We investigated the correlations of deletions of mitochondrial DNA in skeletal muscle with clinical manifestations of mitochondrial myopathies, a group of disorders defined either by biochemical abnormalities of mitochondria or by morphologic changes causing a ragged red appearance of the muscle fibers histochemically. We performed genomic Southern blot analysis of muscle mitochondrial DNA from 123 patients with different mitochondrial myopathies or encephalomyopathies. Deletions were found in the mitochondrial DNA of 32 patients, all of whom had progressive external ophthalmoplegia. Some patients had only ocular myopathy, whereas others had Kearns-Sayre syndrome, a multisystem disorder characterized by ophthalmoplegia, pigmentary retinopathy, heart block, and cerebellar ataxia. The deletions ranged in size from 1.3 to 7.6 kilobases and were mapped to different sites in the mitochondrial DNA, but an identical 4.9-kilobase deletion was found in the same location in 11 patients. Biochemical analysis showed decreased activities of NADH dehydrogenase, rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase, four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA. We conclude that deletions of muscle mitochondrial DNA are associated with ophthalmoplegia and may result in impaired mitochondrial function. However, the precise relation between clinical and biochemical phenotypes and deletions remains to be defined.

We directly stimulated muscle in three patients with acute quadriplegic myopathy to determine whether paralyzed muscle in this syndrome is electrically excitable. Two of the patients had been treated with neuromuscular blocking agents and corticosteroids, and one patient had been treated with corticosteroids alone. We found that paralyzed muscle is electrically inexcitable in affected patients. Muscle regained electrical excitability over weeks to months. The recovery of muscle excitability paralleled the clinical recovery of patients, suggesting that paralysis in this syndrome is secondary to electrical inexcitability of muscle membrane.

Five new cases and 30 others from the literature were characterized by the clinical triad of progressive external ophthalmoplegia, atypical pigmentary degeneration of the retina, and heart block. The syndrome is sporactic, not hereditary, and begins by the age of 20 years. In many cases there is other evidence of widespread neurological disorder, implicating specific areas: cerebellum; auditory and vestibular systems; skeletal muscle; and, less often, intellectual function or corticospinal tracts. Short stature and delayed sexual maturation are also frequent. The CSF protein content is almost always greater than 100 mgidl. Spongioform encephalopathy was found in 4 postmortem examinations. In all cases so examined, muscle mitochondria were abnormal.The constancy of these manifestations suggests that the disorder is a true entity, not an artificial subclass of the large group of disorders associated with ophthalmoplegia. Several characteristics suggest that the disorder of neuronal and muscle metabolism is induced by persistent viral infection.