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Neurology 2000;55:644-649
© 2000 American Academy of Neurology
Articles

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

C. L. Karadimas, PhD, P. Greenstein, MD, C. M. Sue, MD, J. T. Joseph, MD, PhD, K. Tanji, MD, R. G. Haller, MD, T. Taivassalo, BS, M. M. Davidson, PhD, S. Shanske, PhD, E. Bonilla, MD and S. DiMauro, MD

From the Department of Neurology (Drs. Karadimas, Sue, Tanji, Davidson, Shanske, Bonilla, and DiMauro), Columbia University College of Physicians and Surgeons, New York, NY; the Departments of Neurology (Dr. Greenstein) and Pathology (Dr. Joseph), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and the Institute for Exercise and Environmental Medicine (Dr. Haller and T. Taivassalo), Presbyterian Hospital, Dallas, TX.

Address correspondence and reprint requests to Dr. Salvatore DiMauro, 4-420 College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; e-mail: sd12{at}columbia.edu

OBJECTIVE: To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle.

BACKGROUND: Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with 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 sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR.

RESULTS: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-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 intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.




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