Probing striated muscle mitochondrial phenotype in neuromuscular disorders.

Multisystemic disorders with predominantly neurologic manifestations often present with mitochondrial abnormalities in striated muscle biopsies. Decreased respiratory complex activities and abnormalities in mitochondrial structure and DNA constitute the spectrum of mitochondrial changes used as diagnostic and prognostic indicators in patients with neuromuscular disorders. This study assessed mitochondrial defects present in a cohort of 154 young patients to determine diagnostic efficiency and probe the relationship of mitochondrial to clinical phenotype. Striated muscle biopsies were analyzed for mitochondrial structure and number, levels of enzyme activities of complex I-V and citrate synthase, mitochondrial DNA and specific mitochondrial DNA deletions, and presence of 15 pathogenic mitochondrial DNA point mutations. Reduced complex I, III, IV, and V activities were the most ubiquitous finding, with complex III most commonly affected. Mitochondrial structural defects (39%) included changes in mitochondria sizes/shapes and number and aberrant cristae formation. Mitochondrial DNA deletions were evident in 15 patients, three displayed mitochondrial DNA depletion, and only two harbored pathogenic point mutations. Reductions in specific enzyme activities may be the most sensitive diagnostic indicator, whereas defects in ultrastructure and mitochondrial DNA integrity were frequently accompanied by the full spectrum of mitochondrial abnormalities. Some phenotypes displayed specific mitochondrial abnormalities; however, most clinical phenotypes displayed little specificity with regard to mitochondrial phenotype.