Musumeci et al. (2000) studied a 43-year-old man, originally reported by Bet et al. (1990), who had complained, since childhood, of severe exercise intolerance and myalgia. Morphologic and biochemical studies of muscles showed 40% ragged-red fibers and an approximately 40% reduction of complex I activity consistent with complex I deficiency (MC1DM3). At age 43 years, he still complained of exercise intolerance; neurologic examination showed mild proximal limb weakness but was otherwise normal. His family history was noncontributory. The mother was alive and had always been a very active person. Neither of his 2 sibs complained of exercise intolerance. Musumeci et al. (2000) found an inversion of 7 nucleotides within the ND1 gene, which maintained the reading frame. The inversion, which altered 3 highly conserved amino acids in the polypeptide, was heteroplasmic in the patient's muscle but was not detectable in blood. This was said to be the first report of a pathogenic inversion mutation in human mtDNA. The inversion changed the normal amino acids 199-201 from asp-leu-ala to gly-lys-val. The 7-bp inverted segment was flanked by 8-bp inverted repeats.
Blakely et al. (2006) reported a female infant with the same 7-bp inversion in the MTND1 gene described by Musumeci et al. (2000). However, the infant had a much more severe phenotype and died at age 1 month with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis. The mutation was present at high levels in several tissues including the heart (85%), muscle (84%), liver (87%), and cultured skin fibroblasts (70%). Complex I activity was estimated to be 24% of control values. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. Blakely et al. (2006) noted that their findings illustrated the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasized the need for appropriate genetic counseling for families affected by mtDNA disease.
