This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rett syndrome (RTT) is a disorder that characteristically occurs in females. A majority of patients (~70%) with clinical features of RTT have been identified to have mutations in the MeCP2 gene located in the Xq28 region. The gene is involved in repressing transcription of an unknown number of genes on multiple chromosomes. More recently, males of varying ages who lack classic features of RTT have been identified to have mutations in MeCP2, accounting for a wide clinical spectrum. Except for patients with Kleinfelter syndrome, males have matrilineally transmitted disease. The majority of females are sporadic cases, occurring from paternally transmitted de novo mutations. Patients with RTT have an apparently normal early developmental course followed by microcephaly, and arrest in acquisition of cognitive and motor skills by the end of the first year. Stereotyped movements, seizures, respiratory irregularities, gastrointestinal and nutrition abnormalities, as well as behavioral problems are frequent clinical concomitants. Progressive abnormalities in muscle tone and movement are associated with reduced brain dopamine and melanin content in the substantia nigra pars compacta. In RTT, postmortem brain tissue shows reduced choline acetyltransferase in basal ganglia, which must accentuate the dementia. An age-associated excess of NMDA/glutamate receptors coincide with the epileptic encephalopathy noted in infancy and childhood. The reported presence of NMDA glutamate receptors in osteoblasts warrants consideration of a toxic effect due to their excess, resulting in osteoporosis and increased fractures in RTT. Recent recognition of reductions in volume of the dorsal parietal lobe and insula (Kaufmann et al. unpublished observations), when combined with reduced NAA in these regions by MR-spectroscopy, is of note. EEG shows spikes arising from central temporal regions that maximize in sleep and, together with the MRI/MRS findings, may suggest that ictal activity in sleep involving the insula is a possible cause of sudden unexpected death in these subjects. Clinically, the uniformity of age-associated signs and symptoms in RTT suggest common pathogenetic mechanisms. Our study aims to: 1) identify biological factors common to those with and without mutations in MeCP2 despite classic phenotype, and determine basis for the natural history and phenotypic variability so that appropriate prognosis and treatment options can be provided. 2) identify brain regions that have selective vulnerability, by volumetric analyses of MRI scans and diffusion tensor imaging (DTI), to correlate with specific neurological deficits, and basis for sudden unexpected death. As brain volume is reduced in caudate and fronto-temporal regions along with reduced cerebral blood flow in RTT DTI and MR-spectroscopy will be obtained to determine involvement of regions and pathways contributing to progressive rigidity, seizures, and behavioral aberrations that may be altered with improved treatments in future. 3) ameliorate other complex symptoms, in particular, severe constipation, swallowing difficulties and failure-to-thrive (despite excellent food intake), seizures, behavior problems, and respiratory and sleep irregularities. 4) We will also follow the observed changes in serum lactate and organic acids to determine if mitochondrial function is impaired, so that appropriate therapy can be provided for this dysfunction if needed. 5) In order to determine if there is prolonged QTC interval as reported in the literature we will follow the EKG for any changes in a larger series of patients. We will conduct these investigations in order to follow the clinical severity and course, and correlate with X-inactivation status, and genotype. We anticipate identification of new directions for therapeutic interventions to cure/ameliorate symptoms, and for neuroprotection in early infancy. A separate protocol will be submitted for therapeutic interventions.
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