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Multiple mitochondrial DNA deletions in hereditary inclusion body myopathy
M Jansson1, N Darin, M Kyllerman
1Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
Abstract:
We have recently described an autosomal dominant hereditary inclusion body myopathy (h-IBM). Clinically it is is characterized by congenital joint contractures and slowly progressive, proximal muscle weakness and ophthalmoplegia. There is deterioration of muscle function between 30 and 50 years of age. While young patients show minor pathological changes in muscle, the middle-aged and old patients show rimmed vacuoles and inclusions of filaments measuring 15-18 nm in diameter. Except for the absence of significant inflammation the histopathology is similar to that found in sporadic inclusion body myositis (s-IBM). In s-IBM mitochondrial alterations including cytochrome c oxidase (COX) -deficient muscle fibers are common. These are due to multiple mitochondrial DNA (mtDNA) deletions. In this study we investigated the occurrence of mitochondrial alterations in autosomal dominant h-IBM. Young affected individuals showed no mitochondrial changes but three patients aged 38, 51 and 59 years, respectively, showed ragged red fibers and COX-deficient muscle fibers. Polymerase chain reaction analysis showed multiple mtDNA deletions. By in situ hybridization clonal expansions of mtDNA with deletions were demonstrated in COX-deficient muscle fibers. Most of the analyzed deletion breakpoints showed nucleotide repeats flanking the deletions. The results show that COX-deficient muscle fibers and somatic mtDNA deletions 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.
Insights
Mitochondrial DNA deletions cause muscle fiber damage in hereditary inclusion body myopathy (h-IBM). These findings suggest similar mechanisms underlie both h-IBM and sporadic IBM, impacting muscle function.
Area of Science:
- Neurology
- Genetics
- Mitochondrial Biology
Background:
- Autosomal dominant hereditary inclusion body myopathy (h-IBM) presents with congenital contractures and progressive muscle weakness.
- Histopathology in h-IBM resembles sporadic inclusion body myositis (s-IBM), often showing rimmed vacuoles and filament inclusions.
- Mitochondrial DNA (mtDNA) deletions are a known feature in s-IBM, leading to cytochrome c oxidase (COX)-deficient muscle fibers.
Purpose of the Study:
- To investigate the presence and nature of mitochondrial alterations in autosomal dominant h-IBM.
- To determine if mtDNA deletions occur in patients with h-IBM.
- To compare mitochondrial pathology in h-IBM with that observed in s-IBM.
Main Methods:
- Histopathological examination of muscle biopsies.
- Polymerase chain reaction (PCR) analysis to detect mtDNA deletions.
- In situ hybridization to identify clonal expansion of mtDNA with deletions in COX-deficient fibers.
Main Results:
- Affected individuals aged 38, 51, and 59 showed ragged red and COX-deficient muscle fibers.
- PCR analysis confirmed multiple mtDNA deletions in these patients.
- In situ hybridization demonstrated clonal expansions of deleted mtDNA within COX-deficient muscle fibers.
- Deletion breakpoints frequently contained flanking nucleotide repeats.
Conclusions:
- Somatic mtDNA deletions and COX-deficient muscle fibers are present in autosomal dominant h-IBM.
- The findings suggest shared pathogenic mechanisms for mtDNA deletions in both h-IBM and s-IBM.
- This study highlights the role of mitochondrial dysfunction in the pathogenesis of hereditary inclusion body myopathy.