Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region

Biochim Biophys Acta. 2002 Oct 9;1588(1):79-84. doi: 10.1016/s0925-4439(02)00142-4.


The human pyruvate dehydrogenase complex (PDHC) catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment is very effective for some patients with PDHC deficiency. Among these patients, five mutations of the pyruvate dehydrogenase (E1)alpha subunit have been reported previously: H44R, R88S, G89S, R263G, and V389fs. All five mutations are in a region outside the thiamine pyrophosphate (TPP)-binding region of the E1alpha subunit. We report the biochemical and molecular analysis of two patients with clinically thiamine-responsive lactic acidemia. The PDHC activity was assayed using two different concentrations of TPP. These two patients displayed very low PDHC activity in the presence of a low (1 x 10(-4) mM) TPP concentration, but their PDHC activity significantly increased at a high (0.4 mM) TPP concentration. Therefore, the PDHC deficiency in these two patients was due to a decreased affinity of PDHC for TPP. Treatment of both patients with thiamine resulted in a reduction in the serum lactate concentration and clinical improvement, suggesting that these two patients have a thiamine-responsive PDHC deficiency. The DNA sequence of these two male patients' X-linked E1alpha subunit revealed a point mutation (F205L and L216F) within the TPP-binding region in exon 7.

Publication types

  • Case Reports

MeSH terms

  • Binding Sites
  • Cells, Cultured
  • Child
  • Exons
  • Humans
  • Infant
  • Lactic Acid / blood
  • Lymphocytes / drug effects
  • Lymphocytes / enzymology
  • Male
  • Point Mutation
  • Pyruvate Decarboxylase / metabolism
  • Pyruvate Dehydrogenase Complex / analysis
  • Pyruvate Dehydrogenase Complex / genetics*
  • Pyruvate Dehydrogenase Complex / metabolism
  • Pyruvate Dehydrogenase Complex Deficiency Disease / drug therapy*
  • Pyruvate Dehydrogenase Complex Deficiency Disease / enzymology
  • Pyruvate Dehydrogenase Complex Deficiency Disease / genetics
  • Thiamine / metabolism
  • Thiamine / therapeutic use*


  • Pyruvate Dehydrogenase Complex
  • Lactic Acid
  • Pyruvate Decarboxylase
  • Thiamine