Papers by Debra Weese-Mayer
Pediatric Pulmonology, 2007
Objective: Children with Congenital Central Hypoventilation Syndrome (CCHS) have cardiovascular s... more Objective: Children with Congenital Central Hypoventilation Syndrome (CCHS) have cardiovascular symptoms consistent with the autonomic nervous system dysregulation/ dysfunction (ANSD) phenotype. We hypothesized that children with CCHS would have a relationship between PHOX2B genotype and two clinically applicable cardiovascular measures of ANSD: duration of longest r-r interval and longest corrected QT interval (QTc). Materials and Methods: We studied 501 days of Holter recordings from 39 individuals with PHOX2B mutationconfirmed CCHS, and analyzed longest r-r and QTc intervals with respect to PHOX2B genotype. Results: We determined that longest r-r interval varied by genotype (P ¼ 0.001), with a positive correlation between repeat number and longest r-r interval duration (P ¼ 0.0007). Number of children with a longest r-r interval value !3 sec varied by genotype (P < 0.0001): 0% with the 20/25 genotype, 19% with the 20/26 genotype, and 83% with the 20/27 genotype. Though longest QTc interval did not vary by genotype (P ¼ 0.09), all children with CCHS had at least one Holter with a QTc interval >450 msec, and percent of time with QTc >450 msec exceeded published values. The proportion of subjects who received a cardiac pacemaker due to prolonged r-r interval was greater for the children with the 20/27 genotype (67%) than the 20/25 (0%) or 20/26 genotype (25%) (P ¼ 0.01). Among three children who did not receive a cardiac pacemaker, but who had r-r intervals !3 sec, two died suddenly. Conclusions: These results confirm a disturbance of cardiac autonomic regulation in CCHS, indicate that PHOX2B genotype is related to the severity of dysregulation, predict the need for cardiac pacemaker, and offer the clinician the potential to avert sudden death.
Clinical Autonomic Research, Jun 1, 2023
Pediatric Research, Sep 27, 2016
Mounting Evidence of PHOX2B as the Disease-Defining Gene for CCHS Concurrently, Weese-Mayer and c... more Mounting Evidence of PHOX2B as the Disease-Defining Gene for CCHS Concurrently, Weese-Mayer and colleagues (39) evaluated candidate CCHS genes in a larger cohort of US cases and controls. Surprisingly, PHOX2B mutations were identified in 100% of 67 CCHS cases in this cohort. Sixty-six of these patients had heterozygous PHOX2B PARMs, with expansions ranging from 25-33 alanine repeats. The remaining patient had a nonsense NPARM. This not only confirmed the role of PHOX2B mutations in CCHS, but identified PHOX2B as the disease-defining gene. This study also identified a genotype-phenotype relationship, with longer PARM expansions showing more severe phenotypes. Finally, this study identified somatic mosaicism in parents of a subset of CCHS probands, indicating that PARM expansion length was stable and could be inherited in an autosomal dominant mode. Confirmed: PHOX2B as the Disease-Defining Gene for CCHS In subsequent years, evaluation of PHOX2B in CCHS cohorts expanded. In 2004, cases were reported from Italy, Germany, and the Netherlands (3) that identified PHOX2B PARMs of
Respiratory Physiology & Neurobiology, Dec 1, 2008
Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS) were l... more Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS) were long considered rare disorders of respiratory control and more recently have been highlighted as part of a growing spectrum of disorders within the rubric of autonomic nervous system (ANS) dysregulation (ANSD). CCHS typically presents in the newborn period with a phenotype including alveolar hypoventilation, symptoms of ANSD and, in a subset of cases, Hirschsprung disease and later tumors of neural crest origen. Study of genes related to autonomic dysregulation and the embryologic origen of the neural crest led to the discovery of PHOX2B as the disease-defining gene for CCHS. Like CCHS, SIDS is thought to result from central deficits in control of breathing and ANSD, although SIDS risk is most likely defined by complex multifactorial genetic and environmental interactions. Some early genetic and neuropathological evidence is emerging to implicate serotonin systems in SIDS risk. The purpose of this article is to review the current understanding of the genetic basis for CCHS and SIDS, and discuss the impact of this information on clinical practice and future research directions.
