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.

Objective-To determine longevity in Rett syndrome (RTT) from a large cohort.Study design-The North American Database allows the examination of longevity in a large cohort of individuals with RTT from the US and Canada. This database contains information on 1928 individuals (85.5% typical, 13.4% atypical, and 1.1% with MECP2 mutations but not RTT. KaplanMeier analyses were performed to assess longevity.Results-Earlier decennial cohorts had better survival than recent cohorts, most participants surviving into middle age. Comparing overall survival between typical and atypical RTT, those with typical RTT had greater mortality than those with atypical RTT across the observed lifespan (p<. 0001). Comparing survival for individuals with RTT and identified mutations with those with MECP2 not known, those with unknown MECP2 status had greater mortality than those with mutations (Log-Rank test, p<.0001).Discussion-This analysis provides strong evidence for significant longevity in Rett syndrome 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 atypical RTT may be attributed to more severely affected individuals dying before diagnosis in the former and greater numbers with milder variants (preserved speech and delayed onset) in the latter. KeywordsMECP2; mutations; genetics; survival; Kaplan-Meier Corresponding and reprint request author: Alan K. Percy, MD, Civitan International Research Center, Room 320E, 1530 3 rd Avenue South, Birmingham,, apercy@uab.edu. The authors declare no conflicts of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In order to assess longevity for RTT in the United States and Canada, members of the International Rett Syndrome Association (IRSA) were surveyed (7), providing a robust database with respect to diagnosis, mutation status, date of birth, and date of death, if applicable. This report demonstrates the potential for prolonged survival in individuals with RTT and suggests the need for careful planning for long-term care as well as continued observation of the effects of improved clinical management on longevity. NIH Public Access MethodsIRSA mailed a structured survey to 2,994 members in the US (2,836) and Canada (158) requesting specific information including date of birth; date of death, if applicable; diagnosis (typical RTT, variant or atypical RTT, not RTT, or unknown), discipline of diagnosing physician; mutation testing results, if performed, and testing laboratory; reason why diagnostic testing was not performed; and conta...