Rett syndrome (RS) is a disorder that affects young girls and is characterized by progressive loss of cognitive function and ability to communicate, apraxia of hand movements, seizures, respiratory disturbances, ataxia, corticospinal tract involvement, and characteristic hand-wringing movements. It affects only females with an incidence of 1:10,000-1:15,000. Diagnosis depends upon the presence of a characteristic and remarkably consistent constellation of symptoms and signs. There is no diagnostic marker. It is proposed, but not proven, that RS is an X-linked dominant, lethal in males and reproductively lethal in females, with most cases representing new mutations. The present application is submitted 25 months after the initiation of P01 HD 23540, and requests support for an additional 3 years of multidisciplinary clinical and basic research studies designed to elucidate the pathogenesis of RS and to initiate therapy. It includes four highly interrelated components. Project 1 will conduct multidisciplinary evaluations of clinical features and therapeutic interventions in 100 patients with documented """"""""classical"""""""" RS, and will carry out investigations to help clarify the genetic basis of RS. The other three projects are designed to test and extend a pathogenetic hypothesis developed during the 25 months of the current grant period; namely, that RS is a neurodegenerative disorder that affects most severely dopaminergic neurons in the substantia nigra and basal ganglia and cholinergic neurons in the basal forebrain. This hypothesis will be evaluated by the techniques of neuropathology (Projects 2a and 2b), neurochemistry (Project 3), Positron Emission Tomography (Project 4a) and Magnetic Resonance Imaging (Project 4b). This approach may clarify the pathogenesis of RS, but also will serve as a model of how a neonatal neurodegenerative process differs from disorders such as Alzheimer and Parkinson disease that affect at least in part the same neurons later in life. During this grant period, a series of therapeutic interventions will be sought and implemented.
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