Low-coverage proportions of candidate genes in replication exomes. (XLSX 43 kb)
CRC Press eBooks, Feb 19, 2008
Pediatric Pulmonology, Jan 12, 2018
ObjectiveTo investigate neurocognitive deficits in children with Congenital Central Hypoventilati... more ObjectiveTo investigate neurocognitive deficits in children with Congenital Central Hypoventilation Syndrome (CCHS) by comparing them to their parents, since parents comprise a particularly suitable control group matched on disease‐extrinsic factors that can influence neurocognitive functioning. We compared CCHS patients to their parents and to population norms, hypothesizing that they would obtain lower intelligence test scores than both groups. We also compared patient‐parent differences against patient‐normative differences, to determine whether the two analytic approaches would yield different results.MethodsWe administered an intelligence screening, the Shipley‐2, to 21 school‐aged patients (age 14.2 ± 5.5 years) with PHOX2B mutation‐confirmed CCHS and their parents. Patients also received detailed clinical intellectual assessments using the Wechsler scales.ResultsCCHS patients scored significantly below parents on Shipley‐2 indices of intelligence, vocabulary, and abstraction, with a trend for perceptual reasoning. The CCHS patients scored significantly below population norms on indices of abstraction and perceptual reasoning. Patient‐parent differences were significantly larger than patient‐normative differences for vocabulary scores. CCHS patients scored significantly below population norms on Wechsler indices of intelligence, perceptual reasoning, working memory, and processing speed.ConclusionsCCHS may affect a broader range of cognitive abilities than previous research based on comparisons to population norms has indicated. Comparisons of CCHS children to their parents reveal deficits of vocabulary and abstract reasoning which have not been previously identified. A full understanding of the neurocognitive impact of CCHS requires comparisons between patients and other individuals such as friends, parents, or siblings who closely resemble them on disease‐extrinsic characteristics.
American Journal of Medical Genetics, Jan 23, 2019
Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease characterized by autonomic n... more Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease characterized by autonomic nervous system dysregulation. Central hypoventilation is the most prominent and clinically important presentation. CCHS is caused by mutations in paired‐like homeobox 2b (PHOX2B) and is inherited in an autosomal dominant pattern. A co‐occurrence of two asymptomatic PHOX2B variants with a classical CCHS presentation highlights the importance of clinical PHOX2B testing in parents and family members of all CCHS probands. Despite being an autosomal dominant disease, once a polyalanine repeat expansion mutation has been identified, sequencing of the other allele should also be considered.
Clinics in Chest Medicine, Sep 1, 2014
Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy with disordered res... more Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy with disordered respiratory control and autonomic nervous system regulation. CCHS is caused by mutations in the PHOX2B gene, and the PHOX2B genotype/mutation anticipates the CCHS phenotype, including the severity of hypoventilation, risk of sinus pauses, and risk of associated disorders including Hirschsprung disease and neural crest tumors. It is important to maintain a high index of suspicion in cases of unexplained alveolar hypoventilation, delayed recovery of spontaneous breathing after sedation or anesthesia, or in the event of severe respiratory infection, and unexplained seizures or neurocognitive delay. This will improve identification and diagnosis of milder CCHS cases and later onset/presentation cases, allowing for successful intervention. Early intervention and conservative management are key to long-term outcome and neurocognitive development. Research is underway to better understand the underlying mechanisms and identify targets for treatment advances and drug interventions.
Pediatric Critical Care Medicine, Mar 16, 2022
Study Objectives: The Taser is a small, hand-held electrical immobilization device delivering 25,... more Study Objectives: The Taser is a small, hand-held electrical immobilization device delivering 25,000-50,000 volts of electricity and used by police to briefly paralyze combative suspects. Widespread increase in Taser use and subsequent deaths in the context of that use have raised questions of safety. The etiology of these deaths is unknown. We collected cases of Taser-related death to examine what role the devices may play in patient mortality. Methods: This is a descriptive analysis of Taser deaths in the US. Deaths associated with Taser use were identified by searches on Lexus-Nexus and Google. Letters requesting autopsy reports were then sent to the respective coroners for the counties and states in which the deaths occurred. Data were extracted on age, gender, race, cause of death, pre-existing disease, and results of toxicology. Results: 71 cases of death associated with Taser use were identified. Of those, 28 (39%) autopsy reports were available and obtained for analysis. Average age was 34.8 with a range of 18 to 46. All deaths were males; 39% were White, 46% were Black, and 14% were Hispanic. No deaths were found to occur directly from Taser use, although the possibility of Taser injury being contributory was noted in 6 (21%) reports. Cause of death was thought to be directly drug related in 16 (57%) cases. Excited delirium was thought to be directly or indirectly responsible in 16 (57%) cases. Thirteen (46%) deaths were associated with pre-existing significant cardiac disease; eighteen (68%) were associated with cocaine or methamphetamine use. Conclusions: Tasers do not appear to be the primary cause of death in law enforcement restraint-related fatality. Such deaths appear to be most commonly caused by stimulant abuse, excited delirium, or a combination of the two. Future research should examine whether Taser use increases the risk of death in cases of preexisting cardiac disease or metabolic derangement, as seen in excited delirium or stimulant abuse.
