3-oxothiolase deficiency.
Incidence
Rare. Autosomal recessive condition.
Clinical Characteristics
This is a disorder of branch-chained aminoacid metabolism, in which patients have recurrent episodes of vomiting, ketosis, and acidosis. Some have had hypoglycemia. The ketosis during fasting may be unusually severe. Patient may be intellectually normal but some have had developmental delay, neurological abnormalities and seizures. Neutropenia and thrombocytopenia have been observed in infancy. Elevated concentrations of glycine have been observed in the blood and urine of some but not all patients. The key metabolites are 2-methyl-3-hydroxybutiric acid, 2-methylacetic acid and tiglylglycine. These compounds increase in amounts in the urine following loading with isoleucine. The fundamental defect is in the activity of 2-methylacetoacetyl-CoA thiolase. The product of this reaction are acetyl-CoA and proprionil-CoA. The enzyme has a high degree of specificity, cleaving only 2-methylacetoacetyl-CoA and acetoacetyl-CoA and is activated by potassium. Failure to thrive may be present especially in infancy. The diagnosis is made by measuring the 3-oxothiolase activity in fibroblasts, which is decreased in this condition.
Precipitants
Ingestion of proteins and various aminoacids, notably isoleucine. Continuos vomiting. Fasting will precipitate an attack due to movilization of fat.The ketosis during fasting may be unusually severe.
Provocation Tests
The key metabolites are 2-methyl-3-hydroxybutiric acid, 2-methylacetic acid and tiglylglycine. These compounds increase in amounts in the urine following loading with isoleucine. The loading test is 100mg/kg PO. Then urine is collected for 8 hours for the above organic acids
Diagnostic Procedures
EB-F. The diagnosis is made by measuring the 3-oxothiolase activity in fibroblasts, which is decreased in this condition. The fundamental defect is in the activity of 2-methylacetoacetyl-CoA thiolase. GC/MS in urine for specific organic acids. Sometimes the loading test is the only abnormality found to elucidate the diagnosis. Then enzyme measurement in cultured fibroblasts.