title: A family with pyruvate dehydrogenase complex deficiency due to a novel C>T substitution at nucleotide position 407 in exon 4 of the X-linked Epsilon1alpha gene.
abstract: The pyruvate dehydrogenase complex (PDHc; McKusick 312170), localised in the mitochondrial matrix, is a multienzyme complex which converts pyruvate to acetyl-CoA. A deficiency of PDHc leads to inadequate removal of pyruvate and lactate resulting in lactic acidaemia and insufficient energy production. The major cause of PDHc deficiency is a defect in the E1alpha component. The gene of this component is localised to Xp22.1. We describe two brothers with a relatively mild clinical phenotype of PDHc deficiency. Onset of disease was associated with muscle weakness and swallowing difficulties in both. At follow-up, the older brother developed encephalopathic features consistent with Leigh syndrome. Lactate to pyruvate ratios were low, consistent with a PDHc deficiency which was confirmed by measurements of PDHc activity in thrombocytes. A 407C>T change in exon 4 of the E1alpha gene was found in both brothers and their mother. This substitution predicts a replacement of a conserved alanine at position 136 by valine.
  
  
  CONCLUSIONS
  Due to the X-linked inheritance pattern combined with the overall results of clinical investigations, molecular genetic findings and a corresponding functional deficiency of the gene product we believe that this substitution in the pyruvate dehydrogenase E1alpha gene is a mutation leading to pyruvate dehydrogenase complex deficiency in this family.
authors.affiliation: Department of Paediatrics, Sahlgrenska University Hospital/Ostra, 41685 Göteborg, Sweden. mar.tulinius@vgregion.se
authors.forename: Már
authors.initials: M
authors.lastname: Tulinius
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.forename: Lars-Martin
authors.initials: LM
authors.lastname: Wiklund
authors.forename: Eva
authors.initials: E
authors.lastname: Holmberg
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Eriksson
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.forename: Linda
authors.initials: L
authors.lastname: De Meirleir
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Holme
mesh_terms: D019943:Amino Acid Substitution; D001921:Brain / Q000473:pathology; D002331:Carnitine / Q000097:blood; D002675:Child, Preschool; D005091:Exons; D006801:Humans; D007223:Infant; D019344:Lactic Acid / Q000097:blood; D007888:Leigh Disease / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000235:genetics*; D019289:Pyruvic Acid / Q000097:blood; D035781:Siblings
chemical_list: D019344:Lactic Acid; D019289:Pyruvic Acid; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; D002331:Carnitine