Late onset Leigh syndrome and ataxia due to a T to C mutation at bp 9,185 of mitochondrial DNA

Am J Med Genet A. 2007 Apr 15;143A(8):808-16. doi: 10.1002/ajmg.a.31637.


A T-to-C missense mutation at nucleotide position 9,185 in the protein-coding ATP6 gene of the mitochondrial genome was present at high heteroplasmy in members of a Canadian family with Leigh syndrome with predominant ataxia and peripheral neuropathy. This mutation results in the substitution of a proline residue for an evolutionary-conserved leucine at position of amino acid 220 near the carboxyl terminus of the mitochondrial protein. The index patient and brother, who had an identical clinical presentation, had >90% mutant mtDNA in cultured skin fibroblasts, lymphocytes, and whole blood. Their mother and a maternal uncle, symptomatic with a peripheral neuropathy alone, had 86% and 85% heteroplasmy, respectively. Symptomatic maternal cousins with early onset revealed 90% and 91% mutant mtDNA in all tissues analyzed. Studies of lymphoblasts from the asymptomatic maternal grandmother and eldest brother of the proband were heteroplasmic for mutant mtDNA with 56% and 17%, respectively. Biochemical analysis demonstrated normal respiratory chain enzyme activity in muscle and fibroblasts, normal ATP synthesis, but reduced oligomycin-sensitive H(+)ATPase in cultured lymphoblast mitochondria. We propose that the 9,185T > C mtDNA mutation is pathogenic even though the initial phenotype is mild and the biochemical phenotype not easily detectable.

Publication types

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

MeSH terms

  • Adult
  • Age of Onset
  • Ataxia / genetics*
  • Cells, Cultured
  • Child
  • Conserved Sequence
  • DNA, Mitochondrial / genetics*
  • Family Health
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Leigh Disease / genetics*
  • Lymphocytes / cytology
  • Lymphocytes / metabolism
  • Male
  • Mitochondrial Proteins / genetics
  • Mutation, Missense*
  • Pedigree
  • Peripheral Nervous System Diseases
  • Point Mutation


  • DNA, Mitochondrial
  • Mitochondrial Proteins