title: Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency.
abstract: The pyruvate dehydrogenase (PDH) complex is a mitochondrial multienzyme that catalyses the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA. We report four novel PDHA1 mutations in patients with pyruvate dehydrogenase deficiency. Analysis of PDH activity showed decreased activity in fibroblasts from all four patients, around 16-52% of mean control, similar to what has been found in previous studies. Two of the mutations were missense mutations: c.616G>A (p.Glu206Lys) and c.457A>G (p.Met153Val), one was a 3 bp in-frame deletion: c.429_431delAGG (p.Gly143del), and one was a 65 bp duplication: c.900-6_958dup65. cDNA analysis of the 65 bp duplication showed a small amount of normal transcript in addition to the transcript corresponding to the duplication. The small amount of normal transcript likely explains the survival of the patient, who was a boy. The duplication and one of the missense mutations were associated with decreased amounts of E(1)α And E(1)β protein on western blot analysis, whereas the other two mutations were associated with normal amounts. This study adds four novel mutations to the around 90 reported mutations in PDHA1 (HGMD PDHA1 mutation database). The phenotypes of patients with PDH deficiency have been divided into three groups: a neonatal form with severe lactic acidosis, a form observed only in males and characterized by episodes of ataxia with relapses associated with hyperlactataemia, and an infantile form with hypotonia, lethargy, onset of seizures or dystonia, psychomotor retardation, in some cases Leigh-like lesions and mild to moderate hyperlactataemia. The four patients reported here all belong to the latter group, which is the largest.
authors.affiliation: Department of Clinical Genetics 4062, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen, 2100, Denmark. elsebet.oestergaard@rh.regionh.dk
authors.forename: E
authors.initials: E
authors.lastname: Ostergaard
authors.forename: L Birk
authors.initials: LB
authors.lastname: Moller
authors.forename: H Serap
authors.initials: HS
authors.lastname: Kalkanoglu-Sivri
authors.forename: A
authors.initials: A
authors.lastname: Dursun
authors.forename: M
authors.initials: M
authors.lastname: Kibaek
authors.forename: T
authors.initials: T
authors.lastname: Thelle
authors.forename: E
authors.initials: E
authors.lastname: Christensen
authors.forename: M
authors.initials: M
authors.lastname: Duno
authors.forename: F
authors.initials: F
authors.lastname: Wibrand
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000172:deficiency* / Q000235:genetics*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000145:classification / Q000201:enzymology* / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D024101:Mitochondrial Proteins; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit