Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation

Eur J Pediatr. 2003 Oct;162(10):714-8. doi: 10.1007/s00431-003-1282-z. Epub 2003 Aug 19.

Abstract

A boy with recurrent episodes of hypoglycaemia and ataxia, microcephaly, mental retardation, permanent lactic acidaemia, intermittent 2-oxoglutaric aciduria as well as elevation of serum branched chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3) deficiency. Analysis of genomic DNA revealed compound heterozygosity for two novel mutations: I393T in exon 11, located at the interface domain of the protein and possibly interfering with its dimerisation, and IVS9+1G>A located at a consensus splice site. A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indicating that the mRNA coming from the IVS9+1G>A mutant allele is not stable.

Conclusion: as opposed to the non-neurological phenotype of patients with a homozygous G229C mutation, this patient developed Leigh syndrome. Dihydrolipoamide dehydrogenase and pyruvate dehydrogenase complex activities in muscle were 29% and 14% of the lowest control values, respectively. Pyruvate dehydrogenase complex activity in fibroblasts was normal, however, indicating that the biochemical examination of defects in energy metabolism should be performed in a more energy demanding tissue.

Publication types

  • Case Reports

MeSH terms

  • Child, Preschool
  • Dihydrolipoamide Dehydrogenase / deficiency*
  • Dihydrolipoamide Dehydrogenase / genetics*
  • Fibroblasts / enzymology
  • Heterozygote
  • Humans
  • Leigh Disease / genetics*
  • Male
  • Muscle, Skeletal / enzymology
  • Mutation, Missense
  • Pyruvate Dehydrogenase Complex / genetics
  • RNA Splice Sites

Substances

  • Pyruvate Dehydrogenase Complex
  • RNA Splice Sites
  • Dihydrolipoamide Dehydrogenase