Acetoacetyl CoA thiolase deficiency: a cause of severe ketoacidosis in infancy simulating salicylism.

A female child presented at one year of age with a febrile illness and loose stools, then developed severe ketoacidosis with vomiting; an apparent salicylate level of 11 mg/dl was measured. A sibling had died in similar circumstances nine years earlier. Investigation revealed that the child did not have salicylate intoxication, and that high levels of acetoacetate in blood and urine were giving readings indicative of the presence of salicylate on routine testing. Gas-liquid chromatographic analysis combined with mass spectrometry on urine samples revealed the presence of 2-methyl-acetoacetate, 2-methyl-3-hydroxybutyrate, and tiglyl glycine in appreciable amounts, indicating a defect in isoleucine catabolism located at the beta-ketothiolase step. The oxidation of 14C-isoleucine to CO2 in cultured fibroblasts confirmed that this pathway was defective. We present evidence that beta-ketothiolase deficiency is not simply a defect of isoleucine degradation; the deficient enzyme is the K+ dependent short-chain mitochondrial thiolase, which also plays a major catalytic role in ketone body and fatty acid oxidation.