Mitochondrial encephalomyopathies are important causes of mental retardation in childhood. In the past five years, there has been remarkable progress in our understanding of the genetic basis of mitochondrial disorders, especially those related to defects in mitochondrial DNA (mtDNA), but biochemical correlates and pathogenetic mechanisms remain unclear. This Program Project focuses on the diseases due to point mutations of mtDNA, because they have early onset and are almost always accompanied by mental retardation. Project 1 (Dr. D.C. DeVivo, P.I.) will characterize the cognitive and behavioral deficits associated with mtDNA point mutations and correlate them with cerebral energy metabolism assessed by NMR spectroscopy. It will also attempt to establish a sensitive screening test for patients with mitochondrial diseases based on the calcium-buffering capacity of cultured skin fibroblasts. Project 2 (Dr. S. DiMauro, P.I.) will continue searching for new mtDNA mutations in patients with mental retardation and evidence of mtDNA defects. It will also study the respiratory chain activities in isolated mitochondria. Project 3 (Dr. M.P. King, P.I.) will study the relationship between genotype and phenotype in p/o cybrids harboring two different pathogenic point mutations in tRNA genes. Project 4 (Dr. E.A. Schon, P.I.) will explore the phenotypic expression in p/o cybrids of mutations in polypeptide-coding genes, and will attempt genetic engineering approaches-to therapy. Project 5 (Dr. A.F. Miranda, P.I.) will study the pathogenesis of mitochondrial proliferation in innervated muscle cultures from patients, and will also explore whether the mitochondrial dysfunction due to different point mutations can be corrected by genetic complementation. The Core Unit will provide direction, administration, external consultation, and shared equipment/technical service the project as a whole (Dr. DiMauro, Program Director; Dr. Schon, Co-Director). Drs. Aprille, Rapin, and Shoffner will constitute the External Advisory Committee.
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