Objective-To determine if a relationship exists between the clinical features of Rett Syndrome, an X-linked dominant neurodevelopmental disorder, and specific mutations in MECP2.Method-Cross-sectional study of two hundred and forty-five girls and women with typical Rett Syndrome seen between 1990 and 2004 in tertiary academic out-patient specialty clinics and who had complete MECP2 mutation analysis. A structured clinical evaluation was completed for each participant. The results were grouped by MECP2 mutation and compared.Results-Participants with the R133C mutation are less severely affected than those with R168X or large DNA deletions (p<0.05). Likewise, individuals with the R168X mutation are more severely affected than those with R294X and late carboxy-terminal truncating mutations (p<0.05). Clinical differences are notable in ambulation, hand use, and language, (p<0.004) three cardinal features of Rett Syndrome. Individuals with R168X are less likely to walk (p=0.008), retain hand use (p=0.002), or use words (p=0.001). In contrast, those with carboxy-terminal truncations are more likely to walk (p=0.007) and use words (p<0.001). The R306C mutation, previously found to confer milder features, adversely affects only one clinical feature, language (p<0.05).Conclusions-Specific mutations in MECP2 confer different severity. These results allow the design of therapies targeted towards the amelioration of expected problems. Furthermore, the distinct effects of MECP2 mutations on clinical severity must be considered in clinical intervention trials.

Rett Syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterized by a period of apparently normal development until 6–18 months of age, when motor and communication abilities regress. More than 95% of people with RTT have mutations in Methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity. Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and measures of growth, motor coordination, communicative abilities, respiratory function, autonomic symptoms, scoliosis, and seizures over time. In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p.Arg294X, p.Arg306Cys, 3′ Truncations, and Other Point Mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p.Arg255X, p.Arg270X, Splice Sites, Large Deletions, Insertions, and Deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use, and age at onset of stereotypies are strongly linked to overall disease severity. Thus, we have confirmed that MECP2 mutation type is a strong predictor of disease severity. However, clinical severity continues to become progressively worse with advancing age regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.

Background: Rett syndrome (RTT) is a neurodevelopmental disorder primarily seen in females,

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) 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 RTT females (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%); biliary tract disorders (3%). Height, weight, and BMI z-scores decreased significantly with age; height and weight, but not BMI, z-scores were significantly lower in females with MECP2 mutations than 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 females with MECP2 mutations than those without. Diagnostic evaluations and therapeutic interventions were utilized less frequently than the occurrence of symptoms or diagnoses in the RTT cohort. Conclusion 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.