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

Ann Neurol. 1999 Jun;45(6):820-3. 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • DNA, Mitochondrial / analysis*
  • Exercise / physiology*
  • Humans
  • Male
  • Muscular Diseases / genetics*
  • Muscular Diseases / metabolism
  • Muscular Diseases / physiopathology*
  • Mutation / genetics
  • NADH Dehydrogenase / genetics*


  • DNA, Mitochondrial
  • NADH Dehydrogenase