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Ketolysis involves esterification of acetylacetate (AcAc) to AcAc-coenzyme A (CoA) by succinyl-CoA:3-oxoacid transferase (SCOT, OXCT1 gene) and hydrolysis of AcAcCoA by mitochondrial acetoacetyl-CoA thiolase (T2, ACAT1 gene) to form acetyl-CoA. Inherited disorders of ketolysis involve these 2 enzymes and cause persistent or episodic ketoacidosis. If SCOT is entirely lacking, ketolysis is completely blocked, but if functional T2 is completely absent, some ketolysis is still possible, likely due to the presence of another mitochondrial enzyme, medium chain 3-ketoacyl-CoA thiolase, that has some activity for hydrolyzing AcAcCoA. This latter enzyme may explain in part why permanent ketosis is often observed in SCOT deficiency but not in T2 deficiency. Ketone body production is regulated by the hormones glucagon and catecholamines, which induce free fatty acid (FFA) mobilization from adipose tissue, fatty acid oxidation, and ketogenesis in the liver, while insulin suppresses these steps. Ketogenic stresses including fasting, prolonged exertion, febrile illnesses, and vomiting and diarrhea, leading to both FFA oxidation and ketone body synthesis. The enzymes of ketogenesis (see Chapter 146); hydroxymethylglutaryl-CoA synthase and lyase, generate AcAc, which is then reduced by mitochondrial D-β-hydroxybutyrate (D-βOHB)-dehydrogenase (BDH1) in the liver to D-βOHB. Ketone bodies then circulate to peripheral tissues, where BDH1 regenerates AcAc, allowing SCOT and T2 to generate acetyl-CoA in order to maintain cellular energy production via the tricarboxylic acid (TCA) cycle and spare glucose utilization.
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SUCCINYL-CoA TRANSFERASE DEFICIENCY
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SCOT deficiency (Online Mendelian Inheritance in Man [MIM] no. 245050) is characterized by persistent or exaggerated episodic ketoacidosis, often beginning in infancy, with increased levels of ketone bodies in the blood even in the fed state. A 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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BETA-KETOTHIOLASE DEFICIENCY
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Mitochondrial 3-ketothiolase releases acetyl-CoA from AcAcCoA and from 2-methylacetoacetyl-CoA, an intermediate in isoleucine oxidation (see Chapter 132). Mitochondrial 3-ketothiolase deficiency (MIM no. 203750) can present in infancy with hypoglycemia, elevated transaminases, hyperuricemia, metabolic acidosis, and severe ketosis, or later with fasting- or protein-induced episodes of vomiting, hepatomegaly, ketoacidosis, and encephalopathy.
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In SCOT deficiency, levels of ketones in the blood may be persistently elevated or show episodic increases during illness. Urine organic acid analysis shows increased 3-hydroxybutyrate and acetoacetate levels. In beta-ketothiolase deficiency, urine organic acid analysis shows increased 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine levels, but they may be obscured during acute illnesses by 3-hydroxybutyrate (3HB) and AcAc and may be detectable only between episodes or after an oral load of isoleucine. Glycine levels are often elevated in blood and urine. In blood acylcarnitine analysis, C5:1 acylcarnitine (tiglylcarnitine) and C5-OH acylcarnitine (2-methyl-3-hydroxybutyrylcarnitine) may be elevated, but this is not a consistent finding, and the disorder is not readily detectable by newborn screening. While usually not necessary to establish a diagnosis, the enzyme defects can be demonstrated ...