Mitochondrial DNA Deletions in Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome

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. (N Engl J Med 1989; 320:1293–9.) MITOCHONDRIA are unique among intracellular organelles because they contain their own DNA, which can be transcribed and translated to form proteins. Human mitochondrial DNA is a small (16.5-kilobase [kb]), circular, double-stranded molecule that contains 13 structural genes, 22 transfer RNA genes, and 2 genes encoding the 16S and 12S mitochondrial ribosomal RNAs. All 13 peptides encoded by mitochondrial DNA are components of respiratory-chain complexes, including seven subunits of Complex I (NADH–coenzyme Q oxidoreductase), one subunit of Complex III (ubiquinol–cytochrome c oxidoreductase), three subunits of Complex IV (cytochrome c oxidase), and two subunits of Complex V (ATP synthase). Because all mitochondria . . .