Patients with (70-80%) and those without mutations in MeCP2 gene are recognized to have the clinical features of Rett Syndrome. Although location of mutations can in part be correlated with the phenotype, they do not provide essential prognostic guidelines. We will attempt to delineate the molecular profiles of the various mutations that contribute to phenotypic variability? We will therefore correlate the clinical, gastrointestinal status, and neuroimaging changes (MRI, MRS) to levels of MeCP2, other methyl-binding domain proteins, and histone acetylation in Project III, and with changes in olfactory receptor neurons in Project II. We will also compare these changes to those with the phenotype but without mutations in MeCP2 to determine commonality in factors that may contribute to phenotypic similarities. In collaboration with Dr. Shemer (Israel), we will attempt to identify mutations in the promoter region of the MeCP2 gene in this latter group. The increased expression of the glutamatergic system in younger RS subjects leads us to treat patients below 15 years of age with dextromethorphan to block NMDA/glutamate receptors so as to prevent excitotoxicity and provide neuroprotection. To gain additional insight into the neurobiology of RS, we will conduct SPECT and PET studies in conjunction with Project IB to delineate abnormalities in the cholinergic and glutamatergic systems that would provide future therapeutic strategies in conjunction with studies in murine models in Project IV. Data from interaction between this and other projects will support our hypothesis that the phenotype of RS is the result of the unique effects of different MeCP2 mutations on specific neuronal populations and their interconnections during the dynamic phase of activity-dependant synaptic plasticity.
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