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Mitochondrial DNA mutation and muscle pathology in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes

We sought a relationship between abnormalities of mitochondrial DNA (mtDNA) and muscle pathology in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) at the single fiber level, using histochemistry, in situ hybridization, and single fiber PCR. Most type 1 ragged‐red fibers (RRF) showed positive cytochrome c oxidase (COX) activity at the subsarcolemmal region, while type 2 RRF showed little COX activity. However, there was no difference in the amount of total (mutant and wild‐type) mtDNAs and the proportion of mutant mtDNA between type 1 RRF and type 2 RRF. These observations suggest that mitochondrial proliferation and nuclear factors affect muscle pathology, including COX activity, in MELAS. Total mtDNAs were greatly increased in RRF. The proportion of mutant mtDNA was significantly higher in RRF than in non‐RRF. The amount of both wild‐type and mutant mtDNAs was increased in RRF in MELAS, which fact does not support the contention of a replicative advantage of mutant mtDNA. The proportion of mutant mtDNA was significantly higher in the strongly succinate dehydrogenase–reactive blood vessels (SSV) than in non‐SSV. The similar morphological behavior in these vessels and fibers suggests that increased mutant mtDNA is responsible for mitochondrial proliferation and dysfunction in both tissues. It seems likely that systemic vascular abnormalities involving cerebral vessels lead to the evolution of strokelike episodes in MELAS. © 1995 John Wiley & Sons, Inc.