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

• Published in: Annals of neurology Vol. 45; no. 6; pp. 820 - 823
• Main Authors: Andreu, A. L., Tanji, K., Bruno, C., Hadjigeorgiou, G. M., Sue, C. M., Jay, C., Ohnishi, T., Shanske, S., Bonilla, E., DiMauro, S.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01-06-1999; Willey-Liss
• Subjects: Adult; Biological and medical sciences; Diseases of striated muscles. Neuromuscular diseases; DNA, Mitochondrial - analysis; Exercise - physiology; Humans; Male; Medical sciences; Muscular Diseases - genetics; Muscular Diseases - metabolism; Muscular Diseases - physiopathology; Mutation - genetics; NADH Dehydrogenase - genetics; Neurology; Case study; Human; Striated muscle disease; Enzyme; Nonsense mutation; NADH dehydrogenase; Exploration; Mitochondrial DNA; Oxidoreductases; Myopathy
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/1531-8249(199906)45:6<820::AID-ANA22>3.0.CO;2-W

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. Ann Neurol 1999;45:820–823