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

TLDR

Mitochondrial myopathies include ocular myopathy and multisystem Kearns‑Sayre syndrome, but the link between clinical phenotypes and mtDNA deletions is not fully understood. The study aimed to correlate muscle mtDNA deletions with clinical features of mitochondrial myopathies. The authors used Southern blotting to detect mtDNA deletions in 123 patients and assayed respiratory chain enzyme activities. Deletions were detected in 32 patients, all presenting progressive external ophthalmoplegia, with sizes ranging 1.3–7.6 kb and an identical 4.9‑kb deletion in 11 cases, and were associated with reduced respiratory chain enzyme activity. Published in N Engl J Med 1989; 320:1293–9.

Abstract

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.)