Mitochondrial DNA deletions in inherited recurrent myoglobinuria

We describe two brothers with inherited recurrent exertional myoglobinuria and alcohol intolerance associated with distinct morphological abnormalities of muscle mitochondria and multiple deletions of muscle mitochondrial DNA. Patient 1 (26 years old) and Patient 2 (21 years old) had recurrent episodes of myoglobinuria provoked by strenuous exercise or alcohol intake, from the age of 18 years. Although their serum lactate and pyruvate levels were normal at rest, they were significantly elevated by aerobic exercise. Histochemistry of their biopsied limb muscles showed ragged-red fibers and cytochrome c oxidase-negative fibers as well as degenerating and regenerating fibers. Electron microscopy showed pronounced accumulation of abnormal mitochondria containing paracrystalline inclusions and moderate increases of glycogen particles. The enzyme activities of the electron-transfer complexes in the isolated muscle mitochondria of Patient 2 were within normal ranges. Southern blot analysis revealed multiple deletions of mitochondrial DNA, some of which were common between the patients. Polymerase chain reaction of their muscle mitochondrial DNA detected multiple abnormal fragments indicating mitochondrial DNA deletions. We propose that a defect of the mitochondrial energy-transducing system due to multiple mitochondrial DNA deletions is a novel genetic cause of inherited recurrent myoglobinuria.