Huntingtons Disease Genetic Counseling

Genetic counseling is the process of providing individuals & families w/ information

on the nature, inheritance, & implications of genetic disorders to help them make
informed medical & personal decisions.
Mode of inheritance: Huntington disease [HD] is inherited in an autosomal
dominant manner.
Risk to parents of a proband:
o Although most individuals diagnosed w/ HD have an affected parent, family
history may appear negative for the following reasons:
Failure to recognize the disorder in family members
Early death of the parent before the onset of symptoms
The presence of an intermediate allele (range: 27-35 CAG repeats) or
an HTT allele w/ reduced penetrance (range: 36-39 CAG repeats) in an
asymptomatic parent.
Late onset of the disease in the affected parent.
o Molecular genetic testing is recommended for the parents of a proband w/ an
apparent de novo mutation.
Risk to siblings of a proband:
o The risk to the sibling depends on the genetic status of the probands parent.
o If the parent is affected or has an HTT allele w/ CAG length greater or equal
to 40, the risk is 50%
o If the father has an intermediate HTT allele, the risk to the sibling of
inheriting a mutant allele (greater or equal to 36 CAG repeats) is 5%
o A sibling who inherits an HTT allele w/ reduced penetrance may or may not
develop symptoms of HD.
Risk to offspring of proband:
o Each child of an individual w/ HD as a result of heterozygosity for the HTT
allele has a 50% chance of inheriting the disease-causing mutation.
o Each child of an affected individual who is homozygous for CAG repeat
expansion in HTT will inherit an HD-causing allele.
Risk to other family members:
o Depends on the genetic status of the probands parents. If the parent is
affected or has a CAG expansion then his or her family members are at risk.
Intermediate alleles (IA): 27-35 CAG. Individuals w/ IA are not at risk for
developing HD, but offspring are at risk b/c the instability of the CAG repeat as it is
passed b/w generations can result in CAG repeat expansion.
o Risk of inheriting an expansion or a new mutation of HD depends on
several factors:
The CAG size of the allele. Larger CAG sizes are more prone to
expansion.
The sex & age of transmitting parent. Paternally inherited IA are more
prone to expansion. Expanded IA are preferentially transmitted by
males w/ advanced paternal age.
The DNA sequence in cis configuration w/ the CAG expansion. CAG
tracts interrupted w/ CCG trinucleotides are more stable.
o Risk of inheriting an HTT allele w/ CAG size of 35 is estimated at 6-10%.
Testing for the disease-causing mutation in the absence of definite symptoms of
disease is predictive testing.

o Cant accurately predict age of onset, severity, type of symptoms, or rate of

progression.
o When testing at-risk individuals for HD, its helpful to test for CAG expansion
in HD in an affected family member to confirm that the disorder in the family
is HD.
o Testing of asymptomatic at-risk adult family members usually involves
pretest interviews in which the motives for requesting the test, the
individuals knowledge of HD, the possible impact of positive & negative test
results & neurologic status are assessed.
The Dilemma of Confidentiality in Huntington Disease
-

Is genetic info the confidential property of tested individuals, or do biological

relatives also have rights to this info?
Obligations to pt include confidentiality, respect for autonomy & nonmaleficence.
Obligation to family includes beneficience
Answer would be a compromise in which the physician avoids breaking
confidentiality w/ the mother yet allows the daughter to become aware of all the
information relevant to her decision regarding pregnancy. Outcome accomplished
w/ time & open communication w/ both mother & daughter.

