title: Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency.
abstract: Pyruvate dehydrogenase deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. Most cases are caused by mutations in the X-linked gene for the E1alpha subunit of the complex. Mutations in DLAT, the gene encoding dihydrolipoamide acetyltransferase, the E2 core component of the complex, have not been described previously. We report two unrelated patients with pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both patients are less severely affected than typical patients with E1alpha mutations and both have survived well into childhood. Episodic dystonia was the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent. The patients had neuroradiological evidence of discrete lesions restricted to the globus pallidus, and both are homozygous for different mutations in the DLAT gene. The clinical presentation and neuroradiological findings are not typical of pyruvate dehydrogenase deficiency and extend the clinical and mutational spectrum of this condition.
authors.affiliation: Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Head
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Brown
authors.forename: Zarazuela
authors.initials: Z
authors.lastname: Zolkipli
authors.forename: Raveen
authors.initials: R
authors.lastname: Shahdadpuri
authors.forename: Mary D
authors.initials: MD
authors.lastname: King
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.forename: Garry K
authors.initials: GK
authors.lastname: Brown
mesh_terms: D001324:Autoantigens / Q000235:genetics*; D015153:Blotting, Western / Q000379:methods; D001923:Brain Chemistry / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D005347:Fibroblasts / Q000201:enzymology; D005917:Globus Pallidus / Q000473:pathology; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007930:Leucine / Q000235:genetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D010649:Phenylalanine / Q000235:genetics; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014162:Transfection / Q000379:methods
chemical_list: D001324:Autoantigens; D024101:Mitochondrial Proteins; D018698:Glutamic Acid; D010649:Phenylalanine; C052359:DLAT protein, human; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D007930:Leucine