Natural History of Rett Syndrome, MECP2 duplications, and Rett-related disorders

Effective treatment of Rett syndrome hinges on understanding the natural history of this disorder through carefully conducted longitudinal assessments and genotype/ phenotype correlations. Symptomatic therapy is currently altering the natural history of RTT- well exemplified by improvements in the management of nutritional and gastrointestinal aspects, scoliosis, seizures, and sleep. The near-term potential for meaningful therapy of this disorder is very promising in light of recent discoveries 1) that switching on a silenced copy of the Mecp2 gene in a knockout animal model for RTT achieves complete or nearly complete reversal of the clinical phenotype and 2) that small, non-toxic molecules capable of reading-through stop mutations have shown promise in laboratory studies Increased identification of MeCP2 target genes offers the opportunity for direct intervention. The Rett Natural History project is providing periodic assessments in individuals with RTT, with or without mutations in MECP2, with such mutations and an alternate phenotype, or in males with duplication of MECP2.

This project involves an inter-institutional group of investigators with long-standing interest in Rett syndrome, Angelman syndrome (AS), and Prader-Willi syndrome (PWS) in a Rare Diseases Clinical Research Center (RDCRC) that is part of the a Rare Diseases Clinical Research Network (RDCRN). The project is establishing a phenotype/genotype correlation over a broad spectrum of Rett phenotypes, is performing longitudinal studies on a broad sample of individuals with Rett, and is conducting a survival study of Rett individuals. As site PI, Dr. Sahin provides oversight for the enrollment of patients for the RDCRN longitudinal cohort, education and training of physicians and other healthcare providers at other sites throughout the U.S., and discussion forums for the parents and other family members.