Diagnosis of Huntington Disease

- HD is a rare, progressive, & fatal autosomal dominant neurodegenerative disorder,
typically of adult onset.
- The discovery of the genetic etiology of HD, a trinucleotide expansion mutation on
chromosome 4p, has led to the development of increasingly reliable & valid
diagnostic tests that an be applied to symptomatic patients individuals at risk for
HD but currently asymptomatic, fetuses & embryos. However, the unstable nature
of the HD mutation, the lack of effective treatments for HD, the mid-adulthood age
of disease onset & the existence of disorders w/ the same clinical presentation but
different etiology all complicates diagnostic testing.
- Conscientious lab work, knowledgeable interpretation of genetic test results & the
availability of pre- & post-test counseling are essential components of HD
diagnosis.
- HD has familial nature & clinical triad of movement abnormality, emotional
disturbance & cognitive impairment.
- HD is a CAG trinucleotide repeat expansion.
- Prevalence: 5/100,000
- Typically occurs b/w the ages of 35-50 but varies from early childhood to >80
years. Death is usually 15-20 yrs after onset.
- Often earliest symptom is involuntary movement abnormality, chorea or
choreoathetosis, continuous & irregular writhing & jerking movements.
- Cognitive abnormalities begin at about the same time as movement abnormalities
& progress in tandem w/ the loss of voluntary movement capacity. As disease
progresses, the dementia becomes more global.
- Mood disorders, personality changes & suicide is common. Fortunately, the
psychiatric manifestations of HD are often responsive to treatment.
- Gross pathology of HD is limited to the brain, w/ atrophy most prominent in the
caudate, putamen & cerebral cortex.
o Brain weight is reduced.
o Basal ganglia atrophy is readily visible.

o Selective neuronal vulnerability is prominent w/ loss of medium spiny

neurons & large neuron loss.
o Presence of intranuclear inclusion bodies, consisting of amyloid-like fibrils
that contain mutant huntingtin, ubiquitin, synuclein & other protein.
HD is one of 9 disorders caused by CAG repeat expansions that give rise to protein
products w/ expanded polyglutamine tracts.
o Repeat is in exon 1 of huntingtin gene on chromosome 4p
o Unaffected range 6-35 repeats
o <27 normal
o 27-35 may rarely expand, do not cause HD
o 36-39 variable penetrance
o >39 fully penetrant
o once in disease range, repeat length is unstable during vertical transmission.
Bias is toward longer repeats in paternal transmission.
o Age of disease onset is inversely correlated w/ repeat length = anticipation,
in which age of onset tends to decrease in successive generations.
o Repeat length can also decrease during vertical transmission.
Differential diagnosis of HD is important in evaluation w/ those who dont have HD
mutation & those who do have HD but originally presented in another disorder.
o The most frequent & obvious manifestation of HD is chorea.
Size of PCR product that only contains the CAG repeat is evaluated w/
polyacrylamide gel electrophoresis. Product length is detected by use of a
radiolabeled primer to generate radiolabeled product.
o Capillary electrophoresis is now used. Control samples of known repeat
length are important b/c repeat expansion may slightly alter the
electrophoretic mobility relative to standard size markers.
o Regardless error of plus or minus one triplet. Longer expansions = more
difficult to precisely define repeat length due to PCR artifact & mosaicism in
lymphocytes.
o Advantageous to test multiple members of the family, especially in
presymptomatic diagnosis to directly compare allele length.
Usually lab result accurately reflects repeat length homozygosity
o Genomic Southern blot analysis will yield a definitive result, although the
exact length will be hard to discern.
o Polymorphism to prevent proper annealing.
sporadic HD
o de novo expansions from nonpenetrant but unstable repeats in 27-35 range.
o Anticipation, age of onset in child before parent
o Adoption, false paternity
o Lack of family history is not sufficient evidence to exclude HD diagnosis.
Pretesting genetic counseling is imperative so that the at-risk individual can make
a knowledgeable decision about the risks & benefits of completing the testing
protocol
Interpreting the implications of a repeat at the margin of the disease range is often
difficult b/c of error rate of plus or minus 1 repeat.
Adult grandchild of individual w/ HD desires presymptomatic testing whereas the
middle-aged child of the affected individual does not want to know.
o Exclusion testing, genotype markers linked to the HD gene, whether the
grandchild received an allele from the affected grandparent or the
unaffected spouse of the grandparent. If allele is inherited from the

unaffected grandparent the risk of HD is low, if the allele is inherited from the
affected grandparent, the risk of HD is 50% b/c it is not known whether the
allele inherited from the affected grandparent is the allele w/ or without the
mutation.
The most prominent concerns include failure or inaccuracy of the standard testing
protocol, ambiguous clinical implications of repeat expansions in the nonpenetrant
range & the ambiguity of negative presymptomatic testing results in the absence
of info about molecular diagnosis of affected family members