title: A cognitively normal PDH-deficient 18-year-old man carrying the R263G mutation in the PDHA1 gene.
abstract: Pyruvate dehydrogenase (PDH) is a crucial multienzyme system linking glycolysis to the tricarboxylic acid cycle by catalysing the decarboxylation of pyruvate to acetyl-CoA. Deficiency in pyruvate dehydrogenase is most commonly secondary to mutations in the X-linked PDHA1 gene encoding the E1 alpha subunit. There is a wide range of clinical presentations from severe neonatal lactic acidosis to chronic encephalopathy (Leigh syndrome). In recent years, a small subset of patients was recognized with less severe involvement, presenting initially only with intermittent symptoms, mainly of ataxia. Most of these patients remain stable for a number of years before developing progressive neurological deterioration around puberty at the latest. There does not appear to be a reliable correlation between genotype, phenotype, or enzyme activity. This makes counselling in a clinical setting challenging. We report a case with a previously known common mutation in PDHA1 (R263G) with an excellent outcome at 18 years of age. Previous patients with this mutation have presented with mental retardation and/or Leigh syndrome, while our patient's clinical outcome is exceptional. He is cognitively normal and has normal brain MRI. His management includes a stringent carbohydrate-free diet, as well as supplementation with thiamine, carnitine and vitamin E. This case further broadens the clinical spectrum, including now an example of a cognitively normal adult with PDH deficiency.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bachmann-Gagescu
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Merritt
authors.forename: S H
authors.initials: SH
authors.lastname: Hahn
mesh_terms: D000293:Adolescent; D003071:Cognition; D004252:DNA Mutational Analysis; D050528:Diet, Carbohydrate-Restricted; D019587:Dietary Supplements; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010641:Phenotype; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000523:psychology / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit