Encephalopathies associated with mt-DNA point mutations have been recognized with increasing frequency as a cause of mental retardation and developmental disabilities. This proposal addresses some of the important clinical issues that confront the physician when evaluating and managing patients and family members with these maternally-inherited conditions. Probands and oligosymptomatic relatives will be admitted to the Irving Clinical Research Center for a comprehensive evaluation including neuropsychological assessment to define their cognitive and neurobehavioral profiles longitudinally, in collaboration with Dr. Sano. Parallel studies of cerebral energetics will be performed in the HATCH NMR Research Center using the 5.0 Tesla scanner in collaboration with Drs. Hilal and Shungu. A questionnaire will be developed as part of the neuropsychological inventory to evaluate the natural history of these clinical syndromes. This questionnaire also will be designed for telephone use to evaluate other patients who have come to our attention, in an effort to expand our understanding of the natural history and prognosis of these conditions. This information is vitally important as baseline information for future therapeutic efforts. A screening test will be developed using cultured human skin fibroblasts from these patients to evaluate the energy-dependent buffering of intracellular calcium following depolarization. Preliminary studies in collaboration with Dr. Rothman show impaired buffering in MELAS, and other mitochondrial diseases when the affected cell lines are loaded with the calcium-sensitive dye, fura-2. These findings will be correlated with the point mutation abundance in collaboration with Dr. DiMauro (Project 2). These studies will be extended to cultured muscle cells from the same patients in collaboration with Dr. Miranda (Project 6), and correlated with parallel observations being made by Dr. Schon (Project 4) using aggregation dyes to evaluate the mitochondrial membrane potential. These cells will be examined by 1H and 31P NMR spectroscopy in collaboration with Drs. Hilal and Shungu. These studies are intended to expand our understanding of the cognitive and neurobehavioral disturbances, and natural history of these clinical syndromes, and to correlate these clinical domains with in vivo and in vitro measures of cellular energy failure. A sensitive and specific screening test will provide important information regarding the frequency of these conditions in a pediatric setting.
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