Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA

Objective: To elucidate the molecular basis of a mitochondrial myopathy ass ociated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficie ncy in muscle. Background: Recurrent; myoglobinuria is typically seen in pa tients with inborn errors of carbohydrate or lipid metabolism, the main sou rces of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients wit h otherwise unexplained recurrent myoglobinuria. Methods: Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors seque nced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed r estriction fragment length polymorphism analysis and single-fiber PCR. Resu lts: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in C OX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. Conclusions: The G5920A mutation caused COX deficiency in muscle, explaining the exercise intoleran ce and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone s uggests that it arose de novo in myogenic stem cells after germ-layer diffe rentiation. Mutations in mtDNA-encoded COX genes should be considered in pa tients with recurrent myoglobinuria.