failure to thrive, and of the unmetabolizable substance from the
hepatomegaly (enlarged liver). Seizures, hy- diet, and often large oral doses of biotin (vi-
potonia, vomiting, and cataracts are also tamin B7) or, in the case of methylmalonic
common. Examples are glycogen storage dis- aciduria, vitamin B12.
eases, galactosemia, and hereditary fructose
intolerance. Untreated, all can lead to early Fatty Acid Oxidation Disorders
death, but strict adherence to a diet low in
the unmetabolizable substance reduces or Considered as a group, fatty acid oxidation
eliminates most adverse effects. disorders may be among the most common
IEMs (Stanley & Bennett, 2007). Major
symptoms include hypoketotic hypoglyce-
Amino Acid Metabolism Defects mia, hyperammonemia, hypotonia, vomit-
The major effects of amino acid metabo- ing, encephalopathy, cardiomyopathy, and
lism defects are the same as those for car- hepatomegaly; these often appear after 8–12
bohydrate metabolism defects, except for hours of fasting, not an unusual period be-
the absence of enlarged liver and inclusion tween dinner and breakfast. Sudden infant
of seizures, vomiting, and food aversions. death may result, and rate of death in previ-
In addition, hypo- and hypertonia, behav- ously undiagnosed cases is high. Diagnosis
ior problems, and unusual bodily odor are is made through testing for specific abnor-
common. Examples are urea cycle disorders, mal substances in blood or urine. Treatment
PKU and its variants, tyrosinemia, maple in acute episodes involves prevention of hy-
syrup urine disease, and homocystinuria. poglycemia by providing frequent snacks
Diagnosis can be made through routine and avoiding infections. Oral carnitine is
newborn blood testing for abnormal metab- effective in some cases. Examples are three
olites. Treatment involves elimination of the disorders associated with deficiencies in en-
unmetabolizable substance from the diet, zymes of fatty-acid ß-oxidation: very-long-
adherence to a synthetic diet, or administra- chain and medium-chain acyl-coenzyme A
tion of a substance that substitutes for the dehydrogenase deficiency, and long-chain
missing enzyme. Without treatment, pro- 3-hydroxyacyl CoA dehydrogense deficiency
gressively severe mental retardation, seizure (e.g., Stanley & Bennett, 2007; Thomas &
disorders, and other neurological disorders Van Hove, 2007).
are predictable. With lifelong treatment be-
ginning in the newborn period, development
Purine Metabolism Disorders
can be nearly normal in most cases except
for specific learning problems. Effects of As with several other categories of IEMs, se-
variants are less severe. verity, onset, and progression of symptoms
vary widely among the purine metabolism mannosidosis varies from severe symptoms,
disorders. Commonly, they are associated including mental retardation, to mild symp-
with overproduction of uric acid. Many lead toms with near-normal intelligence. Of the
to mental retardation, seizure and move- lipidoses, several have different forms with
ment disorders, muscle cramps, autistic and different age of onset, and at least three (type
other abnormal behavior, and susceptibility 1 Gaucher, acute Niemann–Pick, and Tay–
to infections. Some, however, are essentially Sachs) are particularly common among Ash-
asymptomatic. The most common is gout, in kenazi Jews of Eastern European descent,
which crystals of uric acid are deposited in whereas type D Niemann–Pick is more com-
joints, causing severe pain. Gout can develop mon among those of Nova Scotian descent.
from childhood to adulthood. Lesch–Nyhan Symptoms of type 1 Gaucher, the most com-
syndrome is a well-known purine metabo- mon LSD, can appear from childhood to
lism disorder (see Wodrich & Long, Chapter adulthood. Affected individuals have low
23). Adenylosuccinate lyase deficiency and blood platelets, enlarged livers and spleens,
phosphoribosyl pyrophosphate synthetase skeletal deformities, and potential lung and
defects are purine metabolism disorders kidney disorders. It is non-neurological and
associated with severe mental retardation, associated with normal lifespan. Type 2
seizures, and autistic behavior. No effective Gaucher has early infant onset of liver and
treatment is available. Some reports (e.g., spleen enlargement, with progressive brain
Page & Coleman, 2000) suggest that as damage and death by 2 years of age. Type
many as 20% of those with autism have un- 3 Gaucher has variable onset of liver and
usually high levels of uric acid in their urine, spleen enlargement, as well as brain dam-
but the relationship between the excess uric age reflected in seizures and motor coordi-
acid and autism is unclear. nation dysfunction. Death in adolescence or
young adulthood is characteristic. Enzyme
treatment is effective for types 1 and 3, but
Lysosomal Storage Disorders
no effective treatment is available for type
Lysosomes break down substrate in cells 2 (NINDS, 2009a). Niemann–Pick disease
into usable materials, and each lysosomal occurs in four types with different ages
storage disorder (LSD) is caused by a defi- of onset. Type A has acute infant onset of
ciency in the enzyme that deals with a spe- jaundice, enlarged liver, major brain dam-
cific substrate, leading to its accumulation in age, and death usually by 18 months of age.
cells. As a group, LSDs are highly variable Type B is non-neurological; enlarged spleen
in severity. Characteristic symptoms include and liver occur prior to adolescence. Types
short stature, skeletal abnormalities, coarse C and D have childhood to adulthood onset
facies, splenomegaly, neurological dysfunc- of enlarged liver and spleen, as well as major
tion, and visual and auditory impairments. brain damage causing motor disturbances,
Major symptoms of more severe disorders loss of vision and hearing, seizures, and
include mental retardation, developmen- mental retardation. Death is variable, but
tal regression, seizures, behavior disorders, often in childhood. No effective treatment is
macrocephaly, and hepatomegaly. Initial di- available for type A, and only potentially ef-
agnosis may be made through urine screen- fective ones for the others (NINDS, 2009c).
ing tests, but must be confirmed by appro- Infants with Tay–Sachs appear normal at
priate enzyme analyses. birth, but as lipids accumulate in nerve cells,
Most LSDs can be placed in one of three mental, physical, and sensory abilities rap-
subgroups based on the accumulating sub- idly deteriorate, and seizures, severe mental
stance: mucopolysaccharidoses, mucolipi- retardation, and paralysis develop. No effec-
doses, or lipidoses. Severity varies widely tive treatment is available, and death usually
even within subgroup: Of the mucopoly- occurs by 4 years of age.
saccharidoses (see M. Brown, Chapter 15),
Hurler and Sanfilippo syndromes are associ-
Peroxisomal Disorders
ated with severe mental retardation, Hunter
syndrome with mental retardation of vary- Major effects of the peroxisomal disorders
ing degrees, and Scheie syndrome with include mental retardation, seizures, regres-
normal intelligence. Of the mucolipidoses, sions in development, behavior abnormali-
ties, and susceptibility to infections. These 1. Silent disorders are initially asymptom-
disorders involve absence or reduced levels atic and progress slowly, becoming apparent
of various peroxisomes—cellular organelles generally in childhood. Affected children do
essential for metabolism of very-long-chain not show symptoms such as seizures, vomit-
fatty acids (VLCFAs), plasmalogen producing, or coma shortly after birth, but develop
tion, and bile acid synthesis. “Abnormal ac- slowly and show progressive mental and
cumulation of VLCFAs . . . is the hallmark of other impairments. Examples include PKU
peroxisomal disorders” (Chedrawi & Clark, and congenital hypothyroidism.
2007, paragraph 5). 2. Disorders presenting in acute metabol-
Leukodystrophies, a subgroup of progres- ic crisis produce severe symptoms, includ-
sive peroxisomal disorders, lead to degen- ing seizures, vomiting, lethargy, and coma
eration of white matter in the brain owing shortly after birth. As these conditions are
to maldevelopment of myelin sheaths. Each also symptomatic of many other newborn
leukodystrophy involves a defect in one disorders (e.g., infections; brain hemorrhage;
gene. In general, they appear in infancy or and pulmonary, cardiac, and gastrointesti-
childhood and involve progressive declines nal abnormalities), immediate diagnosis and
in movement (e.g., gait, speech, and eat- treatment are difficult if bodily fluids are not
ing), vision and hearing, cognitive function- tested for specific metabolic problems. In the
ing, and physical development. Symptoms absence of treatment, virtually all affected
vary according to the specific type of leu- individuals will die in infancy. Even with the
kodystrophy, and may be difficult to recog- most extreme intervention, many will die,
nize in the early stages of the disease. They and others show severe impairments. Ex-
vary greatly in severity, with the most severe amples are urea cycle disorders and organic
forms essentially untreatable and resulting acidemias.
in early death. Specific leukodystrophies in- 3. Disorders with progressive neurologi-
clude Zellweger syndrome, metachromatic cal deterioration are, like silent disorders,
leukodystrophy (MLD), X-linked adrenoleu- asymptomatic for some time after birth. At
kodystrophy, and Refsum disease. Zellweger ages ranging from a few months to years, the
and Refsum syndromes are, respectively, per- motor and/or cognitive skills of affected in-
haps the most and least severe. Several have dividuals begin to deteriorate. Untreated, the
different forms, with the early-onset version deterioration leads to death by childhood in
being the most severe. Zellweger syndrome severe cases. A few examples, among many,
involves excessive iron and copper in blood are carbohydrate metabolism defects, amino
and tissue. Symptoms include enlarged liver, acid metabolism defects, LSDs, peroxisomal
specific abnormal facies, mental retardation, disorders, fatty acid oxidation disorders,
and seizures. Affected infants may be severe- and mitochondrial disorders.
ly hypotonic and unable to suck or swallow.
Damage in severe cases may begin prena-
tally. Death generally occurs by 6 months of Initial Appearance and Development
age. Late infantile MLD begins to manifest
itself at 12–18 months of age with irritability Although onset can occur at any time in life,
and inability to walk; it progresses to muscle the most severe IEMs manifest themselves
wasting, seizures, hypotonia, mental retar- in newborns or infants who generally ap-
dation, and death before about age 10 years pear normal at birth, but develop symptoms
(Chedrawi & Clark, 2007; NINDS, 2007, within days or weeks (e.g., Rezvani, 2007a;
2009b). Weiner, 2009c). Most of these severe disor-
ders have neurodevelopmental effects that,
unless treated immediately, can result in
Timing/Manner
permanent impairments or death. For some,
of Symptom Manifestation
no effective treatment is now available, and
Batshaw and Tuchman (2007) described adverse outcomes are inevitable. Tay–Sachs
three types of IEMs in terms of their onset and late infantile MLD are two examples. In
and progression when the disorders go un- both of these, onset is in late infancy, with
recognized and untreated: progressive deterioration in functioning
leading to death in early childhood. Most histories are unlikely to provide clues to diag-
IEMs that impair developing neural tissue nosis. However, if one offspring has an IEM,
are progressive, with symptoms becoming the probability is high that others will also;
increasingly severe. Thus the longer any ef- thus detailed information on serious illness
fective treatments are postponed, the greater in siblings may be valuable. Identification of
the ultimate symptom severity. an IEM in one child may call for assessment
Most IEMs that lead to severe symptoms in of siblings who may also have the disorder,
newborn or infant periods have variants that particularly one of the less severe variants.
appear later, progress more slowly, and often
have less severe or episodic effects. For ex-
Prenatal Identification
ample, MLD appears in three forms: late in-
fantile, juvenile, and adult. In the most com- Many IEMs can be diagnosed prenatally
mon, late infantile MLD (mentioned above), through amniocentesis or chorionic villus
gait and balance problems appear, followed sampling, but specific analyses are needed
by hypotonia, major motor deterioration, for identification of most IEMs. Therefore,
and cognitive impairment. Progressive gen- diagnosis of de novo cases is unlikely.
eral deterioration leads to death by age 5–6
years. The juvenile form generally does not
Mandated Newborn Screening
appear until age 5–10 years, when cogni-
tive and motor functioning begin to decline. A number of fatty acid oxidation disorders,
Overall motor control then deteriorates, fre- amino acid metabolism defects, organic acid
quent and difficult-to-control tonic–clonic disorders, and other IEMs can be tenta-
seizures appear, and death generally occurs tively identified through mandated newborn
at about age 15–16 years. The adult form has screening using tandem mass spectroscopy.
highly variable onset, from about age 20 to These include PKU, maple syrup urine syn-
50 years; it begins with memory, personal- drome, galactosemia, and propionic aca-
ity, and psychiatric problems that slowly demia (see National Newborn Screening
(perhaps over a decade or more) progress to and Genetics Resource Center, 2009, for a
motor disturbances, such as spasticity and complete list). Since the test is intentionally
seizures, and then to overall unresponsive- set to produce a low rate of false-negative
ness (Johnston, 2007; Weiner, 2009c). results, it necessarily has high rates of false
positives. Positive results therefore call for
confirmation with more specialized tests.
Diagnosis
Suggestive General Symptoms
Because their effects overlap not only with
those of other IEMs but with those of nu- An IEM should be expected when an oth-
merous other disorders, diagnosis of IEMs erwise normal newborn, infant, or young
can be difficult. Since treatment is specific to child shows deterioration of functioning
each disorder, delayed or erroneous diagnosis unattributable to another disorder. Other
can lead to delayed or erroneous treatment potential symptoms include failure to thrive,
with potentially disastrous consequences. abnormal physical features, skeletal malfor-
Many methods of identifying a disorder as mations, major organ failure, poor feeding,
a potential or specific IEM are available. vomiting, diarrhea, abnormal reflexes or
Owing to the complexity of the subject, only movement, unusual susceptibility to illness,
a brief overview is given here. Much of this coma, and seizures.
section, unless otherwise attributed, is based In older children, adolescents, or adults,
on Weiner (2009c). symptoms similar to those above that occur
during illness, stress, or change in diet or
lifestyle may reflect an undiagnosed IEM.
Family History
Other potential concerns are otherwise un-
Since IEMs are autosomal recessive or X- attributed neurological abnormalities, ab-
linked disorders, they virtually always ap- normal behavior, mental retardation, autis-
pear de novo. Thus past-generation family tic behaviors, learning disabilities, anxiety
disorders, seizures, motor dysfunction, and Treatment

lethargy, among others.
Of particular concern in older children Treatment obviously is specific to each disor-
is partial ornithine transcarbamylase defi- der; in some cases, it is also specific to vari-
ciency, a urea cycle defect, which may first ants of the disorder and to the individual
become apparent in adolescence as “a life- patient (Weiner, 2009d). Several have been
threatening metabolic catastrophe . . . [which described at other places in this chapter, al-
is] observed particularly in adolescent fe- though in highly condensed form. Generally,
males with a history of protein aversion, ab- synthetic or restricted diets, medication, en-
dominal pain, and migrainelike headaches” zyme replacement, and bone marrow and
(Weiner, 2009c, paragraph 19). organ transplants are useful for many IEMs.
Weiner (2009d) describes acute and long-
term intervention in more detail, includ-
Unusual Body Odor
ing use of some relatively broadly effective
Several IEMs (mainly amino acid and or- drugs.
ganic acid disorders) are associated with un- An important, but often neglected, aspect
usual and characteristic body or fluid odors of treatment and intervention is consider-
that begin to appear at about a day after ation of the family unit’s needs. Care for
birth, when first feedings should have been most individuals affected by IEMs is de-
metabolized. Examples (taken from Rez- manding, time-consuming, and expensive,
vani, 2007b) of amino acid disorders, with and requires adherence to rigid protocols.
their commonly described characteristic Given that an affected individual may resist
urine odors in parentheses, are as follows: or resent aspects of treatment, stress on care-
PKU (mousy), maple syrup urine syndrome givers may be further increased. Unaffected
(maple syrup), tyrosemia (boiled cabbage), siblings are also likely to suffer because care
and hawkinsinuria (swimming pool). Worth of the affected child may limit parents’ time
noting is the culturally specific nature of with them and because they will often have
some of these terms. Those unfamiliar with to share caretaking. Family therapy and
maple syrup, for example, will probably have monitoring will often be useful adjuncts to
a different term to describe the odor, and I treatment of the affected individuals them-
myself, although familiar with many swim- selves.
ming pools, am at a loss as to the nature of
any single characteristic odor.
Concluding Remarks
Symptoms of Sepsis
IEMs are challenging not only for physicians,
Unexplained sepsis in newborns and infants as stated in the epigraph to this chapter, but
may reflect onset of an IEM: “Of term infor all clinicians who interact with potential
fants who develop symptoms of sepsis with- or known cases. Their sheer and increas-
out known risk factors, as many as 20% ing numbers; their variants; their complex
may have an inborn error of metabolism” symptoms (which overlap with both those
(Weiner, 2009c, paragraph 6). Sepsis is a of other IEMs and those of numerous other
widespread infection that involves the sys- disorders); their varied onsets, progressions,
temic inflammatory response syndrome and ultimate phenotypes; and their frequent
(SIRS). SIRS is an “inflammatory cascade nonresponsiveness to intervention all con-
that . . . occurs when the host defense system tribute to these challenges. But as with so
does not recognize or clear the infection. many other things, not knowing about them
SIRS can also occur from a number of non- is far worse than knowing about them.
infectious etiologies” (Enrione & Powell, On the positive side, a great deal has
2007, p. 1094). Symptoms include very high changed in our understanding of IEMs since
temperature, tachycardia, high respiratory I first wrote about them almost 25 years ago
rate, and elevated or depressed leukocyte (Brown, 1986). Many more have been dis-
count. With increasing number and severity covered, accurately described, and effective-
of symptoms, SIRS can progress to severe ly treated. Treatments known at that time
sepsis, septic shock, and death. have been refined and made more effective,
and many new treatments have been devel- orders (12th ed.). Baltimore: Johns Hopkins Uni-
oped. Many more effective treatments can versity Press.
be expected through stem cell replacement, National Institute of Neurological Disorders and
Stroke (NINDS). (2007). NINDS Zellweger syn-
enzyme replacement, and genetic modifica-
drome information page. Retrieved September
tion. 18, 2009, from www.ninds.nih.gov/disorders/
zellweger/zellweger.htm
National Institute of Neurological Disorders and
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Index
Page numbers followed by f indicate figure, t indicate table
Academic Performance and ADHD Rating Adult care and treatment Prader–Willi syndrome and, 491
Scales, 141–142 autism spectrum disorders and, 245 Rett syndrome and, 429
Academic skills Down syndrome and, 376 Animal models
comorbid conditions and, 121 fragile X syndrome and fragile anxiety disorders and, 192–193
Down syndrome and, 375 X–associated disorders and, 282 autism spectrum disorders and, 233
Klinefelter syndrome and, 389–390, 393 inborn errors of metabolism (IEMs), Lesch–Nyhan syndrome and, 447
learning disabilities and, 116–118, 116t, 575–576 mitochondrial metabolism disorders
117t Klinefelter syndrome and, 393–394 and, 515
mucopolysaccharidoses (MPS disorders), Noonan syndrome and, 314 neural tube defects (NTDs) and, 555
304–307 phenylketonuria (PKU) and, 412t, neurofibromatosis type 1 (NF1) and, 333
neurofibromatosis type 1 (NF1) and, 414–415 phenylketonuria (PKU) and, 400–401
330–331 Prader–Willi syndrome and, 499, 505 Rett syndrome and, 430–431
Noonan syndrome and, 316 Rett syndrome and, 429 Anorexia nervosa, 267, 392, 409
phenylketonuria (PKU) and, 407–408 spina bifida myelomeningocele and, 564t Anticipation, 35t, 46, 47
Prader–Willi syndrome and, 492 Turner syndrome and, 267–268, 269 Antidepressants, 286. See also
sickle cell disease (SCD) and, 348–351, See also Treatment Psychopharmacological interventions;
356 Age Selective serotonin reuptake inhibitors
Tourette syndrome and, 178 aggressive behavior, ODD, and CD, 155 (SSRIs)
Turner syndrome and, 267 autism spectrum disorders, 229 Antiepileptic medication, 453. See also
ACID (Arithmetic, Coding, Information, expressivity and penetrance and, 45 Psychopharmacological interventions
and Digit Span subtest) pattern, 115 inborn errors of metabolism (IEMs), 574 Antipsychotic medications, 181, 242.
ACTION program, 220, 221 mitochondrial metabolism disorders See also Psychopharmacological
Adaptation, 139, 369, 412t and, 519t interventions
Adaptive symptoms, 491–502, 493t, 497t, mucopolysaccharidoses (MPS disorders), Antisocial behaviors, 156–157. See also
498t, 501t 296 Aggression; Conduct disorder (CD);
Adjustment, 88–89, 269–270, 356, seizure disorders and, 461, 462, 479 Oppositional defiant disorder (ODD)
391–392 Aggression Antisocial personality disorder (APD), 158
Adolescence assessment and, 162–163 Anxiety
ADHD and, 139–140 autism spectrum disorders and, 240 autism spectrum disorders and, 244, 245
anorexia nervosa and, 267 biological and neuropsychological developmental course of, 188–189
antisocial behaviors and, 156 markers, 158–161 Lesch–Nyhan syndrome and, 456
Down syndrome and, 375, 376 developmental course of, 153–157 Tourette syndrome and, 173, 178,
fragile X syndrome and fragile genetics and family patterns, 157–158 182–183
X–associated disorders and, 278 history, 151–153, 152t, 153t Anxiety disorders
inborn errors of metabolism (IEMs), Lesch–Nyhan syndrome and, 449 assessment and, 189, 197–199, 198t
575–576 mucopolysaccharidoses (MPS disorders), autism spectrum disorders and, 244
Klinefelter syndrome and, 392, 393–394 299, 302 biological markers, 192–195
mood disorders and, 211–212, 215 overview, 151, 165 epidemiology and comorbidity of,
Noonan syndrome, 313–314 phenylketonuria (PKU) and, 402 189–191, 190t, 191t
phenylketonuria (PKU) and, 408, 410, Rett syndrome and, 436–437 genetics and family patterns, 191–192
414 risk factors for, 161–162, 161t inborn errors of metabolism (IEMs),
Prader–Willi syndrome and, 499, 505 treatment and, 163–165 575–576
Rett syndrome and, 429 Alpers–Huttenlocher syndrome, 517–518, longitudinal course, 191
spina bifida myelomeningocele and, 564t 530 neuroimaging technologies and,
Tourette syndrome and, 173–174 Amygdala, 234–235, 280, 432 196–197
Turner syndrome and, 262, 265–267 Anencephaly, 20t, 541t, 545–547 overview, 188, 202
Adolescent Coping with Depression Angelman syndromes phenylketonuria (PKU) and, 408
Course (CWD-A), 220, 221 behavioral phenotypes, 55t Prader–Willi syndrome and, 500–501
Adolescent Psychopathology Scale (APS), Fluorescent in situ hybridization (FISH) risk factors for, 195–196
218t and, 37–38 sickle cell disease (SCD) and, 356
Adolescent Symptom Inventory–4 (ASI-4), neuroimaging technologies and, 61–62 Tourette syndrome and, 182–183
218t nontraditional inheritance and, 46–47 treatment and, 199–201, 200t
Adoption studies, 157–158, 213 overview, 35t, 39, 41 Apert syndrome, 46, 47, 48, 60f
579
580 Index
Applied behavior analysis (ABA), pervasive developmental disorders medical genetics and, 54–55, 55t
239–240, 375 (PDD) and, 71–72 neuropsychological evaluation and, 13
Asperger syndrome, 245, 284–285. See phenylketonuria (PKU) and, 406–407 overview, 410, 543
also Autism spectrum disorders psychopharmacological interventions phenylketonuria (PKU) and, 412
Assessment and, 182 Prader–Willi syndrome and, 491–502,
ADHD and, 140–142 referral for evaluation and, 17 493t, 496–502, 497t, 498t, 501t
aggressive behavior, ODD, and CD, schools and, 14 See also Symptoms
162–163 Tourette syndrome and, 173, 178, 180, Behavioral treatments
anencephaly, 547 182, 182–183 autism spectrum disorders and, 239–240
anxiety disorders and, 197–199, 198t treatment and, 142–143 Down syndrome and, 374–375
approaches and instruments for, Attribution theories, 85–86 fragile X syndrome and fragile
14–17, 15t, 16t. See also individual Atypical antipsychotics, 181, 242. See also X–associated disorders and, 288
instruments Psychopharmacological interventions Lesch–Nyhan syndrome and, 452t,
autism spectrum disorders, 229 Auditory discrimination, 122–123, 455–457
Down syndrome and, 372–373 349–350 mucopolysaccharidoses (MPS disorders),
fragile X syndrome and fragile Auditory Discrimination in Depth 302
X–associated disorders and, 284–285 program, 122–123 overview, 434
Klinefelter syndrome and, 389, 391 Auditory–verbal processes, 116–118, 116t, Prader–Willi syndrome and, 504–505
learning disabilities and, 106, 108 117t Tourette syndrome and, 181, 183
Lesch–Nyhan syndrome and, 450–451 Autism Diagnostic Interview—Revised See also Treatment
lissencephaly, 549 (ADI-R), 229 Benign rolandic epilepsy, 466t, 468–469.
mitochondrial metabolism disorders Autism Diagnostic Observation Schedule See also Seizure disorders
and, 532 (ADOS), 229, 280 Biological factors
mood disorders and, 216–217, 218t Autism spectrum disorders aggressive behavior, ODD, and CD,
mucopolysaccharidoses (MPS disorders), adult care and treatment, 245 158–161
304–305 comorbid conditions and, 244–245 anencephaly, 546
Noonan syndrome and, 317–319 controversial topics regarding, 242–244 anxiety disorders and, 192–195
other information needed for, 18 DNA technology and, 284–285 Lesch–Nyhan syndrome and, 452t
phenylketonuria (PKU) and, 411–413, environmental factors, 232–233 lissencephaly, 548–549
412t etiological considerations, 230–233 mitochondrial metabolism disorders
Prader–Willi syndrome and, 489–491, executive functioning and, 160 and, 513, 531–532
490t, 496–497 fragile X syndrome and fragile mood disorders, 214–215
schizencephaly, 544–545 X–associated disorders and, 279–280 schizencephaly, 543
seizure disorders and, 469–477, 472f gender and, 230 Tourette syndrome, 175–176, 182
sickle cell disease (SCD) and, 356 history, 228–229 Biological treatments, 243–244, 451, 453–
spina bifida myelomeningocele and, 562 inborn errors of metabolism (IEMs), 455. See also Psychopharmacological
Tourette syndrome, 178–180 575–576 interventions
Turner syndrome and, 268 incidence rates of, 230 Bipolar disorder
See also Neuropsychological assessment memory and learning and, 20t adolescence and, 211–212
Attentional bias, 195, 196 multifactorial inheritance and, 49 anxiety disorders and, 191–192
Attentional functioning neural mechanisms, 233–236 assessment and, 216
memory and, 20 neurobiology of, 236–239 cognitive-behavioral therapy and, 221
neurofibromatosis type 1 (NF1) and, neuroimaging technologies and, 69–72, developmental course of, 211
328–329 70f, 71f diagnosis and, 209–210
neuropsychological evaluation and, 12 overview, 35t, 228–230, 245–246 genetics and family patterns and, 213
Noonan syndrome and, 316 phenylketonuria (PKU) and, 402 Klinefelter syndrome and, 392
overview, 132–133, 135 prevalence of, 230 prevalence of, 210
phenylketonuria (PKU) and, 412, 412t Rett syndrome and, 440 psychopharmacological interventions
seizure disorders and, 471, 472f, social adjustment and, 89 and, 217
473–474 treatment and, 239–242, 245 See also Mood disorders
sickle cell disease (SCD) and, 342–344, vaccine controversy and, 244 Birthweight, 20t, 520, 524
349–350, 353–354 Autism Spectrum Quotient, 390 Bladder control, 557, 563
spina bifida myelomeningocele and, Autistic-like features, 279–280, 285 Boston Diagnostic Aphasia Examination,
561–562 Autosomal dominant disorders, 42, 29
Tourette syndrome and, 176 174–175, 383 Boston Naming Test, 29
Turner syndrome and, 271 Autosomal recessive disorders, 42–43, Boston Process Approach, 29
See also Attention-deficit/hyperactivity 383, 398 Bowel control, 557, 563
disorder (ADHD) Brain functioning, 471–472, 472f
Attention-deficit/hyperactivity disorder Basal ganglia, 175, 432, 559 Brain structures
(ADHD) Battelle Developmental Inventory, 374 autism spectrum disorders and, 233–236
aggressive behavior, ODD, and CD and, Bayley Scales of Infant and Toddler neurofibromatosis type 1 (NF1) and, 332
157, 159–160 Development, Third Edition, 10 pervasive developmental disorders
anxiety disorders and, 190–191, Beck Depression Inventory–II (BDI-II), (PDD) and, 69–72, 70f, 71f
198–199 218t sickle cell disease (SCD) and, 342
autism spectrum disorders and, Behavior Assessment System for Children, spina bifida myelomeningocele and, 558
244–245 Second Edition (BASC-2), 13, See also Neuroimaging methods
comorbidity and, 138–140 141–142 Brain-deprived neurotropic factor (BDNF),
definitions of, 132–136 Behavior checklists, 217. See also 232
developmental course of, 138–140 Assessment
diagnosis and, 133–135, 141–142 Behavior management interventions, 143, Café au lait spots, 44–45, 48, 318, 323,
Down syndrome and, 366 372–373, 436, 455–457. See also 324–325
etiological considerations, 136–138 Behavioral treatments California Verbal Learning Test, 29
evaluation for, 141–142 Behavioral assessment, 372–373. See also Callosal dysgenesis, 20t
executive functioning and, 160 Assessment Candidate genes, 48
fragile X–associated disorders and, 276, Behavioral symptoms Carbohydrate metabolism defects, 572
283–284, 285 behavior problems as, 266–267, Cardiomyopathy, 526, 530–531
