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

Abstract

UNLABELLED:

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.

• Authors: Olga Grafakou, Konrad Oexle, Lambert van den Heuvel, Roel Smeets, Frans Trijbels, Hans H Goebel, Nils Bosshard, Andrea Superti-Furga, Beat Steinmann, Jan Smeitink
• Journal: European journal of pediatrics (Eur J Pediatr) Vol. 162 Issue 10 Pg. 714-8 (Oct 2003) ISSN: 0340-6199 [Print] Germany
• PMID: 12925875 (Publication Type: Case Reports, Journal Article)

Chemical References

• Pyruvate Dehydrogenase Complex
• RNA Splice Sites
• Dihydrolipoamide Dehydrogenase

Topics

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