NATURAL HISTORY, SEARCH FOR A MARKER AND THERAPY

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The goal of this project is to define the natural history, identify a diagnostic marker, understand the mechanism of neuronal dysfunction, and apply specific therapies early in the evolution of the disease to improve neurological status in Rett syndrome (RS). Based on the postulate that RS is a disorder of early brain growth, AIM 1 focuses on the identification of younger patients and delineation of early clinical features. Familial cases and their pedigrees will be documented in search of a genetic abnormality. Cases identified in Aim 1 will be a vital resource for all projects. In Aim 2 gene(s) defective in RS will be sought by classical cytogenetic approaches, and by representational difference analysis (RDA). Aim 2 will also search for proteins, and expressed genes that have up- or down regulated in RS, which may serve as a molecular fingerprint for the disease. Aim 3 is designed to study olfactory receptor neurons (ORNs) obtained from biopsies of olfactory neuroepithelium in RS girls, and compared to ORNs from normal and disease controls. A cell culture approach will provide direct access to RS neurons early in the course of the disease, and permit study of the evolution of neuronal defects in this disorder. In Aim 4 therapeutic interventions will attempt to prevent the devastating consequences of increased glutamate NMDA, and AMPA receptor induced neuronal injury by specific treatments with receptor antagonists, dextromethorphan and topiramate. To compensate for the significant reductions in choline acetyltransferase levels, treatment with an acetylcholine esterase inhibitor-donepezil hydrochloride- to improve cognition will be tested. Efficacy of treatment will be monitored by clinical and neuroimaging techniques. Careful study of the nutritional status, and the role of dysphagia in growth failure will be examined in the light of therapeutic interventions. Use of growth factors or gene therapy will be considered when efficacy is established in the animal model.