LATE-ONSET MITOCHONDRIAL MYOPATHY

In the majority of patients with mitochondrial encephalomyopathies, si gns and symptoms appear in the first three decades of life. Here we re port on a group of 9 older patients (>69 years old) with late-onset sk eletal myopathy characterized by focal accumulations of deleted mitoch ondrial DNAs (mtDNAs) and altered muscle energy status, suggestive of a primary mitochondrial disease. The clinical phenotype was somewhat v ariable. However, all patients shared a common feature of insidious mo derate proximal muscle weakness; some also showed fatigability and axi al muscle weakness. In situ hybridization analysis demonstrated accumu lations of messenger RNAs transcribed from deleted mtDNAs in a relativ ely large number of muscle fibers in the patient group. These fiber se gments appeared as ragged red with the modified Gomori trichrome stain and hyperreactive with a modified succinate dehydrogenase stain. Most were negative for cytochrome c oxidase activity. On transverse sectio ns their mean frequency was 0.69% (trichrome) and 1.97% (succinate deh ydrogenase) significantly above control levels. Multiple mtDNA deletio ns were demonstrated by the polymerase chain reaction in both the pati ents and an age-matched control group, but not in younger control subj ects. Phosphorus 13 magnetic resonance spectroscopy of resting muscle showed a decreased phosphocreatine-inorganic phosphate ratio in the pa tient group. The myopathy in this group of patients appears to result from mitochondrial dysfunction related to the clonal expansion of diff erent mtDNA deletions in individual fiber segments. While the origin o f the mtDNA mutations is not clear, the phenotype seems to represent a n exaggerated form of what is observed in the normal aging process.