Clinical and biochemical characteristics in patients with a high mutant load of the mitochondrial T8993G/C mutations

Am J Med Genet A. 2006 Apr 15;140(8):863-8. doi: 10.1002/ajmg.a.31194.


We retrospectively analyzed the clinical, histological, and biochemical data of 11 children, five of which carried the maternally-inherited mitochondrial T8993C and six carrying the T8993G point mutations in the ATP synthase 6 gene. The percentage of heteroplasmy was 95% or higher in muscle and in blood. All patients had an early clinical presentation with muscle hypotonia, severe extrapyramidal dysfunction and Leigh disease demonstrated by the cranial MRI. A slower clinical progression and more frequent sensory-neuronal involvement were noted in the patients carrying the T8993C mutation in a high mutation load in muscle and blood. No histological abnormality was found. In 9 out of 11 patients a decreased ATP production was detected, and complex V activity was deficient in all children. The activities of the respiratory enzyme complexes II and IV were normal, whereas an associated combined complex I and III deficiency were present in two patients. No obvious difference was found between the biochemical parameters of the two patient groups harboring different mutations in the same gene. No correlation was found between the degree of complex V enzyme deficiency and the severity of the phenotype. We confirmed an impaired assembly/stability of complex V in our patients. This is the first report of decreased activity and impaired assembly/stability of complex V in patients with T8993C mutations measured in muscle tissue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Alanine / genetics
  • Basal Ganglia Diseases / diagnosis
  • Basal Ganglia Diseases / enzymology
  • Basal Ganglia Diseases / genetics
  • Child
  • Child, Preschool
  • DNA, Mitochondrial / genetics*
  • Female
  • Gene Dosage
  • Humans
  • Infant
  • Lactic Acid / blood
  • Leigh Disease / blood
  • Leigh Disease / diagnosis
  • Leigh Disease / enzymology
  • Leigh Disease / genetics*
  • Mitochondria / enzymology
  • Mitochondria / genetics*
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Phenotype
  • Point Mutation*
  • Polymorphism, Single Nucleotide*
  • Severity of Illness Index


  • DNA, Mitochondrial
  • Lactic Acid
  • Adenosine Triphosphate
  • ATP synthase subunit 6
  • Mitochondrial Proton-Translocating ATPases
  • Alanine