title: Neurodevelopmental abnormalities and lactic acidosis in a girl with a 20-bp deletion in the X-linked pyruvate dehydrogenase E1 alpha subunit gene.
abstract: We describe a girl with developmental abnormalities of the CNS and a lactic acidosis whose cultured fibroblasts showed a profound deficiency of pyruvate dehydrogenase complex (PDHC) activity (patient = 0.14 nmol/mg protein per minute, controls = 0.7 to 1.1 nmol/mg protein per minute). Immunocytochemistry demonstrated the fibroblast culture to be mosaic, with 14% of cells expressing the PDHC E1 alpha subunit protein in normal amounts and the remaining 86% having no detectable immunoreactive activity. Direct sequencing of cDNA for the X-linked PDHC E1 alpha subunit established that the patient was heterozygous for a 20-bp deletion beginning in the codon for Ser300 of the derived amino acid sequence. The pattern of methylation at the DXS255 locus suggested predominant expression of the X chromosome carrying the mutant allele in the fibroblast culture. There was a good correlation between the residual PDHC activity, the proportion of cells with immunoreactive E1 alpha protein, and the X chromosome inactivation ratio, demonstrating the importance of X-inactivation for expression of this X-linked neurometabolic disease in females.
authors.affiliation: Department of Biochemistry, University of Oxford, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Matthews
authors.forename: R M
authors.initials: RM
authors.lastname: Brown
authors.forename: L
authors.initials: L
authors.lastname: Otero
authors.forename: D
authors.initials: D
authors.lastname: Marchington
authors.forename: J V
authors.initials: JV
authors.lastname: Leonard
authors.forename: G K
authors.initials: GK
authors.lastname: Brown
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics / Q000503:physiopathology*; D001483:Base Sequence; D002478:Cells, Cultured; D002675:Child, Preschool; D017931:DNA Primers; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D015151:Immunoblotting; D046911:Macromolecular Substances; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D009030:Mosaicism; D009422:Nervous System Diseases / Q000235:genetics* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics* / Q000378:metabolism; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D017384:Sequence Deletion; D012867:Skin / Q000201:enzymology; D014960:X Chromosome
chemical_list: D017931:DNA Primers; D046911:Macromolecular Substances; D011768:Pyruvate Dehydrogenase Complex