genetic factors and, 136–138 298–299, 302, 306 Cardiovascular problems
learning disabilities and, 119 Down syndrome, 371–372 Down syndrome and, 364
memory and learning and, 20t fragile X syndrome and fragile Klinefelter syndrome and, 386
multifactorial inheritance and, 49 X–associated disorders and, 278–280, mitochondrial metabolism disorders
neurofibromatosis type 1 (NF1) and, 278t, 286 and, 518t, 522, 525t, 526
329, 332 inborn errors of metabolism (IEMs), mucopolysaccharidoses (MPS disorders),
neuroimaging technologies and, 59 573–574 298, 301
neuropsychological impairments and, inhibition, 193–194 Noonan syndrome and, 314–315
140–141 Klinefelter syndrome and, 389 Rett syndrome and, 433
overview, 131–136, 143 Lesch–Nyhan syndrome and, 447, 449 Category Test, 14, 15–16, 15f
Index 581
Central nervous system (CNS) Cognitive Assessment System, 142 autism spectrum disorders and, 245
disturbances Cognitive functioning, 302, 472–477 Down syndrome and, 371
autism spectrum disorders and, 238–239 Cognitive impairment, 89, 331–333, Klinefelter syndrome and, 392
complex functional systems and, 13 341, 469–470. See also Cognitive phenylketonuria (PKU) and, 408–409
learning disabilities and, 106, 110 symptoms Prader–Willi syndrome and, 500,
Lesch–Nyhan syndrome and, 445 Cognitive learning models, 106–107 504–505
monitoring and managing symptom Cognitive problem-solving skills training sickle cell disease (SCD) and, 356
expression and, 11 (CPST), 163–164 Tourette syndrome and, 173
neuropsychological evaluation and, 17 Cognitive symptoms. See also Mood disorders
overview, 3 Down syndrome and, 368, 370–371 Dermatological conditions, 364
schools and, 13–14 fragile X syndrome and fragile Detection rate, 107
seizure disorders and, 463 X–associated disorders and, 278–280 Developmental course
sickle cell disease (SCD) and, 339, Klinefelter syndrome and, 388 ADHD and, 138–140
341–342, 346 Lesch–Nyhan syndrome and, 448 aggressive behavior, ODD, and CD,
spina bifida myelomeningocele and, neurofibromatosis type 1 (NF1) and, 153–157
558–560 327–331, 331–333 anencephaly, 546
Cerebellum, 235–236, 559 Prader–Willi syndrome and, 491–502, anxiety disorders, 188–189
Cerebral cortex, 432, 539–540, 539f 493t, 497t, 498t, 501t cerebral cortex, 539–540, 539f
Cerebral palsy, 20t, 428, 429 schizencephaly, 543–544 Down syndrome and, 367–370
Cerebrospinal fluid, 433, 541, 542f See also Symptoms inborn errors of metabolism (IEMs),
Cerebrovascular accidents Cognitive-behavioral therapy (CBT) 574–575
Klinefelter syndrome and, 386 anxiety disorders and, 199, 200–201, Klinefelter syndrome and, 386–389
sickle cell disease (SCD) and, 339–340, 200t Lesch–Nyhan syndrome and, 447–449
349, 351, 354–355 mood disorders and, 220–221 lissencephaly, 548
Child and Adolescent Psychiatric Turner syndrome and, 271 mitochondrial metabolism disorders
Assessment (CAPA), 217 Color Form Test, 15, 16f and, 518–531, 518t, 519t, 520–521,
Child Behavior Checklist (CBCL) Colorado Family Reading Study, 111 521f, 523t, 525t, 527t, 528f
ADHD and, 141–142 Colorado Twin Study, 112 mood disorders, 210–212
aggressive behavior, ODD, and CD, 163 Communication skills, 305, 435 mucopolysaccharidoses (MPS disorders),
Down syndrome and, 366 Comorbid conditions 293–297, 294t
Lesch–Nyhan syndrome and, 449 ADHD and, 138–140, 182 neurofibromatosis type 1 (NF1) and, 331
Prader–Willi syndrome and, 497, 498 aggressive behavior, ODD, and CD Noonan syndrome, 313–316
Childhood and, 157 phenylketonuria (PKU) and, 402–406,
inborn errors of metabolism (IEMs), anxiety disorders, 189–191, 190t, 191t 414
575–576 autism spectrum disorders and, 244–245 Rett syndrome and, 425, 427–429
mitochondrial metabolism disorders Down syndrome and, 363–367 schizencephaly, 542–543
and, 524–531, 525t, 527t, 528f Klinefelter syndrome and, 384–386 sickle cell disease (SCD) and, 341–342
Noonan syndrome and, 313–314 learning disabilities and, 108, 118–121 spina bifida myelomeningocele and,
phenylketonuria (PKU) and, 412t, 414 overview, 118–119 562–563
Rett syndrome and, 428–429 phenylketonuria (PKU) and, 409 Tourette syndrome, 173–174
seizure disorders and, 466–469, 466t Prader–Willi syndrome and, 500–502, treatment and, 414
sickle cell disease (SCD) and, 344, 353 501t Diabetes, 262, 385–386
spina bifida myelomeningocele and, 564t sickle cell disease (SCD) and, 356 Diagnosis
Turner syndrome and, 265–267 social adjustment and, 89 ADHD and, 133–135, 139, 141–142
See also Adolescence; Developmental Tourette syndrome and, 173, 180, 182, aggressive behavior, ODD, and CD,
course; Infancy 182–183 162–163
Childhood absence epilepsy, 466t, 469. See Comprehensive Teacher’s Rating Scale, autism spectrum disorders, 229
also Seizure disorders 141–142 behavioral phenotypes, 54
Childhood Attention Problems Scale, Comprehensive Trail-Making Test benefits of, 52–54, 52t
141–142 (CTMT), 15 conduct disorder (CD), 152, 152t
Childhood Autism Rating Scale (CARS), Computed tomography (CT), 59, 545. See Down syndrome, 372
229 also Neuroimaging methods inborn errors of metabolism (IEMs),
Childhood characteristics, 154–155, 173 Computer-based interventions, 287–288, 575–576
Childhood disintegrative disorder, 229. See 375 integrative developmental
also Autism spectrum disorders Concentration, 12, 316, 472f, 473–474 neuropsychology and, 92–93
Children’s Depression Inventory (CDI), Concordance rates, 111–112, 113–114 Klinefelter syndrome, 383–384
218t Conduct disorder (CD) Lesch–Nyhan syndrome and, 447–449
Chromosome disorders assessment and, 162–163 medical genetics and, 49–54, 50f, 51t,
autism spectrum disorders and, 231 biological and neuropsychological 52t
behavioral phenotypes, 54, 54–55, 55t markers, 158–161 mitochondrial metabolism disorders
comorbid conditions and, 121 developmental course of, 153–157 and, 522, 532
learning disabilities and, 113, 121 diagnosis and, 152, 152t mood disorders, 209–210, 216–217
medical genetics and, 37–41, 38f, 39f, genetics and family patterns, 157–158 mucopolysaccharidoses (MPS disorders),
40f history, 151–153, 152t, 153t 299–307, 300t, 303t
overview, 34, 35t overview, 151, 165 multifactorial syndromes and, 69
See also individual disorders Prader–Willi syndrome and, 500 neurofibromatosis type 1 (NF1) and,
Chromosome 15, 113, 500 risk factors for, 161–162, 161t 323–324
Chromosome 6, 136 treatment and, 163–165 Noonan syndrome and, 317–319
Classroom Assessment of Development Conners 3rd Edition, 141–142 phenylketonuria (PKU) and, 402, 404
Skills, 374 Cooperative Study of Sickle Cell Disease Prader–Willi syndrome and, 484–485,
Classroom environment (CSSCD), 339, 343, 347 489–491, 490t, 496–497, 500–501
Down syndrome and, 369–370, 375 Coping style, 88–89, 90–92, 270 report writing and, 30
educational modifications and, 19 Copy number variations (CNVs), 232 Rett syndrome and, 433, 440
Klinefelter syndrome and, 393 Corpus callosum, 432, 558 seizure disorders and, 463
Treatment and Education of Autistic and Craniofacial syndromes, 59–61, 60f. See Diagnostic and Statistical Manual of
related Communication-Handicapped also inidividual syndromes Mental Disorders (DSM), 133–135.
Children (TEACCH), 240 Cultural factors, 95–96, 215–216, See also DSM-III; DSM-III-R; DSM-
Clinical Assessment of Depression (CAD), 356–357 IV; DSM-IV-TR
218t Diagnostic Interview for Children and
Clinical interview, 198, 217. See also Delinquency, 154, 158, 178 Adolescents (DICA), 217
Assessment Dementia, 298, 365, 500 Diagnostic Interview Schedule for Children
Clinician-observer rating scales, 178–179. Dental problems, 298, 301 Version IV (DISC-IV), 163, 197, 217
See also Assessment Depression Differential diagnosis, 180, 489–491, 490t
Cloning, 47, 48f adolescence and, 211–212 Differential reinforcement of incompatible
Cognitive assessment, 372, 450–451. See anxiety disorders and, 190, 198–199 behaviors (DRI) interventions, 456.
also Assessment assessment and, 216–217 See also Behavioral treatments
582 Index
Differential reinforcement of other Noonan syndrome and, 319 Lesch–Nyhan syndrome and, 449–450
behavior (DRO) interventions, 455. Prader–Willi syndrome and, 503–504 lissencephaly, 548
See also Behavioral treatments See also Treatment mitochondrial metabolism disorders
Diffusion tensor imaging (DTI), 58. See Electroencephalography (EEG), 194–195, and, 531
also Neuroimaging methods 234, 412, 461 mood disorders, 212–214, 221
Disruptive behavior disorders, 190–191, Emotional interventions, 319, 392–393. mucopolysaccharidoses (MPS disorders),
213–214 See also Interventions 302–303, 303t
DNA technology Emotional regulation, 189, 195, 286 neural tube defects (NTDs) and, 555
autism spectrum disorders and, 231 Emotional symptoms, 135–136, 371, 390, neurofibromatosis type 1 (NF1) and,
fragile X syndrome and fragile 408–409, 543 326–327
X–associated disorders and, 280, Employment, 376, 503–504. See Noonan syndrome and, 312–313
284–285 Vocational functioning Tourette syndrome, 174–175
genetic heterogeneity and, 45 Endocrine disorders, 20t, 366, 525t See also Families and family
learning disabilities and, 113 Environmental factors environment; Genetic factor
linkage and, 47–49, 48f anxiety disorders and, 192 Family systems model, 92–95
mitochondrial metabolism disorders autism spectrum disorders and, 232–233 Fatty acid oxidation disorders, 572
and, 513, 514f, 516 genetic factors and, 555–556 Febrile seizures, 466t, 467. See also Seizure
Noonan syndrome and, 318 integrative developmental disorders
Doose syndrome, 466t, 467. See also neuropsychology and, 85–86 Fetal alcohol syndrome (FAS), 51–52, 55t,
Seizure disorders learning disabilities and, 110–111 233, 410–411
Dopaminergic system mood disorders, 212 Fine motor skills, 404, 560
ADHD and, 137 mucopolysaccharidoses (MPS disorders), Finger Localization Test, 15f
Lesch–Nyhan syndrome and, 445, 447, 303 Finger Tapping Test, 15f, 16, 16f
453–454, 456 seizure disorders and, 461 Fingertip Writing Perception Test, 15f
phenylketonuria (PKU) and, 400, 404–405 Tourette syndrome and, 171–172 5-HT, 192–193, 236–237
Tourette syndrome and, 181–182 Epidemiology, 189–191, 190t, 191t, 517. 5-HTT gene, 193
Down syndrome See also Prevalance statistics 5-HTTLPR gene, 193, 197
adolescence and, 376 Epilepsy Fluid-attenuated inversion recovery
adult care and treatment, 376 autism spectrum disorders and, 232 (FLAIR), 63, 63f, 64f, 65, 65f. See
assessment and, 372–373 classification schemes, 462–469, 464t, also Neuroimaging methods
autism spectrum disorders and, 233 465t, 466t Fluorescent in situ hybridization (FISH),
behavioral presentation of, 54–55, 55t, neuropsychological sequelae associated 37–38, 490–491
371–372 with, 469–477, 472f Fragile X mental retardation protein
cognitive presentation of, 370–371 overview, 460–461, 479 (FMRP), 66
comorbid conditions and, 363–367 schizencephaly and, 544 Fragile X syndrome (FXS)
developmental course of, 367–370 See also Seizure disorders ADHD and, 138
emotional presentation of, 371 Ethnicity, 215–216, 277 adult outcome, 282
genetics and family patterns, 362–363 Etiology assessment and, 284–285
medical complications and, 363–367 ADHD and, 136–138 autism spectrum disorders and, 231
memory and learning and, 20t autism spectrum disorders and, 230–233 behavioral phenotypes, 55t
neuroimaging technologies and, 59, 60f learning disabilities and, 110–114, 121 case illustrations of, 280–282, 283–284
overview, 35t, 39, 362, 376 mucopolysaccharidoses (MPS disorders), DNA technology and, 48, 284–285
phenotype and, 41 293–297, 294t inheritability of, 276–278, 278f
phenylketonuria (PKU) and, 409 seizure disorders and, 477–479 memory and learning and, 20t
prevalence of, 362 Turner syndrome, 261–262 molecular–clinical correlations, 282
treatment and, 373–376 Evaluation, 141–142. See also Assessment multifactorial inheritance and, 49
DSM-III, 134–135 Executive functioning neuroimaging technologies and, 66
DSM-III-R, 152–153, 152t, 153t, 190 aggressive behavior, ODD, and CD, 160 nontraditional inheritance and, 47
DSM-IV neurofibromatosis type 1 (NF1) and, overview, 35t, 276–277, 288–289
ADHD and, 134–135 328–329 phenotypes of, 278–280, 278t
anxiety disorders and, 197 Noonan syndrome and, 317 Prader–Willi syndrome and, 495
obsessive–compulsive disorder (OCD) phenylketonuria (PKU) and, 411–412, 412t premutation involvement, 282–284
and, 501 seizure disorders and, 471, 472f, 476–477 prevalence of, 277
pervasive developmental disorders sickle cell disease (SCD) and, 354–355 treatment and, 285–288
(PDD) and, 71–72 spina bifida myelomeningocele and, See also Fragile X–associated disorders
Prader–Willi syndrome and, 501 561–562 (FXDs)
DSM-IV-TR Tourette syndrome and, 176 Fragile X–associated disorders (FXDs)
ADHD and, 133–135, 141 Exposure with response prevention (ERP), adult outcome, 282
anxiety disorders and, 197 181 assessment and, 284–285
comorbid conditions and, 119 Expressive language, 12, 374, 429 case illustrations of, 280–282, 283–284
conduct disorder (CD), 152, 152t, 162 Expressivity, 43–44, 45, 312–313. See also DNA technology and, 284–285
learning disabilities and, 119 Symptoms inheritability of, 276–278, 278f
mood disorders, 210 molecular–clinical correlations, 282
oppositional defiant disorder (ODD), Factor-analysis, 114, 116–118, 116t, 117t overview, 276–277, 288–289
152–153, 153t, 162–163 Familial aggregation and transmission, 158 phenotypes of, 278–280, 278t
overview, 425 Families and family environment premutation involvement, 282–284
Prader–Willi syndrome and, 500–501 ADHD and, 138 prevalence of, 277
subtyping of learning disabilities and, 115 coping within, 90–92 treatment and, 285–288
Dubowitz Neurological Assessment, 410 Down syndrome and, 375–376 See also Fragile X syndrome (FXS)
Dyslexia, 113, 121. See also Learning family involvement in treatment, 221 Freedom from Distractibility Index, 329
disability family support, 52t Frontal lobe, 194–195, 354–355
inborn errors of metabolism (IEMs) Functional MRI (fMRI)
Early intervention programs, 305, and, 576 anxiety disorders and, 196, 197
373–374. See also Interventions learning disabilities and, 108, 110–111 autism spectrum disorders and, 236
Ecological-systems theory, 86–87, 86f. See mucopolysaccharidoses (MPS disorders), learning disabilities and, 110
also Social–ecological model 299 overview, 58
Education for All Handicapped Children Prader–Willi syndrome and, 499 Tourette syndrome and, 175–176
Act of 1975, 376 Rett syndrome and, 436–437 See also Neuroimaging methods
Educational functioning, 304–307 See also Family patterns; Parent
Educational treatment approaches Family patterns GABA (gamma-aminobutyric acid),
autism spectrum disorders and, 240 aggressive behavior, ODD, and CD, 238–239, 280, 453
fragile X syndrome and fragile 157–158 Gastrointestinal anomalies
X–associated disorders and, 288 anxiety disorders, 191–192 Down syndrome and, 364
Klinefelter syndrome, 393 family genetic studies, 174–175 Klinefelter syndrome and, 386
Lesch–Nyhan syndrome and, 457–458 fragile X syndrome and fragile X–associated mitochondrial metabolism disorders
mucopolysaccharidoses (MPS disorders), disorders and, 277–278, 278f and, 518t, 525t
304–307 Klinefelter syndrome, 383–384 Rett syndrome and, 436
Index 583
Gender Halstead–Reitan Neuropsychological Test Information processing

ADHD and, 137 Battery for Older Children, 14, 15f anxiety disorders and, 195
autism spectrum disorders, 230 Hearing loss, 298, 301, 365, 434 phenylketonuria (PKU) and, 412
delinquent behavior and, 158 Heart defects, 262, 312, 314–315, Prader–Willi syndrome and, 494
Down syndrome, 362 364, 386. See also Cardiovascular seizure disorders and, 471
fragile X–associated disorders and, problems sickle cell disease (SCD) and, 342–344
276, 280 Heterogeneity, 45, 112–113 Inheritance, 276–278, 278f
learning disabilities and, 109 Hippocampus, 235, 432 Inherited metabolic disorders, 62–66, 63f,
Lesch–Nyhan syndrome and, 449–450 Hopkins Motor and Vocal Tic Scale 64f, 65f. See also individual disorders
mitochondrial metabolism disorders (HMVTS), 179 Instruction
and, 518, 519t, 524 Hormonal disturbances, 384–385 educational modifications and, 19
mood disorders and, 215 Hormonal treatments, 267, 269 learning disabilities and, 106, 122–123
neurofibromatosis type 1 (NF1) and, Hormone testing, 383–384 mucopolysaccharidoses (MPS disorders),
331–332 HTT gene, 53 304–307
phenylketonuria (PKU) and, 398, Human Genome Project, 47–48 strengths of the child and, 1718
408–409 Hunter syndrome, 294, 295, 296. See Integrative developmental neuropsychology
Rett syndrome and, 426–427, 428, also Mucopolysaccharidoses (MPS critical variables, 87–92
431–432 disorders) diagnosis and, 92–93
Turner syndrome and, 265–267 Huntington disease, 35t, 47, 53 models, 85–87, 86f
Gene identification, 47, 48f Hurler syndrome, 294–295, 295–296. See overview, 84–85, 96
General Cognitive Index, 410 also Mucopolysaccharidoses (MPS patterns of family interaction and,
Generalized anxiety disorder (GAD), 197, disorders) 93–95
199–200. See also Anxiety disorders Hurler–Scheie syndrome, 294–296. See social culture and, 95–96
Genetic counseling, 35–37, 52t, 303–304, also Mucopolysaccharidoses (MPS Intelligence
393–394 disorders) ADHD and, 138
Genetic disorders Hydrocephalus aggressive behavior, ODD, and CD, 154
genetic services, 35–37 executive functioning and, 160 autism spectrum disorders and, 229, 245
mucopolysaccharidoses (MPS disorders), memory and learning and, 20t Down syndrome and, 368, 372
300t mucopolysaccharidoses (MPS disorders), fragile X syndrome and fragile
neuroimaging technologies and, 73 296, 298 X–associated disorders and, 280, 282
overview, 33–34 spina bifida myelomeningocele and, heritability of, 5
prevalence of, 35 559–560 Kaufman Assessment Battery for
types of, 34–35, 35t Hyperactivity, 133–134, 271, 285, Children, Second Edition (KABC-II)
See also inidividual disorders; Medical 296. See also Attention-deficit/ and, 26–27
genetics hyperactivity disorder (ADHD) Klinefelter syndrome and, 388
Genetic factors Hyperphagia, 285, 486, 496, 497 Lesch–Nyhan syndrome and, 448, 451
ADHD and, 136–138 Hyperthyroidism. See Thyroid functioning mitochondrial metabolism disorders
aggressive behavior, ODD, and CD, Hypogonadism, 384–385, 485 and, 531
157–158 Hypothyroidism. See Thyroid functioning neurofibromatosis type 1 (NF1) and,
anxiety disorders, 191–192, 192, 193 Hypotonia, 287, 484, 520–521 327, 329, 332
autism spectrum disorders and, 230–232 Hypoxanthine–guanine neuropsychological evaluation and, 12
comorbid conditions and, 119 phosphoribosyltransferase (HPRT), Noonan syndrome and, 316
Hunter syndrome, 194 445, 446–447, 446f phenylketonuria (PKU) and, 398–399,
Klinefelter syndrome, 383–384 403, 404, 410–411
learning disabilities and, 111–114, 119 Imprinting disorders, 61–62. See also Prader–Willi syndrome and, 491–492,
Lesch–Nyhan syndrome and, 449–450 inidividual syndromes 498–499
lissencephaly, 548 Impulsivity premutation involvement, 282
mitochondrial metabolism disorders ADHD and, 133–134, 135 seizure disorders and, 469–470, 470, 477
and, 521, 526–531, 527t, 528f, 531 autism spectrum disorders and, 240 sickle cell disease (SCD) and, 344–348
mood disorders, 212–213, 212–214 phenylketonuria (PKU) and, 402 spina bifida myelomeningocele and,
mucopolysaccharidoses (MPS disorders), sickle cell disease (SCD) and, 342–344 559, 560
294 Inborn errors of metabolism (IEMs) Turner syndrome and, 262–263, 265
neurofibromatosis type 1 (NF1) and, appearance and development of, See also IQ testing
326–327 574–575 Internalizing Symptoms Scale for Children
Noonan syndrome and, 312–313 background of, 571 (ISSC), 218t
phenylketonuria (PKU) and, 401–402 classification schemes, 571–574 Interpersonal psychotherapy for depressed
Prader–Willi syndrome and, 487–489 diagnosis and, 575–576 adolescents (IPT-A), 220–221, 221
Rett syndrome and, 429–430 overview, 20t, 570–571, 576–577 Interventions
seizure disorders and, 461 treatment and, 576 aggressive behavior, ODD, and CD, 153
Tourette syndrome, 174–175, 182 See also Lesch–Nyhan syndrome; diagnosis and, 52t
Turner syndrome and, 262 Metabolic disorders; Phenylketonuria learning disabilities and, 106, 110–111,
See also Family patterns (PKU) 122–123
Genetic heterogeneity, 45, 49 Individualized education program (IEP), mucopolysaccharidoses (MPS disorders),
Genetic linkage studies, 113–114 19, 305, 503–504 299–307, 300t, 303t
Genomic imprinting, 35t, 46, 484, 488–489 Infancy Noonan syndrome and, 319
Genomic structure, 33–34 ADHD and, 138 Prader–Willi syndrome and, 502–505,
Genotype, 4, 44f, 401 anencephaly, 546 502t
Gilles de la Tourette syndrome. See Down syndrome and, 373–374 Rett syndrome and, 433–436
Tourette syndrome inborn errors of metabolism (IEMs), sickle cell disease (SCD) and, 351
Glucose metabolism, 341, 385 574–575 social adjustment and, 90
Grip Strength test, 15f, 16f mitochondrial metabolism disorders targets for, 90
Growth abnormalities and, 518–531, 518t, 519t, 521f, 523t, Turner syndrome and, 268–271
Down syndrome and, 370 525t, 527t, 528f See also Treatment
fragile X syndrome and fragile neuropsychological assessment and, IQ. See Intelligence
X–associated disorders and, 278 9–10 IQ testing, 18, 262–263, 451. See also
mitochondrial metabolism disorders Noonan syndrome, 313 Intelligence
and, 522 phenylketonuria (PKU) and, 412t, 414
Noonan syndrome and, 313–314 Rett syndrome and, 427–428 Juvenile absence epilepsy, 466t, 469. See
Prader–Willi syndrome and, 487 seizure disorders and, 463–466, 464t, also Seizure disorders
Rett syndrome and, 431 465t Juvenile myoclonic epilepsy, 466t, 469. See
spina bifida myelomeningocele and, sickle cell disease (SCD) and, 341–342, also Seizure disorders
562–563 344
Turner syndrome and, 267, 269 spina bifida myelomeningocele and, 564t Kaufman Assessment Battery for Children
Infantile myoclonic epilepsy, 466t, 467. See (K-ABC), 25
Halstead–Reitan batteries, 12, 14 also Seizure disorders Kaufman Assessment Battery for Children,
Halstead–Reitan Neuropsychological Test Infantile spasms, 466, 466t. See also Second Edition (KABC-II), 12,
Battery, 14, 470 Seizure disorders 25–26, 27–28
584 Index
Kearns–Sayre syndrome, 35t, 526–527, Lissencephaly, 541t, 547–550 Memory

527, 527t Liver functioning, 365, 524 neurobiology of, 20–21
Kidney problems, 262, 445 Lower-motor-neuron (LMN) syndrome, neurofibromatosis type 1 (NF1) and, 329
Klinefelter syndrome 556, 557t neuropsychological evaluation and, 12,
academic performance and, 289–290 Lurian processing models, 24–25 19–24, 20t, 22t, 23t
adolescence and, 393–394 Luria–Nebraska Neuropsychological Noonan syndrome and, 317
adult care and treatment, 393–394 Battery—Children’s Revision (LNNB- Prader–Willi syndrome and, 494
assessment and, 391 CR), 12, 25, 28–29, 28t seizure disorders and, 469–470, 471,
behavioral presentation of, 55t, 389 472f, 474–475
comorbid conditions and, 384–386 Magnetic resonance imaging (MRI) sickle cell disease (SCD) and, 343,
developmental course of, 386–389 autism spectrum disorders and, 233–234 349–350, 353–354
emotional presentation of, 390 Down syndrome and, 365 Meningocele, 554–555. See also Neural
genetics and family patterns, 383–384 Klinefelter syndrome and, 387 tube defects (NTDs)
learning disabilities and, 113, 121 Lesch–Nyhan syndrome and, 454 Mental health. See Psychiatric conditions;
medical complications and, 384–386 mitochondrial metabolism disorders Psychopathology
neuroimaging technologies and, 66–67 and, 521, 521f, 528f Mental retardation
overview, 35t, 39, 382–383, 394 neurofibromatosis type 1 (NF1) and, 332 fragile X–associated disorders and, 276
social problems and, 390 overview, 11, 58, 340 inborn errors of metabolism (IEMs),
treatment and, 391–393 phenylketonuria (PKU) and, 405, 571, 573–574, 575–576
412–413 lissencephaly, 548–549
Language skills schizencephaly, 545 memory and learning and, 20t
Down syndrome and, 368–369, 371 sickle cell disease (SCD) and, 341, 345, neurofibromatosis type 1 (NF1) and, 327
Klinefelter syndrome and, 388–389 347–348 phenylketonuria (PKU) and, 398–399
language processing, 110, 114–115, spina bifida myelomeningocele and, 559 Prader–Willi syndrome and, 494–495,
349–350 Tourette syndrome and, 175–176 497, 502
neurofibromatosis type 1 (NF1) and, 328 See also Neuroimaging methods Rett syndrome and, 425, 431
Noonan syndrome and, 317 Major depressive disorder (MDD) schizencephaly, 543
phenylketonuria (PKU) and, 412t anxiety disorders and, 190, 194, 197 Metabolic disorders, 428, 570–577. See
Prader–Willi syndrome and, 495 assessment and, 216–217 also individual disorders
seizure disorders and, 472f, 475–476 developmental course of, 210–212 Metabolic error, 572–574
sickle cell disease (SCD) and, 352–353 prevalence of, 210 Methods for Epidemiology of Child and
spina bifida myelomeningocele and, 561 Marfan syndrome, 45 Adolescent Mental Disorders Study, 210
Lateral Dominance Aphasia Screening Maroteaux–Lamy syndrome, 295, 297. See Microdeletion syndromes, 39, 41, 484. See
Test, 15f, 16f also Mucopolysaccharidoses (MPS also individual syndromes
Learning disorders) Millon Clinical Multiaxial Inventory–III
ADHD and, 139 Matching Familiar Figures Test, 142 (MCMI-III), 218t
Down syndrome and, 369–370 Matching Pictures test, 15, 16f Minimal brain injury (MBD), 105–106.
neuropsychological evaluation and, 12, Matching V’s and Figures test, 15, 16f See also Learning disability
19–24, 20t, 22t, 23t Maternal PKU, 409–411. See also Minnesota Multiphasic Personality
Noonan syndrome and, 317 Phenylketonuria (PKU) Inventory, 119
phenylketonuria (PKU) and, 407–408 Math skills, 350–351, 407, 492, 560 Mitochondrial disorders
seizure disorders and, 472f, 474–475 McCarthy Scales of Children’s Abilities, assessment and, 532
sickle cell disease (SCD) and, 353–354 410 background of, 512–517, 514f
spina bifida myelomeningocele and, Medical complications biological and neuropsychological
560–561 autism spectrum disorders and, 231–232 markers, 531–532
Learning disability Down syndrome and, 363–367 clinical presentation of, 520–521,
comorbid conditions, 118–121 Klinefelter syndrome and, 384–386 525–529, 525t, 527t, 528f
comprehensive neuropsychological mucopolysaccharidoses (MPS disorders), developmental course of, 518–531, 518t,
evaluation and, 118 297–299, 300–302 519t, 521f, 523t, 525t, 527t, 528f
etiology of, 110–114 Noonan syndrome and, 314–316 epidemiology of, 517
fragile X–associated disorders and, 276 phenylketonuria (PKU) and, 409 genetic etiologies and, 529–531
inborn errors of metabolism (IEMs), Prader–Willi syndrome and, 487, 503 history, 517–518
575–576 See also Physical symptoms overview, 34, 35t, 512, 533
interventions and, 122–123 Medical genetics treatment and, 532–533
memory and learning and, 20t autism spectrum disorders and, Mitochondrial encephalomyopathies,
neurofibromatosis type 1 (NF1) and, 231–232 35t, 52
322, 330–331 behavioral phenotypes, 54–55, 55t Mitochondrial encephalomyopathy, lactic
neuropsychological model for chromosome disorders, 37–41, 38f, acidosis, and stroke-like episodes
assessment, 116–118, 116t, 117t, 123 39f, 40f (MELAS), 526, 527t, 528f
overview, 35t, 105–107, 123 diagnosis and, 49–54, 50f, 51t, 52t Mitochondrial neurogastrointestinal
Prader–Willi syndrome and, 492 DNA technology and, 47–49, 48f encephalopathy (MNGIE), 529–530,
prevalence of, 107–110 genomic structure, 33–34 532–533
subtyping, 114–115 genotype–phenotype relationships and, Monogenic conditions
Tourette syndrome and, 173, 182–183 43–46, 44f multifactorial inheritance and, 49
Leber hereditary optic neuropathy monogenic disorders, 41–43, 42f nontraditional inheritance and, 47
(LHON), 517, 527t multifactorial inheritance, 49 overview, 34, 35t, 41–43, 42f
Leigh syndrome, 521–522, 527t, 529, 531 nontraditional inheritance, 46–47 Mood disorders
Lennox–Gastaut syndromes, 429, 462, overview, 33, 55–56 assessment and, 216–217, 218t
466t, 467–468. See also Seizure principles of, 37–54, 38f, 39f, 40f, 42f, autism spectrum disorders and, 244
disorders 44f, 48f, 50f, 51t, 52t biological and neuropsychological
Lesch–Nyhan syndrome types of genetic disorders, 34–35, 35t markers, 214–215
assessment and, 450–451 types of genetic services, 35–37 developmental course of, 210–212
developmental course of, 447–449 See also Genetic disorders diagnosis and, 209–210
genetics and family patterns, 449–450 Medical interventions. See also Down syndrome and, 371
history and background of, 445–447, Interventions genetics and family patterns, 212–214
446f Down syndrome and, 373 history, 209–210
memory and learning and, 20t fragile X syndrome and fragile Klinefelter syndrome and, 392
overview, 445, 458 X–associated disorders and, 286–287 overview, 209–210, 221–222, 531
phenotypic expression, 450 mucopolysaccharidoses (MPS disorders), Prader–Willi syndrome and, 500–501,
treatment and, 451–458, 452t 300–302 504–505
See also Inborn errors of metabolism Noonan syndrome and, 319 prevalence of, 210, 211t
(IEMs) spina bifida myelomeningocele and, 563 risk factors for, 215–216
Leukemia, 12–13, 315 Turner syndrome and, 268–269 sickle cell disease (SCD) and, 356
Limbic–hypothalamic–pituitary–adrenal Medication. See Psychopharmacological Tourette syndrome and, 182–183
(LHPA) axis, 237–238 interventions treatment and, 217, 219–221
Linkage, 47–49, 48f, 137, 231 Melatonin, 238, 435–436 See also Depression
Index 585
Morquio syndrome, 295, 297. See also cognitive profile of, 327–331 Noonan syndrome
Mucopolysaccharidoses (MPS developmental considerations, 331 ADHD and, 138
disorders) diagnosis and, 49–50, 51t, 323–324 assessment and, 317–319
Mortality, 367, 519t, 520, 525, 546–547 genetics and family patterns, 326–327 behavioral phenotypes, 55t
Mosaicism, 35t, 46, 261–262, 368 history, 322–323 developmental course of, 313–316
Motor development, 404, 427–428, 435 multifactorial inheritance and, 49 diagnosis and, 317–319
Motor functioning overview, 322 genetics and family patterns, 312–313
Down syndrome and, 370 prevalence of, 323, 324t medical complications and, 314–316
inborn errors of metabolism (IEMs), 576 research needs, 333–334 multifactorial inheritance and, 49
Noonan syndrome and, 316 Neuroimaging methods neurological features, 314
schizencephaly, 543 anxiety disorders and, 196–197, 201 neuropsychological impairments and,
seizure disorders and, 471–472, 476, 477 autism spectrum disorders and, 233–234 316–317
spina bifida myelomeningocele and, craniofacial syndromes, 59–61, 60f overview, 311–312, 319–320
556–557, 557t, 560–561, 562, 563 imprinting disorders, 61–62 pleiotropy and, 45
Motor tic, Obsessions and compulsions, inherited ataxias, 68 prevalence of, 312
Vocal tic, Evaluation Survey inherited metabolic disorders, 62–66, psychosocial features, 314
(MOVES) scale, 179–180 63f, 64f, 65f treatment and, 319
Motor tics, 171–172. See also Tics; learning disabilities and, 121
Tourette syndrome mitochondrial metabolism disorders Obesity
mtDNA genome and, 528f Down syndrome and, 365, 366, 370
genetic factors and, 526–531, 528f, multifactorial syndromes, 69–73, 70f, fragile X syndrome and fragile
5207t 71f X–associated disorders and, 285
inheritance and bottleneck effect and, neurocutaneous syndromes, 68–69, 68f Prader–Willi syndrome and, 485–486,
515–516 neurofibromatosis type 1 (NF1) and, 499, 502, 502t, 503
nuclear–mitochondrial intergenomic 332, 334 treatment and, 503
communication and, 56–57 overview, 58–59, 73 Turner syndrome and, 262
overview, 513, 514f phenylketonuria (PKU) and, 412–413 Obsessive–compulsive disorder (OCD)
See also Mitochondrial disorders schizencephaly, 544–545 assessment and, 198
Mucopolysaccharidoses (MPS disorders), treatment and, 201 executive functioning and, 160
293–297, 293t, 294t, 307–308 X-linked syndromes, 66–67 fragile X syndrome and fragile
Multidimensional Anxiety Scale for See also individual methods X–associated disorders and, 285
Children (MASC), 198t Neurological problems Klinefelter syndrome and, 385
Multifactorial syndromes, 34, 35t, 49, Down syndrome and, 365–366 Prader–Willi syndrome and, 500–502,
69–73, 70f, 71f. See also inidividual Klinefelter syndrome and, 385, 387 501t
syndromes mitochondrial metabolism disorders Tourette syndrome and, 173, 174, 178,
Multiscore Depression Inventory for and, 518t, 520–521, 525t 180
Children (MDI-C), 218t Noonan syndrome and, 314 treatment and, 199–200, 200t
Multiscore Depression Inventory (MDI), sickle cell disease (SCD) and, 341 See also Anxiety disorders
218t Neuropathology, 432–433, 461–462, 558 Occupational therapy, 241, 287
Mutation, genetic, 41, 45–46. See also Neuropathy, ataxia, retinitis pigmentosa Online Mendelian Inheritance in Man
Monogenic conditions (NARP), 527t (OMIM) database, 59
Myelin abnormalities, 398, 399, 400 Neuropsychological assessment Ophthalmological concerns, 363, 525t
Myelomeningocele, 554–555. See also approaches and instruments for, Oppositional defiant disorder (ODD)
Neural tube defects (NTDs) 14–17, 15t, 16t. See also individual anxiety disorders and, 190–191
Myoclonic–astatic epilepsy, 466t, 467. See instruments assessment and, 162–163
also Seizure disorders learning disabilities and, 116–118, 116t, biological and neuropsychological
Myoclonus, epilepsy with ragged red fibers 117t markers, 158–161
(MERRF), 527, 527t, 529 Lurian processing models and, 24–25 developmental course of, 153–157
monitoring and managing symptom diagnosis and, 152–153, 153t
National Comorbidity Survey Replication expression, 10–11 genetics and family patterns, 157–158
Adolescent Supplement (NCS-A), other information needed for, 18 history, 151–153, 152t, 153t
190–191 overview, 9–10, 11–12, 12–14, 17–19, overview, 151, 165
National Down Syndrome Society (NDSS), 29–30 risk factors for, 161–162, 161t
373 reason for referral and, 17 treatment and, 163–165
National Society of Genetic Counselors seizure disorders and, 469–477, 472f Organization, problems with, 317,
(NSGC), 36 Neuropsychological Battery for Epilepsy, 353–354, 494
Neocortex, structural anomalies 470 Orthopedic problems
anencephaly, 545–547 Neuropsychological Deficit Scale, 16 Down syndrome and, 373
case illustrations of, 550–551 Neuropsychological deficits, 140–141, 154, neurofibromatosis type 1 (NF1) and, 326
cerebral cortex development and, 176, 298 Noonan syndrome and, 315–316
539–540, 539f Neuropsychological impairment, 3, Rett syndrome and, 425
lissencephaly, 547–550 11–12, 316–317, 342–356, 404–406, spina bifida myelomeningocele and, 557
overview, 539, 551 531–532 Oxidative phosphorylation (OXPHOS),
schizencephaly, 540–545, 541f, 542f Neuropsychological markers 52, 513
Neonatal development. See Infancy aggressive behavior, ODD, and CD,
Neural mechanisms, 233–236 158–161 Parent management training, 164, 303
Neural networks, 236, 539–540, 539f anencephaly, 546 Parent rating scales, 179–180. See also
Neural tube defects (NTDs), 546–547, lissencephaly, 548–549 Assessment
554–556. See also Spina bifida mood disorders, 214–215 Parents
myelomeningocele neurofibromatosis type 1 (NF1) and, aggressive behavior, ODD, and CD,
Neurobiological factors, 110, 175–176, 322 154–155, 161
236–239 schizencephaly, 543 anxiety disorders and, 193–194
Neurocognitive disorders, 121, 344–348, spina bifida myelomeningocele and, Down syndrome and, 367–368, 375–376
356 560–562 maternal PKU, 409–411
Neurocutaneous syndromes, 68–69, 68f. Tourette syndrome, 175–176 mood disorders and, 212
See also inidividual syndromes Turner syndrome and, 262–265 mucopolysaccharidoses (MPS disorders),
Neurodevelopmental abnormalities, 20t, Neuropsychological testing, 10 299, 302–303, 303t
461–462 Nonverbal learning disorders (NLD). See neural tube defects (NTDs) and,
Neurodevelopmental disorders, also Learning disability 555–556
12–13, 19–24, 20t, 22t, 23t. See also comorbid conditions and, 119–120 overview, 110–111, 191–192, 212–214
individual disorders neurofibromatosis type 1 (NF1) and, 330 parenting practices, 154–155, 195–196
Neuroendocrine system, 237–238 neuropsychological model for Prader–Willi syndrome and, 488, 504
Neurofibromatosis (NF), 20t, 35t, 69, 138 assessment, 117–118 Rett syndrome and, 436–437
Neurofibromatosis type 1 (NF1) spina bifida myelomeningocele and, Peabody Picture Vocabulary Test, Fourth
behavioral phenotypes, 55t 560–561 Edition, 450–451
