[Myoglobinuria caused by multiple deletions of mitochondrial DNA].
We report two brothers with inherited recurrent myoglobinuria 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. 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 a pronounced accumulation of abnormal mitochondria containing paracrystalline inclusions and moderate increases of glycogen particles. Southern blot analysis revealed multiple deletions of mitochondrial DNA, some of which were common to both patients. By the primer shift polymerase chain reaction method, we detected multiple abnormal fragments indicating mitochondrial DNA deletions. Nucleotide sequencing of the deleted regions disclosed directly repeated sequences of 1 to 12 bp on each side of the deletions. Since the end points of mitochondrial DNA deletions were within 20 bp of the major non-coding region, probable mutations in this region contribute to the pathogenesis of multiple mitochondrial DNA deletions found in these patients. 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.