Fran Annese

Epilepsy and the natural history of Rett syndrome

Background: Rett syndrome (RTT) is a neurodevelopmental disorder primarily seen in females, most with a mutation in MECP2. Epilepsy has been reported in 50%–80%. Previous reports were based on small sample sizes or parent-completed questionnaires, or failed to consider the impact of specific MECP2 mutations. Methods: The Rare Disease Consortium Research Network for RTT is an NIH-funded project to characterize the clinical spectrum and natural history of RTT in advance of clinical trials. Evaluations include clinical status (classic vs atypical RTT), MECP2 mutations, clinical severity, and presence, frequency, and treatment of seizures. Results: Enrollment as of June 2008 is 602; 528 (88%) meet clinical criteria for classic RTT. Of these, 493 (93%) have MECP2 mutations. Age range was 8 months to 64 years. A total of 360 (60%) were reported to have seizures, including 315 (60%) classic and 45 (61%) atypical RTT. Physician assessment of the 602 indicated that 48% had seizures. There was no significant difference in seizure occurrence by race/ethnicity. A significant age impact for seizures was seen and seizures were infrequent before age 2 years. MECP2 mutations most frequently associated with epilepsy were T158M (74%) and R106W (78%), and less frequently R255X and R306C (both 49%). Individuals with seizures had greater overall clinical severity, and greater impairment of ambulation, hand use, and communication. Discussion: Seizures are common in Rett syndrome, have an age-related onset and occurrence, vary by mutation, and are associated with greater clinical severity. This information represents a key consideration for designing clinical trials.

Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome.

Objective: We conducted a nationwide survey to determine the prevalence of common gastrointestinal and nutritional disorders in Rett syndrome (RTT) based on parental reporting and related the occurrence of these problems to age and methyl-CpG-binding protein 2 (MECP2) gene status. Methods: We designed a questionnaire that probed symptoms, diagnoses, diagnostic tests, and treatment interventions related to gastrointestinal and nutritional problems in RTT. The International Rett Syndrome Foundation distributed the questionnaire to 1666 family-based members and forwarded their responses for our review. We interrogated the Rare Disease Clinical Research Network database to supplement findings related to medications used to treat gastrointestinal problems in RTT. Results: Parents of 983 female patients with RTT (59%) responded and identified symptoms and diagnoses associated with gastrointestinal dysmotility (92%), chewing and swallowing difficulties (81%), weight deficits or excess (47%), growth deficits (45%), low bone mineral content or fractures (37%), and biliary tract disorders (3%). Height-for-age, weight-for-age, and body mass index z scores decreased significantly with age; height- and weight-, but not body mass index-for-age z scores were significantly lower in female subjects with MECP2 mutations than in those without. Vomiting, nighttime awakening, gastroesophageal reflux, chewing difficulty, and choking with feeding were significantly less likely to occur with increasing age. Short stature, low bone mineral content, fractures, and gastrostomy placement were significantly more likely to occur with increasing age. Chewing difficulty, choking with feeding, and nighttime awakening were significantly less likely to occur, whereas short stature was significantly more likely to occur, in female subjects with MECP2 mutations than in those without. Diagnostic evaluations and therapeutic interventions were used less frequently than the occurrence of symptoms or diagnoses in the RTT cohort. Conclusions: Gastrointestinal and nutritional problems perceived by parents are prevalent throughout life in girls and women with RTT and may pose a substantial medical burden for their caregivers. Physician awareness of these features of RTT may improve the health and quality of life of individuals affected with this disorder.

Rett Syndrome : North American Database

The International Rett Syndrome Association (IRSA) North American database is the first comprehensive compilation of information in the United States and Canada on individuals with Rett syndrome or with another diagnosis in association with MECP2 mutations. The database contains specific information by diagnosis, mutation status, and mutation type and frequency on 1928 participants. Among the 1928 participants, 85.5% were typical, 13.4% were atypical, and 1.1% had MECP2 mutations but did not have Rett syndrome. MECP2 mutations were identified in 914 of 1059 participants (86%): 799 of 870 (92%) participants with typical Rett syndrome had an MECP2 mutation, 94 of 162 (58%) with atypical Rett syndrome had a mutation, and all 21 individuals diagnosed as Not Rett syndrome had a mutation. Missense-type mutations (39.0%) were slightly more common than nonsense type (35.1%). Individual mutation frequency for the 8 common mutations varied from 11.9% for T158M to 4.4% for R106W; large deletions accounted for 6.4% and C-terminal truncations occurred in 8.8%. The remaining mutations (14.3%) occurred singly or in small numbers. This database provides a unique resource for expanding our understanding of Rett syndrome, for comparison with other national databases, and for future study including organization of clinical trials based on the expected emergence of fundamental therapies.