clinical presentation of, 323–326, 324t Turner syndrome and, 265, 271 Pearson syndrome, 527, 527t
586 Index
Pediatric Anxiety Rating Scale (PARS), treatment and, 413–415 neural tube defects (NTDs) and,
198t See also Inborn errors of metabolism 555–556
Pediatric autoimmune neuropsychiatric (IEMs) Noonan syndrome, 313
disorder associated with streptococcal Physical symptoms schizencephaly, 545
infection (PANDAS), 177–178 Down syndrome and, 365 seizure disorders and, 463
Pediatric OCD Treatment Study (POTS) fragile X syndrome and fragile spina bifida myelomeningocele and, 562
Team, 199 X–associated disorders and, 278–280, Prenatal screening, 36–37
Peer relationships 279f Preschool children
ADHD and, 139, 143 Klinefelter syndrome and, 385–386 Down syndrome and, 374–375
integrative developmental mucopolysaccharidoses (MPS disorders), phenylketonuria (PKU) and, 412t, 414
neuropsychology and, 87 294–295 sickle cell disease (SCD) and, 344
mucopolysaccharidoses (MPS disorders), Noonan syndrome, 317–318 spina bifida myelomeningocele and, 564t
307 spina bifida myelomeningocele, 556–558 Prevalence statistics
sickle cell disease (SCD) and, 344 Turner syndrome, 262 aggressive behavior, ODD, and CD,
social adjustment and, 89–90 See also Medical complications; Symptoms 153, 155
Pegylated recombinant phenylalanine Picture Exchange Communication System anencephaly, 546
ammonia lyase, 404 (PECS), 241 attention-deficit/hyperactivity disorder,
Penetrance, 44–45, 49 Pierre Robin sequence, 284–285 131
Perceptual processes, 116, 328 Pivotal response training (PRT), 240 autism spectrum disorders, 230
Performance IQ scores PKU (phenylketonuria) Down syndrome, 362
Klinefelter syndrome and, 388 ADHD and, 138 fragile X syndrome and fragile
mitochondrial metabolism disorders adult care and treatment, 414–415 X–associated disorders and, 277
and, 531 assessment and, 411–413, 412t genetic factors and, 35, 555–556
Prader–Willi syndrome and, 492 behavioral, academic and emotional learning disabilities and, 107–110
sickle cell disease (SCD) and, 346 presentation of, 406–409 mitochondrial metabolism disorders
Turner syndrome and, 262–263, 265 developmental course of, 402–406 and, 517
See also Intelligence diagnosis and, 402, 404 mood disorders, 210, 211t
Personality, 13, 302, 408–409. See also executive functioning and, 160 neural tube defects (NTDs) and,
Temperament genetics and family patterns, 401–402 554–555
Personality disorders, 72–73 historical and theoretical background neurofibromatosis type 1 (NF1) and,
Personality Inventory for Children, 390 of, 398–401 323, 324t
Personality measures, 268. See also maternal PKU, 409–411 Noonan syndrome and, 312
Assessment medical comorbidity and, 409 schizencephaly, 543
Pervasive developmental disorders (PDD) memory and learning and, 20t Tourette syndrome, 172
fragile X syndrome and fragile neuroimaging technologies and, 62–63, Turner syndrome and, 261
X–associated disorders and, 280 63f, 64f Prevention strategies, 153, 457. See also
neuroimaging technologies and, 69–72, overview, 4–5, 415–417 Treatment
70f, 71f symptom expression and, 10 Prognosis, 52t, 217, 219–221
overview, 228 treatment and, 413–415 Progressive external ophthalmoplegia
Rett syndrome and, 440 See also Inborn errors of metabolism (PEO), 527, 527t
See also Autism spectrum disorders (IEMs) Progressive Figures test, 15, 16f
Pervasive developmental disorders not Polygenic disorders, 34, 35t Progressive unilateral encephalopathy,
otherwise specified (PDD-NOS), 229, Positive reinforcement, 374–375, 456. See 466t, 468. See also Seizure disorders
284–285, 500 also Behavioral treatments Psychiatric conditions, 365–366, 408–409.
Pharmacological treatments. See Positron emission tomography (PET) See also Psychopathology
Psychopharmacological interventions autism spectrum disorders and, 233–234 Psychiatric treatments, 504–505. See also
Phenotypic expression learning disabilities and, 110 Treatment
aggressive behavior, ODD, and CD, overview, 11, 59 Psychoeducational assessment, 304–305.
161–162, 161t schizencephaly, 545 See also Assessment
anencephaly, 546–547 sickle cell disease (SCD) and, 341, 345 Psychoeducational manifestations,
anxiety disorders, 195–196 Tourette syndrome and, 175–176 262–265
autism spectrum disorders and, See also Neuroimaging methods Psychological factors, 178, 297–299
244–245 Prader–Willi syndrome Psychopathology, 366, 496–502, 497t,
behavioral phenotypes, 54–55, 55t behavioral phenotypes, 55t 498t, 501t. See also Psychiatric
fragile X syndrome and fragile clinical presentation of, 485–487, 486f, conditions
X–associated disorders and, 278–280, 487f Psychopharmacological interventions
279f cognitive, adaptive, and behavioral ADHD and, 142–143
genotype–phenotype relationships and, phenotypes of, 491–502, 493t, 497t, aggressive behavior, ODD, and CD, 164
44f 498t, 501t anxiety disorders and, 192–193,
Lesch–Nyhan syndrome and, 450 diagnosis and, 489–491, 490t 199–200
lissencephaly, 549 Fluorescent in situ hybridization (FISH) autism spectrum disorders and, 242
mood disorders and, 215–216 and, 37–38 black-box warnings, 219–220
overview, 4, 41 fragile X syndrome and fragile fragile X syndrome and fragile
spina bifida myelomeningocele and, X–associated disorders and, 285 X–associated disorders and, 285–287
558–560 future directions in, 505 Lesch–Nyhan syndrome and, 451,
Tourette syndrome and, 176–178 interventions and, 502–505, 502t 453–455
Turner syndrome and, 268 memory and learning and, 20t mood disorders and, 217, 219–220
Phenylketonuria (PKU) neuroimaging technologies and, 62 mucopolysaccharidoses (MPS disorders),
ADHD and, 138 nontraditional inheritance and, 46–47 302
adult care and treatment, 414–415 overview, 35t, 39, 41, 484–485, 505 Prader–Willi syndrome and, 505
assessment and, 411–413, 412t psychopathology and, 366 Rett syndrome and, 436
behavioral, academic and emotional Rett syndrome and, 428 Tourette syndrome and, 181–182, 183
presentation of, 406–409 Prefrontal cortex (PFC), 196, 404–405 Turner syndrome and, 271
developmental course of, 402–406 Pregnancy, 518, 520, 524 See also Epidemiology
diagnosis and, 402, 404 Prenatal factors Psychosocial factors, 265–268, 299, 302,
executive functioning and, 160 ADHD and, 138 314, 355–356
genetics and family patterns, 401–402 anencephaly, 546 Psychosocial treatments, 220–221,
historical and theoretical background autism spectrum disorders and, 232–233 269–271, 319, 391–392. See also
of, 398–401 diagnosis and, 51–52 Cognitive-behavioral therapy (CBT);
maternal PKU, 409–411 Down syndrome and, 365 Treatment
medical comorbidity and, 409 inborn errors of metabolism (IEMs), 575 Psychotropic agents, 181–182, 453.
memory and learning and, 20t maternal PKU and, 109–111 See also Psychopharmacological
neuroimaging technologies and, 62–63, memory and learning and, 20t interventions
63f, 64f mitochondrial metabolism disorders Puberty, 386–387, 392, 429. See also
overview, 4–5, 415–417 and, 524 Developmental course; Sexual
symptom expression and, 10 mood disorders and, 213 development
Index 587
Race, 215–216, 277 Scheie syndrome, 295–296. See also Sibling relationships, 90, 436–437
Rasmussen syndrome, 466t, 468. See also Mucopolysaccharidoses (MPS Sickle cell anemia, 49, 138
Seizure disorders disorders) Sickle cell disease (SCD)
Rating scales, 217, 218t. See also Schizencephaly, 540–545, 541f, 541t, 542f cerebrovascular accidents and, 339–340
Assessment Schizophrenia, 20t, 35t, 392, 500 developmental course of, 341–342
Reactivity, 367–368, 406, 477 Schizotypal personality disorder, 284–285 neurocognitive functioning and,
Reading disabilities School achievement. See Academic skills 344–348
assessment and, 108 School-based interventions, 351. See also neuroimaging technologies and, 65–66,
chromosome disorders and, 113 Interventions 65f
comorbid conditions and, 121 Schools, 13–14, 139, 351 neurological features, 341
genetic factors and, 111, 112–113 Scoliosis neuropsychological impairments and,
overview, 105 neurofibromatosis type 1 (NF1) and, 342–356
subtyping, 114–115 323, 326 overview, 338
See also Learning disability; Reading Rett syndrome and, 425, 435 pathophysiology, 339
skills Turner syndrome and, 262 research needs, 356–357
Reading skills Screen for Child Anxiety Related Single-photon emission computed
phenylketonuria (PKU) and, 407 Emotional Disorders (SCARED), 198t tomography (SPECT), 11, 59,
Prader–Willi syndrome and, 492 Screening 175–176, 545. See also Neuroimaging
sickle cell disease (SCD) and, 350 autism spectrum disorders, 229 methods
spina bifida myelomeningocele and, diagnosis and, 52t Sleep patterns, 238, 296, 299, 302
560, 561 Down syndrome and, 373 Sly syndrome, 295, 297. See also
Turner syndrome and, 265 inborn errors of metabolism (IEMs), 575 Mucopolysaccharidoses (MPS
See also Reading disabilities sickle cell disease (SCD) and, 351 disorders)
Receptive language, 12, 429 spina bifida myelomeningocele and, 562 Social Communication Questionnaire
Rehabilitation, 18–19, 563–564, 564t. See See also Assessment (SCQ), 229
also Interventions Segregation analysis, 49, 112–114, Social factors, 89–90, 90–92, 95–96,
Reiss Screen for Maladaptive Behavior, 497 174–175 297–299, 369–370
Reitan–Indiana batteries, 14 Seizure disorders Social problems, 139, 212, 238, 390
Reitan–Indiana Neuropsychological Test classification schemes, 462–469, 464t, Social referencing, 196
Battery (for ages 5–8), 15–17, 16t 465t, 466t Social skills, 263–264, 329–330
Reproductive counseling, 376, 393–394 cognitive functioning and, 472–477, Social skills training, 241–242
Research Units on Pediatric 472f Social support, 307
Psychopharmacology (RUPP) Autism etiological considerations, 477–479 Social Thinking Curriculum, 241
Network, 242 inborn errors of metabolism (IEMs), 576 Social–ecological model, 85, 87–92,
Respiratory disorders lissencephaly, 548 96. See also Ecological-systems
Down syndrome and, 364 memory and learning and, 20t theory; Integrative developmental
mitochondrial metabolism disorders neurodevelopmental and neuropsychology
and, 518t, 522 neuropathological aspects of, Socioeconomic status
mucopolysaccharidoses (MPS disorders), 461–462 learning disabilities and, 108–109,
298, 301 neuropsychological sequelae associated 110–111
Rett syndrome and, 433 with, 469–477, 472f mood disorders and, 212, 215–216
Rett syndrome overview, 460–461, 479 neural tube defects (NTDs) and, 555
autism spectrum disorders and, 229, 231 precipitating factors, 461 sickle cell disease (SCD) and, 356–357
behavioral phenotypes, 55t See also Seizures Spatial functioning, 329, 407, 494,
case illustrations of, 437–438, 439f Seizures 560–561
coping and, 92 fragile X syndrome and fragile Special education, 349, 351
developmental course of, 427–429 X–associated disorders and, 285–286 Speech delays, 317, 448, 543, 561. See also
diagnosis and, 426–427, 426t, 427t, 440 inborn errors of metabolism (IEMs), Language skills
genetics and family patterns, 429–430 573–574 Speech Sounds Perception Test, 15f
history and background of, 426 lissencephaly, 548 Speech therapy, 241, 287
in males, 431–432 mitochondrial metabolism disorders Spelling skills, 407–408
memory and learning and, 20t and, 520–521 Spina bifida myelomeningocele
mouse models of, 430–431 schizencephaly, 543, 544, 545 assessment and, 562
multifactorial inheritance and, 49 See also Seizure disorders developmental course of, 562–563
neuroimaging technologies and, 67 Selective serotonin reuptake inhibitors neuropathology in, 558
neuropathology, 432–433 (SSRIs) neuropsychological phenotype, 560–562
overview, 425–426, 440 anxiety disorders and, 192–193, 199–200 overview, 554–555, 564
parents and siblings and, 436–437 autism spectrum disorders and, 242 physical aspects of, 556–558
treatment and, 433–436 black-box warnings, 219–220 risk factors for phenotypic expression,
Rett Syndrome Handbook (Hunter, 2007), fragile X syndrome and fragile 558–560
437 X–associated disorders and, 286 See also Neural tube defects (NTDs)
Revised Behavior Problem Checklist, 371 mood disorders and, 219 Stanford–Binet Intelligence Scales, Fifth
Revised Children’s Manifest Anxiety Scale See also Psychopharmacological Edition, 372
(RCMAS), 189, 198t interventions Star Drawing test, 15
Reynolds Adolescent Depression Scale— Self-concept, 88–89, 392 State–Trait Depression Adjective Checklist
2nd Edition (RADS-2), 218t Self-esteem, 88–89, 265–266, 269, 392 (ST-DACL), 218t
Reynolds Child Depression Scale, 218t Self-injurious behavior, 448–449, 451, Stem cell transplant, 532–533
Reynolds Intellectual Assessment Scales 454–455, 456 Stress
(RIAS), 12 Self-regulation, 343, 375 mucopolysaccharidoses (MPS disorders),
Risk factors Self-report scales, 179–180. See also 299
aggressive behavior, ODD, and CD, 154, Assessment overview, 87–88
161–162, 161t Sensory skills Prader–Willi syndrome and, 499
anencephaly, 546–547 Noonan syndrome and, 316 Rett syndrome and, 437
anxiety disorders, 195–196 seizure disorders and, 472f Turner syndrome and, 269, 270
lissencephaly, 549 sickle cell disease (SCD) and, 351–352 Strokes, 339–340, 349, 351, 354–355
mood disorders, 212–213, 215–216 spina bifida myelomeningocele and, Suicidal ideation, 245
spina bifida myelomeningocele and, 556–557, 557t Support groups, 270
558–560 Sensory-motor effects, 556–557, 557t Support systems, 307
Tourette syndrome, 173, 176–178 Sensory–Perceptual Examination, 15f, 16f Symptoms
Sequential processing, 25–26, 353–354 conduct disorder (CD), 152t
Sanfilippo syndrome, 295, 296–297. See Serotonin (5-HT), 192–193, 236–237 Down syndrome and, 363
also Mucopolysaccharidoses (MPS Sex chromosome disorders, 113, 121, 392 fragile X syndrome and fragile
disorders) Sexual development, 267–268, 285, 392. X–associated disorders and, 278–280,
Schedule for Affective Disorders and see also Puberty 278t
Schizophrenia for School-Age Shapiro Tourette’s Syndrome Severity Scale inborn errors of metabolism (IEMs),
Children (K-SADS), 190, 197, 217 (STSSS), 179 571–574, 575–576
588 Index
Symptoms (cont.) habilitation and rehabilitation Prader–Willi syndrome and, 492

