This is a multidisciplinary research program for the study of the clinical, communicative, neurophysicological, neurochemical, epidemiologic, molecular genetic, and neuropathological aspects of Rett syndrome. Diverse analytic modalities will be employed to address the fundamental mechanism(s) responsible for this disorder affecting females in early childhood. The clinical assessment will utilize systematic neurologic, developmental, and motor-behavioral analyses to validate the existing staging system for Rett syndrome, to lend precision to the clinical diagnosis, and to provide a basis for the evaluation of potential treatment strategies. Clinical laboratory investigations will focus on previously-described abnormalities in cerebrospinal fluid (biogenic amine metabolites, biopterin, and B-endorphins). Pharmacologic intervention will be evaluated by the systematic assessments noted and compared with suitable controls. The status of communication skills in Rett syndrome will be examined by behavioral assessment of speech and language and by quantitative electrophysiologic evaluation of the auditory system. These modalities represent additional objective measures for the study of treatment strategies. Characteristics alterations in respiratory pattern and the electroencephalogram will be examined by sophisticiated video EEG methodologies. This study will also evaluate upper airway muscles where possible dysfunction similar to that in extra-pyramidal disorders has been noted; provide rigorous analysis of the seizure types seen in Rett syndrome; and assess the EEG prior to the following neuropharmacological treatment. Epidemiologic studies are designed to examine the occurrence of Rett syndrome in a defined-geographic locale and to search for prenatal and perinatal risk factors using case-control methodology. Molecular genetics studies will include the pattern of X-inactivation and the search for submicroscopic deletions using highly polymorphic probes. An important element of this study is evaluation of familial cases using X-specific, highly polymorphic probes as well as males with the Rett phenotype. Studies of pathology in Rett syndrome will examine available tissue from necropsy as well as analysis of muscle and peripheral nerves using quantitative methodologies. This research program has evolved from the concerted efforts of clinical and basic researcher and represents an important opportunity to extend these collaborations.
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