European Journal of Pediatrics

, Volume 162, Issue 10, pp 714–718 | Cite as

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

  • Olga Grafakou
  • Konrad Oexle
  • Lambert van den Heuvel
  • Roel Smeets
  • Frans Trijbels
  • Hans H. Goebel
  • Nils Bosshard
  • Andrea Superti-Furga
  • Beat Steinmann
  • Jan Smeitink
Original Paper


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.


Dihydrolipoamide dehydrogenase Lactic acidaemia Neurodegenerative disease Pyruvate dehydrogenase Splice-site mutation 



citrate synthase


cytochrome c oxidase


dihydrolipoamide dehydrogenase


menadione-linked alpha glycerophosphate dehydogrenase


pyruvate dehydrogenase complex


succinate dehydrogenase


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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Olga Grafakou
    • 1
  • Konrad Oexle
    • 2
  • Lambert van den Heuvel
    • 1
  • Roel Smeets
    • 1
  • Frans Trijbels
    • 1
  • Hans H. Goebel
    • 3
  • Nils Bosshard
    • 2
  • Andrea Superti-Furga
    • 2
  • Beat Steinmann
    • 2
  • Jan Smeitink
    • 1
  1. 1.Nijmegen Centrer for Mitochondrial DisordersUniversity Medical Centre Nijmegen, Department of Paediatrics Nijmegen The Netherlands
  2. 2.Division of Metabolism and Molecular PaediatricsChildren's Hospital, University of ZurichZurich Switzerland
  3. 3.Department of NeuropathologyJohannes Gutenberg-University Medical CentrerMainz Germany

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