| The mitochondrial encephalomyopathies are a heterogeneous group of neuromuscular diseases associated with abnormal mitochondria and defects in oxidative phosphorylation (OXPHOS). Although these diseases have been recognized and studied for the past two decades, they have not been fully characterized biochemically and genetically and, therefore, their classification has not been possible. It is the objective of my research to characterize the biochemical and genetic basis of these diseases and elucidate the possible features of nDNA and mtDNA mutations that may cause the diseases.;To accurately identify OXPHOS enzyme activities in patients, the biochemical procedures for preparing mitochondria and assaying OXPHOS enzyme activities have been improved and refined. With the optimized method, my collaborators and I have been able to make a detailed clinical, biochemical, and genetic evaluation of two patients and their families, one with Myoclonic Epilepsy and Ragged-red Fiber Disease (MERRF) and the other with Lethal Infantile Mitochondrial Myopathy (LIMM).;The MERRF pedigree exhibited all of the characteristics expected for a mtDNA mutation. It was maternally transmitted; it was associated with an OXPHOS defect in Complexes I and IV; the OXPHOS enzyme levels varied among maternal relatives and correlated with the severity of the symptoms; and the patients' organ systems were affected sequentially as the OXPHOS defect increased, consistent with threshold expression.;The LIMM pedigree, by contrast, was best explained by a nDNA mutation. It showed Mendelian inheritance; there was total loss of Complex I and IV enzyme activity; and the phenotypic expression was tissue and developmental stage-specific.;Therefore, this research has for the first time begun to subdivide the mitochondrial encephalomyopathies into genetic subgroups: mtDNA and nDNA mutations. This biochemical and genetic understanding of the diseases provides new criteria for identifying patients with these diseases, for their diagnosis, and for genetic counseling. |
