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.

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.

Although bone mineral deficits have been identified in Rett syndrome (RTT), the prevalence of low bone mineral density (BMD) and its association with skeletal fractures and scoliosis has not been characterized fully in girls and women with RTT. Accordingly, we measured total body bone mineral content (BMC) and BMD using dual energy x-ray absorptiometry in a cross-sectional group of 50 females, aged 2-38 y, with RTT. Methyl-CpG-binding 2 (MECP2) mutations, skeletal fractures, and scoliosis were documented. The prevalence of BMC and BMD z scores ϽϪ2 SD was 59 and 45%, respectively. Although absolute BMC and BMD increased significantly with increasing age, BMC, and BMD z scores were significantly lower in older than in younger females. The prevalence of fractures and scoliosis was 28 and 64%, respectively. Low BMD z scores were positively associated with fractures and scoliosis. Deficits in BMD were identified across a broad range of MECP2 mutations. This study identified associations among low BMD, fractures, and scoliosis, and underscored the need for better understanding of the molecular mechanisms of MECP2 in the regulation of bone mineral metabolism. (1) documented early, profound deficits of total body bone mineral content (BMC) and bone mineral density (BMD) in girls with RTT compared with unaffected girls and children with other neurologic disorders. Haas et al. (1) showed that total body BMC did not improve with advancing age, whereas our study suggested that the accretion of total body BMC throughout childhood was possible (5). All of these studies were limited because of the small number and narrow age range of the participants (1,5,6). They also captured total body BMC and BMD when less emphasis was placed on the nutritional and physical rehabilitation of females with RTT.In the present study, we expanded the number and age range of the participants and used body composition and ambulation as proxies for nutritional status and physical activity to better understand the prevalence of bone mineral deficits and the relation between bone mineral deficits, MECP2 mutations, and occurrence of bone-related disorders in RTT. We hypothesized that: 1) the early decrease in BMC and BMD persists over time in a cross-sectional cohort of females with RTT, 2) bone mineral deficits occur across a range of MECP2 mutations, and 3) the reduction in BMC and BMD correlates with the occurrence of fractures and scoliosis. We anticipated that this study would facilitate the development of strategies to promote bone mineral health in RTT. SUBJECTS AND METHODS Subjects.Fifty females who met the clinical criteria for RTT were enrolled (7). MECP2 mutations, if known, were recorded. All participants were female because males with MECP2 mutations have a different phenotype and rarely meet the diagnostic clinical criteria (8). The eligible age range was 0 -40 y, with individuals divided among groups of 5-y intervals. Individuals were excluded if they received oral Ca supplements 6 mo before study, had previous therapy with ...

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.

Gastrostomy placement for aggressive nutritional therapy favorably altered the natural history of growth failure and undernutrition in RTT, but did not restore height and weight z scores to birth values, regardless of the age at which surgery occurred and in the presence or absence of a fundoplication.