Lesch–Nyhan syndrome and, 447–449 considerations and, 18–19 sickle cell disease (SCD) and, 345, 347
mood disorders and, 216 neuroimaging technologies and, 70, 71f Turner syndrome and, 262–263, 265
mucopolysaccharidoses (MPS disorders), neuropsychological evaluation and, See also Intelligence
293–297, 294t 12–13 Vineland Adaptive Behavior Scales, 369,
neurofibromatosis type 1 (NF1) and, schools and, 14 492, 495
323–326, 324t Treatment Visual Perception Test, 15f
Noonan syndrome, 312–313 ADHD and, 142–143 Visual treatment approaches, 241. See also
oppositional defiant disorder (ODD), adult care and treatment, 245 Treatment
153t aggressive behavior, ODD, and CD, Visual–motor processes, 116–118, 116t,
Prader–Willi syndrome and, 489–491, 163–165 117t, 412t
490t anencephaly, 547 Visual–perceptual skills, 351–352, 562
Rett syndrome, 426–427, 426t, 427t, anxiety disorders and, 199–201, 200t Visual–spatial skills, 328, 351–352
429–430 assessment and, 216 Vocal tics, 171–172. See also Tics;
symptom expression, 10–11 autism spectrum disorders and, Tourette syndrome
Turner syndrome, 262–268, 270–271 239–242, 245 Vocational functioning, 306–307, 376,
Synaptosomal protein of 25 kilodaltons diagnosis and, 52t 503–504
(SNAP-25) gene, 136 Down syndrome and, 373–376 von Recklinghausen neurofibromatosis,
Systems theory, 85, 87–92, 92–93, 93–95, fragile X syndrome and fragile 312–313, 318
96. See also Integrative developmental X–associated disorders and, 285–288
neuropsychology habilitation and rehabilitation Washington University in St. Louis
considerations and, 18–19 K-SADS (WASH-U-K-SADS), 217
T2-weighted MRI, 332. See also inborn errors of metabolism (IEMs), 576 Wechsler Abbreviated Scales of
Neuroimaging methods Klinefelter syndrome and, 391–393 Intellegence, 411–412
Tactile Form Recognition test, 15f Lesch–Nyhan syndrome and, 451–458, Wechsler Adult Intelligence Scale—
Tactual Performance Test, 14, 15f, 16, 452t Revised, 29, 478–479
16f, 476 lissencephaly, 549 Wechsler Adult Intelligence Scale—Third
Temperament mitochondrial metabolism disorders Edition, 29
ADHD and, 138–139 and, 530, 532–533 Wechsler Individualized Achievement
aggressive behavior, ODD, and CD, mood disorders and, 216, 217, 219–221 Test, 18
154–155, 159 mucopolysaccharidoses (MPS disorders), Wechsler Intelligence Scale for Children,
Down syndrome and, 367–368 299–307, 300t, 303t 114, 154, 478, 493t
Klinefelter syndrome and, 390 Noonan syndrome and, 319 Wechsler Intelligence Scale for Children—
mucopolysaccharidoses (MPS disorders), phenylketonuria (PKU) and, 402–406, Third Edition, 29
302 413–415 Wechsler Memory Scale, 20
phenylketonuria (PKU) and, 408–409 Prader–Willi syndrome and, 502–505, Wechsler Preschool and Primary Scale of
Temporal lobe epilepsy, 474, 475–479. see 502t Intelligence—Third Edition, 27
also Seizure disorders report writing and, 30 Wechsler scales
Test of Memory and Learning—Second Rett syndrome and, 431, 433–436 Boston Process Approach and, 29
Edition (TOMAL-2), 12, 21–24, 22t, schizencephaly, 545 Klinefelter syndrome and, 388
23t, 25 Tourette syndrome and, 181–182, 183 mood disorders and, 214
Testosterone replacement therapy, 391, See also Interventions; neurofibromatosis type 1 (NF1) and,
392, 394 Psychopharmacological interventions 329
Thyroid functioning Treatment and Education of Autistic and neuropsychological evaluation and, 12
Down syndrome and, 365, 366, 368 related Communication-Handicapped Noonan syndrome and, 316
fragile X syndrome and fragile Children (TEACCH), 240, 245 phenylketonuria (PKU) and, 411–412
X–associated disorders and, 283 Treatment for Adolescents with Depression Turner syndrome and, 262–263
phenylketonuria (PKU) and, 409 Study (TADS) Team, 219 See also individual scales
Tic disorders, 174, 500. See also Tourette Tuberous sclerosis, 44–45, 68, 68f Weight issues, 499. See also Obesity
syndrome Turner syndrome Weinberg Depression Scale for Children
Tics, 171–172, 285. See also Tourette ADHD and, 138 and Adolescents (WDSCA), 218t
syndrome assessment and, 268 Wernicke’s area, 110
Toddlerhood, 344, 414, 428 clinical presentation of, 262–268 West syndrome, 466, 466t. See also
Tourette syndrome etiological considerations, 261–262 Seizure disorders
ADHD and, 138 interventions and, 268–271 Wide Range Assessment of Memory and
assessment and, 178–180 memory and learning and, 20t Learning (WRAML2), 21
biological and neuropsychological multifactorial inheritance and, 49 Williams syndrome
markers, 175–176 neuroimaging technologies and, 67 ADHD and, 138
developmental course of, 173–174 Noonan syndrome and, 312, 318 behavioral phenotypes, 54–55, 55t
executive functioning and, 160 overview, 35t, 39, 261, 271 diagnosis and, 53
fragile X syndrome and fragile phenotype and, 41 fluorescent in situ hybridization (FISH)
X–associated disorders and, 284–285, Turner Syndrome Society of the United and, 37–38
285 States, 270 multifactorial inheritance and, 49
genetics and family patterns, 174–175 22q11.2 deletion syndrome, 37–38 neuroimaging technologies and, 61
history, 172–173 Twin studies overview, 39, 41
memory and learning and, 20t ADHD and, 137 Wisconsin Card Sorting Test (WCST),
multifactorial inheritance and, 49 aggressive behavior, ODD, and CD and, 476
neuroimaging technologies and, 72 157–158 Woodcock–Johnson battery, 18
overview, 171–172, 182–183 autism spectrum disorders and, 230–231 Woodcock–Johnson III Tests of
psychological factors, 178 comorbid conditions and, 119 Achievement, 118
risk factors for, 176–178 learning disabilities and, 111–112,
schools and, 14 113–114, 119, 121 X chromosome, 261
treatment and, 181–182 Rett syndrome and, 429–430 X-linked disorder, 43, 44f
Tourette Syndrome Symptom List (TSSL), Tourette syndrome and, 175 X-linked syndromes, 66–67, 231, 312,
180 twin concordance studies, 49 383. See also individual syndromes
Tourette’s Disorder Scale—Parent Rated XXY syndrome, 14, 20t
(TODS-PR), 180 Upper-motor-neuron (UMN) syndrome, XYY syndrome, 20t
Toxins, 12–13, 20t, 138 556, 557t
Trail Making Test, 14–15, 15f, 476 Yale Global Tic Severity Scale (YGTSS),
Traumatic brain injury (TBI) Verbal IQ 179
Comprehensive Trail-Making Test Klinefelter syndrome and, 388 Yale–Brown Obsessive–Compulsive Scale,
(CTMT) and, 15 mitochondrial metabolism disorders 501
executive functioning and, 160 and, 531 Youth’s Inventory–4 (YI-4), 218t
PLATE 4.1. (A) During a nonspatial working memory fMRI task, controls displayed significantly
greater activation in the right middle and inferior frontal gyri (Brodmann areas [BA] 45, 46, and 48),
the left and right inferior and superior parietal lobules (BA 7, 39, and 40), and the left and right oc-
cipital lobes (BA 19) than children with VCFS did. (B) Participants with VCFS displayed significantly
greater activation in the left orbitofrontal cortex (BA 11), the right cingulate (BA 32), and the right
cuneus and occipital cortex (BA 19) than controls did. Superior–inferior distance from the anterior
commisure–posterior commisure line is indicated in both panels. The bar is a visual representation
of the range of z values present in this activation map. From Kates et al. (2007). Copyright 2007 by
Elsevier. Reprinted by permission.
PLATE 4.2. Relative reductions (blue/pink) and increases (red/yellow) in gray matter volume in chil-
dren with WS versus controls (cluster threshold = .05, p = .003, confidence interval = ± 2.1) corrected
for gender and total gray volume). The maps are oriented so that the right side of the brain is shown
on the left side of each panel. The z coordinate for each row of axial slices in the standard space of
Talairach and Tournoux is given in millimeters. From Campbell et al. (2009). Copyright 2009 by El-
sevier. Reprinted by permission.
PLATE 4.3. Gyrification effects in children and adults with WS. The two upper rows reveal the aver-
age distribution of local gyrification in healthy controls (CTL) and individuals with WS. Curvature
values are expressed in degrees, with blue and purple colors indicating regions of lower gyrification,
while yellow and red indicate areas of higher gyrification. The third row demonstrates the mean dif-
ferences between participants with WS and healthy controls. Areas with higher gyrification in persons
with WS appear in yellow and red, whereas blue and purple indicate higher gyrification in control
subjects. The last row illustrates regions of significantly increased gyrification in persons with WS
compared to normal controls (threshold p < 0.001; corrected for multiple comparisons using false dis-
covery rate). From Gaser et al. (2006). Copyright 2006 by Elsevier. Reprinted by permission.
PLATE 4.4. DTI tractography of the corpus callosum overlaid on T1-weighted MRI scans. The ex-
pected pattern of corpus callosum tractography is demonstrated in the typically developing control
individual in the top right corner. Eight individuals with AS demonstrate abnormalities in pattern
or paucity of “streamlines” generated by tractography. Green color indicates fibers coursing in an
anterior-to-posterior direction; red color indicates fibers coursing in a right-to-left direction; and blue
color represents fibers coursing in a superior-to-inferior direction.
PLATE 4.5. DTI tractography of the left arcuate fasciculus in an age- and gender-matched control
child versus a child with AS, demonstrating marked reduction in the fiber pattern detected via trac-
tography.
PLATE 4.6. DTI tractography of the left uncinate fasciculus in an age- and gender-matched control
child versus a child with AS, demonstrating marked reduction in the fiber pattern detected via trac-
tography.
PLATE 4.7. Three-dimensional rendering of the relative volumes of structures found to differ in a
cohort of children with AS versus age- and gender-comparable control children. Structures such as the
cerebellum, amygdala, corpus callosum, and basal ganglia are highlighted.
PLATE 4.8. Blue areas represent regions of significant cortical thinning in a cohort of children with
AS versus age- and gender-comparable control children, located primarily in the temporal lobes. Red
areas represent areas of increased cortical thickness in the children with AS, and are located in the
frontal lobes.
PLATE 4.9. Significance maps for group differences in local brain volume between individuals with
FXS and controls. Significant volume differences between persons with FXS and healthy controls are
shown for males (left panels in a and b), for females (middle panels in a and b), and for all subjects
(right panels in a and b). In all maps, the persons with FXS have significant excess volumes in the
ventricle and caudate regions (blue colors in panel a). Panel b shows that subjects with FXS have sig-
nificant volume deficits in medial occipital regions and some temporal lobe regions. From A. D. Lee et
al. (2007). Copyright 2007 by Elsevier. Reprinted by permission.
PLATE 4.10. A three-dimensional representation of aberrant white matter tracts in TS (left frontoparietal cluster is
shown in blue; right prefrontal cluster is shown in green; bilateral internal capsule cluster is shown in red), as derived
from FA maps positioned within a transparent, volumetrically rendered average image of all participants with TS. A,
anterior view; B, sagittal view. From Holzapfel, Barnea-Goraly, Eckert, Kiesler, and Reiss (2006). Copyright 2006 by
the Society for Neuroscience. Reprinted by permission.
PLATE 4.11. (Top) Voxel-based DTI findings related to differences in social responsiveness based on
SRS scores, as shown in the regression plot comparing DTI findings and SRS ratings (bottom). As ex-
pected, SRS scores clearly differentiate most subjects with autism from typically developing controls;
in terms of DTI findings, these are expressed in white matter regions of the CC, STG, and temporal
stem, to highlight some of the major differences. From Petrella, Mattay, and Doraiswamy (2008).
Copyright 2008 by the Radiological Society of North America. Reprinted by permission.
Healthy Group
ADHD Group
COS Group
Total Brain Volume Total Gray Matter Volume
1200 750
700
1100 Volume, cm3
Volume, cm3
650
1000
600
900
550
800 500
4 6 8 10 12 14 16 18 20 22 4 6 8 10 12 14 16 18 20 22
Age. y Age. y
Frontal Gray Matter Volume Total White Matter Volume
230 450
220
400
210
Volume, cm3
200
Volume, cm3
350
190
300
180
170
250
160
150 200
4 6 8 10 12 14 16 18 20 22 4 6 8 10 12 14 16 18 20 22
Age. y Age. y
PLATE 4.12. Different brain development trajectories in typically developing children, those with
ADHD, and those with childhood-onset schizophrenia (COS). From Gogtay, Giedd, and Rapoport
(2002). Copyright 2002 by the American Medical Association. Reprinted by permission.

