The goal of this project is to conduct a multidisciplinary evaluation of 80 new and 50 known patients with classic Rett syndrome (RS), to understand the underlying mechanisms, ascertain the natural history, and identify a biological marker (Aim 1). Based on the hypothesis that RS is a disease of pre- and early postnatal onset, and not a progressive neurodegenerative disease, patients with confirmed diagnosis from the previous two studies will be reevaluated to obtain objective evidence for the presence or absence of neurologic regression. The search for a marker is a prime consideration of this project, and the preliminary observation of candidate proteins in serum will be explored. In addition, this project will be vital to the other projects (neuropathology, neurobiology, and neuroimaging) as verification of diagnosis is essential for recruiting study patients and tissues. To determine a genetic basis for RS, cytogenetic studies and search for evidence of uniparental disomy will be conducted in Aim 2, as well as identification of familial cases to establish genetic mechanisms for the rare familial occurrences.
In Aim 3 therapeutic interventions using agents which are both supportive and specific, and reported to improve the disturbing symptoms of intractable seizures, falling spells, abnormal respiration, gastrointestinal, and motor abnormalities will be examined. Based on the hypothesis that in RS glutamatergic neurotoxicity causes seizures, and abnormalities of movement and tone, we will treat patients with dextromethorphan, a known glutamate/NMDA subtype receptor blocker. The newly released anticonvulsant drug Felbamate, will be tested in those with intractable seizures, as it is effective in suppressing NMDA and quisqualate induced seizures with neuroprotective properties as well. Treatment with growth factors will be considered since definite neurochemical changes corroborated by pathological findings in the dopaminergic and cholinergic system exist in RS. Under experimental conditions, these systems are known to respond to growth factors. Therefore, should their efficacy be proven in Project V, will be administered to RS girls when they become available for human use.
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