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

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.

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

“…Muscle biopsies from patients with KSS or CPEO show ragged-red fibers and cytochrome oxidase-negative fibers [58,59]. Clinical signs vary widely in different syndromes but include muscle weakness, heart block, retinopathy, deafness, diabetes, short stature and dementia [2,60]. We have used microarray in an attempt to link the primary cause of KSS/CPEO/PS with cellular, morphological, and clinical consequences.…”

“…Mitochondrial DNA deletions (ΔmtDNA), when present at concentrations of 30% and greater in muscle tissue, can cause three disorders, Kearns-Sayre Syndrome (KSS), Chronic Progressive External Opthalmoplegia (CPEO), and Pearson's Syndrome (PS) [1][2][3]. Clinical signs include muscle weakness, exercise intolerance, droopy eyelids and weakness of ocular muscles (CPEO), plus heart block, pigmentary retinopathy, ataxia, deafness, and dementia (KSS), and sideroblastic anemia (PS).…”

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

“…Larger mtDNA deletions have been associated with more severe disease and earlier disease onset 15, 16, 17, 18, 19. Whereas a highly significant,20 significant,15, 16, 21, 22 weak,18, 23 or no24 correlation has been reported between the percentage of COX‐deficient fibers and the degree of mtDNA heteroplasmy, most studies found no correlation between the biochemical defects and the nature of the deletion (the number of protein‐encoding genes and the complexes affected by the deletion) or deletion size alone 4, 15, 20, 22, 25. Interestingly, a higher proportion of COX‐deficient ragged‐red fibers was found in patients with deletions encompassing the 3 mtDNA‐encoded COX genes,26, 27 whereas an isolated complex I deficiency was reported in patients with smaller mtDNA deletions removing only complex I genes 26…”

“…Phenotypically, single large‐scale mtDNA deletions are associated with several clinical syndromes including Pearson syndrome,2 Kearns–Sayre syndrome,3 and chronic progressive external ophthalmoplegia (CPEO) 4. A recent prospective study noted ptosis, ophthalmoplegia, muscle weakness, exercise intolerance, and hearing loss as the most common symptoms present at onset 5…”

Mitochondrial disorders

“…Similarly, the abundance of the mutation in accessible tissues (blood, skin fibroblasts, hair roots, urinary tract cells) generally correlates reasonably well with clinical severity in oligosymptomatic maternal relatives of patients with MELAS or MERRF. An apparent exception to this rule is KSS, in that "partial cases" with some but not all the canonical diagnostic features seem to be very rare: we had found only 4 such "probable" cases in our series of 54 patients with PEO and single mtDNA deletions (Moraes et al, 1989) and we have seen very few since then.…”