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Handbook of

Neurodevelopmental and Genetic Disorders

THE GUILFORD PRESS

All rights reserved

No part of this book may be reproduced, translated, stored in a retrieval system,

Printed in the United States of America

This book is printed on acid-free paper.

Last digit is print number: 9 8 7 6 5 4 3 2 1

Library of Congress Cataloging-in-Publication Data

Handbook of neurodevelopmental and genetic disorders in children / edited by Sam

Sam Goldstein, PhD, is Assistant Clinical Instructor in the Department of Psychiatry at

Cecil R. Reynolds, PhD, is Emeritus Professor of Educational Psychology, Professor

Angela Giacoletti Argento, PhD, Department of Physical Medicine and Rehabilitation,

Blythe Corbett, PhD, Vanderbilt Kennedy Center, Department of Psychiatry, Vanderbilt

Nancy L. Nussbaum, PhD, Department of Educational Psychology, College of Education,

whether he or she demonstrates certain symptoms or diagnoses—is what determines his

Sam G oldstein, PhD

Part I. Background

2. Neuropsychological Assessment in Genetically Linked 9

3. Neurodevelopmental Disorders and Medical Genetics: An Overview 33

4. Neuroimaging and Genetic Disorders 58

5. Integrative Developmental Neuropsychology: A General Systems 84

Part II. Disorders Primarily Affecting

6. Learning Disabilities 105

7. Attention-­Deficit/Hyperactivity Disorder 131

8. Oppositional, Conduct, and Aggressive Disorders 151

9. Gilles de la Tourette Syndrome 171

10. Anxiety Disorders 188

11. Mood Disorders 209

12. Autism Spectrum Disorders 228

Part III. Disorders with Broader-­S pectrum Effects

13. Turner Syndrome 261

14. Fragile X Syndrome and Fragile X–Associated Disorders 276

15. The Mucopolysaccharidoses 293

16. Noonan Syndrome 311

17. Neurofibromatosis Type 1 322

18. Sickle Cell Disease 338

19. Down Syndrome 362

20. Klinefelter Syndrome 382

21. Phenylketonuria 398

22. Rett Syndrome: A Truly Pervasive Developmental Disorder 425

23. Lesch–Nyhan Syndrome: A Sex-­Linked Inborn Error of Metabolism 445

24. Seizure Disorders 460

25. Prader–Willi Syndrome 484

26. Disorders of Mitochondrial Metabolism 512

27. Major Structural Anomalies of the Neocortex 539

28. Spina Bifida Myelomeningocele 554

29. Inborn Errors of Metabolism: A Brief Overview 570

Most intellectuals today have a phobia of any explanation

I think I have discovered the secret of life—you just hang

of disorders that have accepted, though as ture of an institutional setting. Increasingly,

ment of brain damaged patients” (p. 7)—a What Is Neuropsychology?

educational setting. This will be where the Assessment Approaches

TABLE 2.1. Halstead–Reitan Neuropsychological Test Battery for Older Children

Note. Data from Reitan and Wolfson (1985).

TABLE 2.2. Reitan–Indiana Neuropsychological Test Battery for Children (Ages 5–8)

Note. Data from Reitan and Wolfson (1985).

TABLE 2.3. Primary Neurodevelopmental Disorders in Which Memory and Learning

Attention-deficit/hyperactivity In utero toxic exposure (e.g., Neurofibromatosis

Note. Based on Reynolds and Bigler (1997).

7. Attention-Deficit/Hyperactivity Disorder 131

Part III. Disorders with Broader-S pectrum Effects

23. Lesch–Nyhan Syndrome: A Sex-Linked Inborn Error of Metabolism 445

tive Reminding subtests to allow an analysis Assessment of Brain –Behavior

Kesler, S. R., Lightbody, A. A., & Reiss, A. L. smoothing-compensated voxel-based analysis.

trajectories of these behaviors and disorders dividuals following the adolescence-limited

or an Obsessive–Compulsive subscale. The sitting quietly alone or in the presence of an

(Grigoroiu-Serbanescu et al., 1989; Weiss- over, as indicated above, these fascinating

Conclusion and nonanxious individuals: A meta-analytic

NOS (Solomon, Goodlin-Jones, & Anders, drug-related dyskinesias (abnormal involun-

with TS. Pavlidis and colleagues (1995) variety of visual-perceptual problems, it is