title: Deficiency of pyruvate dehydrogenase caused by novel and known mutations in the E1alpha subunit.
abstract: Pyruvate dehydrogenase (PDH)-complex deficiency (OMIM 312170) is a clinically heterogeneous disorder, with phenotypes ranging from fatal lactic acidosis (LA) in the newborn to chronic neurological dysfunction. To date, over 80 different mutations have been identified in the PDHA1 gene in patients with PDH complex deficiency, which are thus thought to contribute to the PDH deficient phenotype. We have identified 14 additional patients with total PDH complex deficiency, all of whom were found to contain mutations within the PDHA1 gene (E(1)alpha subunit). The mutations include both missense mutations and duplications. Eight of these patients had novel mutations, and the remaining had mutations that have been identified previously in PDH complex deficient patients, with residual fibroblast activity ranging from 2.4 to 69% of control values. The nature of these mutations illustrates the variability in phenotype for a given gene defect, with intermittent ataxia being the mildest presentation, Leigh syndrome being the most common and severe neonatal LA the most severe.
authors.affiliation: Metabolism Research Programme, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jessie M
authors.initials: JM
authors.lastname: Cameron
authors.forename: Valeriy
authors.initials: V
authors.lastname: Levandovskiy
authors.forename: Neviana
authors.initials: N
authors.lastname: Mackay
authors.forename: Ingrid
authors.initials: I
authors.lastname: Tein
authors.forename: Brian H
authors.initials: BH
authors.lastname: Robinson
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017386:Sequence Homology, Amino Acid
chemical_list: D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit