Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA

Background The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are ma ternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We stud ied the biochemical and molecular characteristics of this sporadic myopathy . Methods We sequenced the mtDNA cytochrome b gene in blood and muscle specim ens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these pa tients with those previously described in four other patients with mutation s in the cytochrome b gene. Results We found a total of three different nonsense mutations (G15084A, G1 5168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (nucleotides 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical ma nifestations included progressive exercise intolerance, proximal limb weakn ess, and in some cases, attacks of myoglobinuria. There was no maternal inh eritance and there were no mutations in tissues other than muscle. The abse nce of these findings suggests that the disorder is due to somatic mutation s in myogenic stem cells after germ-layer differentiation. All the point mu tations involved the substitution of adenine for guanine, but all were in d ifferent locations. Conclusions The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one c ause of the common and often elusive syndrome of exercise intolerance. (N E ngl J Med 1999; 341:1037-44.) (C)1999, Massachusetts Medical Society.