Metabolism of branched-chain amino acids in fibroblasts from patients with maple syrup urine disease and other abnormalities of branched-chain ketoacid dehydrogenase activity

The metabolism of branched-chain amino acids was studied in cultured fibroblasts from patients with branched-chain ketoacid dehydrogenase deficiency using 1-¹⁴C- and UL-¹⁴C-leucine and valine. The formation of ¹⁴CO₂ from 1-¹⁴C-valine or 1-¹⁴C-leucine was 1-3% of normal. In fibroblasts of patients with associated lactic acidemia the values were 4-29% of control. Analysis of organic acid products revealed that in both patients and controls the amount of labeled a-ketoisovalerate recovered after incubation with 1-¹⁴C-valine was one-third of the amount of α-ketoisocaproate recovered after incubation with 1-^l4C-leucine. Very little α-hydroxyisocaproate was produced, while the amount of a-hydroxyisovalerate was about 10% of the α-ketoisovalerate. Unexpectedly β-hy-droxyisobutyrate ws found to be the major metabolic product of UL-¹⁴C-valine in normal fibroblasts. Large accumulations of β-hydroxyisovalerate were found in normal fibroblasts using UL-^I4C-leucine. There were little or no conversions to these compounds in fibroblasts of patients with branched-chain ketoacid dehydrogenase deficiency. There were substantial conversions in the patients in whom dehydrogenase deficiency was associated with lactic acidemia.