Multiple mitochondrial DNA deletions in hereditary inclusion body myopathy

We have recently described an autosomal dominant hereditary inclusion body myopathy (h-IBM). Clinically it is is characterized by congenital joint con tractures and slowly progressive, proximal muscle weakness and ophthalmople gia. There is deterioration of muscle function between 30 and 50 years of a ge. While young patients show minor pathological changes in muscle, the mid dle-aged and old patients show rimmed vacuoles and inclusions of filaments measuring 15-18 nm in diameter. Except for the absence of significant infla mmation the histopathology is similar to that found in sporadic inclusion b ody myositis (s-IBM). In s-IBM mitochondrial alterations including cytochro me c oxidase (COX) -deficient muscle fibers are common. These are due to mu ltiple mitochondrial DNA (mtDNA) deletions. In this study we investigated t he occurrence of mitochondrial alterations in autosomal dominant h-IBM. You ng affected individuals showed no mitochondrial changes but three patients aged 38, 51 and 59 years, respectively, showed ragged red fibers and COX-de ficient muscle fibers. Polymerase chain reaction analysis showed multiple m tDNA deletions. By in situ hybridization clonal expansions of mtDNA with de letions were demonstrated in COX-deficient muscle fibers. Most of the analy zed deletion breakpoints showed nucleotide repeats flanking the deletions. The results show that COX-deficient muscle fibers and somatic mtDNA deletio ns are present in this family with h-IBM. The same factors may be involved in the development of mtDNA deletions in s-IBM and this family with h-IBM.