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Ketolysis involves esterification of acetylacetonate (AcAc) to AcAcCoA by succinyl-CoA: 3-oxoacid transferase (SCOT) and involves hydrolysis of AcAcCoA by 3-ketothiolase to form acetyl-CoA.1

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SCOT deficiency is characterized by episodic ketoacidosis, often beginning in infancy, with increased blood ketone bodies even in the fed state. Diagnosis can be established by enzyme assay in fibroblasts or by mutation analysis, and prenatal diagnosis can be accomplished in the same manner.

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Mitochondrial 3-ketothiolase releases acetyl-CoA from acetoacetyl-CoA and from 2-methylacetoacetyl-CoA, an intermediate in isoleucine oxidation (see Chapter 156). Enzyme deficiency can present in infancy with hyperammonemia, metabolic acidosis, and severe ketosis, or later with fasting- or protein-induced episodes of vomiting, hepatomegaly, ketoacidosis, and encephalopathy.

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Diagnosis

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Urine organic acid analysis shows increased 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine, but they may be obscured during acute illnesses by 3-hydroxybutyrate (3HB) and acetoacetate (AcAc) and may be detectable only between episodes or after an oral load of isoleucine. Glycine levels are often elevated in blood and urine.

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While usually not necessary to establish a diagnosis, the enzyme defect can be demonstrated in fibroblasts and leukocytes, and probably in amniocytes for prenatal diagnosis. The gene encoding the enzyme has been cloned and localized to chromosome 11 (11q22.3-23.1), and a few disease-causing mutations have been identified.

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Treatment

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Acute episodes should be treated with intravenous glucose and sodium bicarbonate. A low-protein diet, coupled with avoidance of fasting, decreases the frequency and severity of acute episodes and permits normal growth and development if irreversible neurological damage has not already occurred.2

1. Saudubray JM, Specola N, Middleton B, et al. Hyperketotic states due to inherited defects of ketolysis. Enzyme. 1987;38:80-90.  [PubMed: 2894307]
2. Robinson BH, Sherwood WG, Taylor J, et al. Acetoacetyl CoA thiolase deficiency: a cause of severe ketoacidosis in infancy simulating salicylism. J Pediatr. 1979;95:228.  [PubMed: 36452]

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