Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene

We report the first molecular defect in an NADH-dehydrogenase gene presenting as isolated myopathy. The proband had lifelong exercise intolerance but no weakness. A muscle biopsy showed cytochrome c oxidase (COX)-positive ragged-red fibers (RRFs), and analysis of the mitochondrial enzymes revealed complex I deficiency. Sequence analysis of the mitochondrial genes encoding the seven NADH-dehydrogenase subunits showed a G-to-A transition at nucleotide 11832 in the subunit 4 (ND4) gene, which changed an encoded tryptophan to a stop codon. The mutation was heteroplasmic (54%) in muscle DNA. Defects in mitochondrially encoded complex I subunits should be added to the differential diagnosis of mitochondrial myopathies.