title: Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation.
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.
  
  
  CONCLUSIONS
  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.affiliation: Nijmegen Centrer for Mitochondrial Disorders, University Medical Centre Nijmegen, Department of Paediatrics, Geert Grooteplein 10, 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Olga
authors.initials: O
authors.lastname: Grafakou
authors.forename: Konrad
authors.initials: K
authors.lastname: Oexle
authors.forename: Lambert
authors.initials: L
authors.lastname: van den Heuvel
authors.forename: Roel
authors.initials: R
authors.lastname: Smeets
authors.forename: Frans
authors.initials: F
authors.lastname: Trijbels
authors.forename: Hans H
authors.initials: HH
authors.lastname: Goebel
authors.forename: Nils
authors.initials: N
authors.lastname: Bosshard
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
mesh_terms: D002675:Child, Preschool; D008058:Dihydrolipoamide Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D005347:Fibroblasts / Q000201:enzymology; D006579:Heterozygote; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology; D020125:Mutation, Missense; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D022821:RNA Splice Sites
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D022821:RNA Splice Sites; D008058:Dihydrolipoamide Dehydrogenase