Rett syndrome diagnostic criteria: Lessons from the Natural History Study

Analysis of 819 participants enrolled in the Rett syndrome (RTT) Natural History Study validates recently revised diagnostic criteria. 765 females fulfilled 2002 consensus criteria for classic (653/85.4%) or variant (112/14.6%) RTT. All participants classified as classic RTT fulfilled each revised main criterion; supportive criteria were not uniformly present. All variant RTT participants met at least 3 of 6 main criteria in the 2002, 2 of 4 main criteria in the current format, and 5 of 11 supportive criteria in both. This analysis underscores the critical role of main criteria for classic RTT; variant RTT requires both main and supportive criteria. Ann Neurol 2010

Growth failure and outcome in Rett syndrome: Specific growth references

Objectives: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes. Methods: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Students t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression. Results: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X). Conclusions: RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations.

Longevity in Rett Syndrome: Analysis of the North American Database

OBJECTIVE To determine longevity in Rett syndrome (RTT) from a large cohort. STUDY DESIGN The North American RTT Database allows the examination of longevity in a large cohort of individuals with RTT from the United States and Canada. This database contains information on 1928 individuals, 85.5% with typical RTT, 13.4% with atypical RTT, and 1.1% with a mutation in the methyl-CpG-binding protein 2 gene (MECP2) but not RTT. Kaplan-Meier analyses were performed to assess longevity. RESULTS Earlier decennial cohorts exhibited better survival than recent cohorts, with most participants surviving into middle age. Comparing overall survival in persons with typical RTT and atypical RTT revealed greater mortality in typical RTT across the observed lifespan (P < .0001). Comparing survival in persons with RTT and identified MECP2 mutations and persons with unknown MECP2 status demonstrated greater mortality in the latter group (P < .0001, log-rank test). CONCLUSIONS This analysis provides strong evidence for significant longevity in RTT and indicates the need for careful planning for long-term care of these women. The disproportionately greater survival seen in earlier time periods and in persons with atypical RTT may be attributed to more severely affected individuals dying before diagnosis in the former and to greater numbers with milder variants (ie, preserved speech and delayed onset) in the latter.

Profiling Scoliosis in Rett Syndrome

To understand scoliosis, related comorbidities, and phenotype-genotype correlations in individuals with Rett syndrome (RTT), the Rare Disease Clinical Research Network database for RTT was probed. Clinical evaluations included a detailed history and physical examination, comprehensive anthropometric measurements, and two quantitative measures of clinical status, Clinical Severity Scale (CSS) and motor-behavioral analysis (MBA). All data were exported to the Data Technology Coordinating Center (DTCC) at the University of South Florida. Scoliosis assessment was based on direct examination and curvature measurements by radiography (Cobb angle). Statistical analyses included univariate and multiple logistic regression models, adjusting for age at enrollment or mutation type. Scoliosis data were available from 554 classic RTT participants, mean age = 10 y (0–57 y). Scoliosis was noted in 292 (53%); mean age = 15 y with scoliosis and 6 y without. Using multiple regression analysis, MBA severity score, later acquisition, loss or absent walking, and constipation were associated with scoliosis. Two common methyl-CpG-binding protein 2 (MECP2) mutations, R294X and R306C, had reduced risk for scoliosis. These findings corroborated previous reports on scoliosis and extended understanding of comorbidities, clinical severity, and relative risk reduction for specific mutations. Clinical trial design should account for scoliosis and related factors judiciously.

Clinical severity and quality of life in children and adolescents with Rett syndrome

Objective: The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. Methods: Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. Results: Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. Conclusions: Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures.

Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome

HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI‐anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5′ and 3′ UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558‐10G>A, that causes an aberrant splice product and a mutation in the 3′UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway.

Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2

Purpose:Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.Methods:Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array–based copy-number variant (CNV) analyses.Results:Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.Conclusion:The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13–19.