Thiamin-responsive maple syrup urine disease in a patient antigenically missing dihydrolipoamide acyltransferase.

Maple syrup urine disease results from inherited defects in human nuclear genes for branched chain alpha-ketoacid dehydrogenase, a mitochondrial multienzyme complex. Thiamin pyrophosphate is necessary for complex activity and a thiamin-responsive form of maple syrup urine disease is known. Here we demonstrate the use of [1-13C]leucine oxidation to [13C]O2 quantified in breath samples as a means of assessing whole body leucine oxidation. Analysis of cultured cells from this patient shows the antigenic lack of the E2 subunit, yet she gained branched chain alpha-ketoacid dehydrogenase activity in response to diet supplementation with pharmacologic doses of thiamin. These cultured cells were used to seek a molecular basis for the observed thiamin response. Despite normal thiamin transport in these cells, medium supplementation of up to 1000 thiamin/liter failed to increase complex activity or cause the antigenic appearance of the missing protein. This lack of response in cultured cells suggests that the observed whole body response to thiamin must be a tissue-specific effect in liver, muscle, or kidney. In addition, allele-specific detection of paternal and maternal mutations was used to genotype family members in this pedigree.

Thiamine response in maple syrup urine disease.

We measured the biochemical response for four patients with maple syrup disease to pharmacologic doses of thiamine, and correlated their response to their branched chain alpha-ketoacid dehydrogenase activity. We observed a linear correlation between the concentrations of each plasma branched-chain amino acid and its corresponding ketoacid analogue. In addition, the renal tubular reabsorption of branched-chain amino and ketoacids was nearly complete within these physiologic concentrations. Three children responded to thiamine therapy with a reduction in concentration of plasma and urinary branched-chain amino and ketoacids. Each responder had at least 5% activity for branched chain alpha-ketoacid dehydrogenase in their mononuclear blood cells and in whole cell fibroblasts from cultured skin when compared to the activity in normal control cells. We propose that each child with maple syrup urine disease be assessed for their response to thiamine by quantifying the concentration of branched-chain amino acids in plasma before and after vitamin supplementation.