A cognitively normal PDH-deficient 18-year-old man carrying the R263G mutation in the PDHA1 gene

J Inherit Metab Dis. 2009 Dec:32 Suppl 1. doi: 10.1007/s10545-009-1101-4. Epub 2009 Jul 29.

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.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Cognition*
  • DNA Mutational Analysis
  • Diet, Carbohydrate-Restricted
  • Dietary Supplements
  • Genetic Predisposition to Disease
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mutation*
  • Phenotype
  • Pyruvate Dehydrogenase (Lipoamide) / genetics*
  • Pyruvate Dehydrogenase Complex Deficiency Disease / diagnosis
  • Pyruvate Dehydrogenase Complex Deficiency Disease / enzymology
  • Pyruvate Dehydrogenase Complex Deficiency Disease / genetics*
  • Pyruvate Dehydrogenase Complex Deficiency Disease / psychology
  • Pyruvate Dehydrogenase Complex Deficiency Disease / therapy
  • Treatment Outcome

Substances

  • Pyruvate Dehydrogenase (Lipoamide)
  • pyruvate dehydrogenase E1alpha subunit