Physiology, Nov 1, 2020
Rett syndrome (RTT), an X-chromosome-linked neurological disorder, is characterized by serious pa... more Rett syndrome (RTT), an X-chromosome-linked neurological disorder, is characterized by serious pathophysiology, including breathing and feeding dysfunctions, and alteration of cardiorespiratory coupling, a consequence of multiple interrelated disturbances in the genetic and homeostatic regulation of central and peripheral neuronal networks, redox state, and control of inflammation. Characteristic breath-holds, obstructive sleep apnea, and aerophagia result in intermittent hypoxia, which, combined with mitochondrial dysfunction, causes oxidative stress—an important driver of the clinical presentation of RTT.
Pediatric Research, Nov 3, 2022
Acta Paediatrica, Mar 1, 2009
Mice lacking pituitary adeniylate cyclase-activating polypeptide (PACAP) are prone to sudden death... more Mice lacking pituitary adeniylate cyclase-activating polypeptide (PACAP) are prone to sudden death in the second post-natal week, having respiratory and metabolic disturbances reminiscent of the human Sudden Infant Death Syndrome (SIDS). Here we test the hypothesis that the human PACAP gene is a site of genetic variance associated with SIDS in a cohort of 92 victims and 92 matched controls. Using polymerase chain reaction and sequencing, we examined the PACAP gene in 92 SIDS cases (46 Caucasians and 46 African Americans) and 92 race- and gender-matched controls. We found no significant associations between PACAP and SIDS in Caucasians. However, in the African Americans, a non-synonymous single nucleotide polymorphism (i.e. an aspartic acid/glycine coding variant, rs2856966) within exon 2 of PACAP was significantly associated with SIDS (p = 0.004), as were haplotypes containing this polymorphism (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Glycine was three times more likely at this location in the African-American SIDS victims (17 cases) than African-American controls (5 cases). These data are the first to suggest an association between a variant within the coding region of the PACAP gene and SIDS. Based on these findings, further investigations are warranted into the functional importance of PACAP signaling in neonatal survival and the role of PACAP-signaling abnormalities in SIDS.
Pediatric Pulmonology, Dec 3, 2009
Objective: Examine indices of neurocognitive functioning in children with PHOX2B mutation-confirm... more Objective: Examine indices of neurocognitive functioning in children with PHOX2B mutation-confirmed neonatal onset congenital central hypoventilation syndrome (CCHS) and relate them to indices of PHOX2B genotype, demographics, and disease severity. Methods: Subjects were 20 patients with PHOX2B mutation-confirmed CCHS diagnosed as neonates who had undergone neurocognitive assessment in the course of clinical care at the Rush Children's Hospital CCHS Center between 1990 and 2006. Neurocognitive variables of interest included Full Scale IQ (FSIQ) and Wechsler-derived marker indices (subtests) of verbal comprehension (Vocabulary), visuoperceptual reasoning (Block Design), working memory (Digit Span), and clerical/processing speed (Coding). Results: Single sample t-tests revealed participants' general intelligence index (FSIQ; mean 84.9, SD 23.6) to be lower than the general population, though the range of FSIQ observed was broad. Visuoperceptual reasoning and clerical/visuographic speed marker indices were similarly depressed. These deficits were related to special education participation but not to PHOX2B genotype status or other demographic and clinical risk factors. Conclusions: PHOX2B mutation-confirmed CCHS confers risk for adverse neurocognitive outcome, though the range of functioning observed raises questions about factors that may contribute to neurocognitive variability. Visuoperceptual reasoning and clerical/visuographic speed appear particularly vulnerable. PHOX2B genotype and disease severity indicators were unrelated to neurocognitive indices, possibly due to our modest sample. Future research should employ comprehensive neurocognitive assessment emphasizing visuoperceptual ability, mental speed, attention, and information processing efficiency. Increased recognition and expedited diagnosis with PHOX2B testing should allow larger studies of the relationship between neurocognitive functioning, PHOX2B genotype/mutation, and disease severity and management. Pediatr.
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Papers by Debra Weese-Mayer