ketothiolase

**Enzyme/biochemistry** - Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2, gene ACAT1) works in two pathways: 1. **Isoleucine catabolism:** it cleaves 2-methylacetoacetyl-CoA into propionyl-CoA and acetyl-CoA. 2. **Ketolysis (ketone body utilization in extrahepatic tissues):** acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA:3-oxoacid CoA transferase (SCOT, also called thiophorase). Ketothiolase then cleaves acetoacetyl-CoA into 2 acetyl-CoA, which enter the TCA cycle. - The reverse reaction (thiolase condensing 2 acetyl-CoA into acetoacetyl-CoA) is the first step of ketogenesis and cholesterol synthesis. This step uses cytosolic or mitochondrial thiolase (ACAT2/ACAT1), and the next step uses HMG-CoA synthase. - The liver lacks SCOT, so it makes ketones but cannot use them.

**Pathophysiology of deficiency (T2 deficiency, a "mitochondrial acetoacetyl-CoA thiolase deficiency")** - It is autosomal recessive. - Isoleucine breakdown is blocked, so 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate and tiglylglycine accumulate. - Ketone utilization is impaired, so ketones accumulate during catabolic stress.

**Clinical features** - Intermittent episodes of severe ketoacidosis, vomiting, dehydration and lethargy, which may progress to coma. These are triggered by fasting, febrile illness or a high-protein meal. - Onset is typically in infancy or early childhood (6-24 months), and development is often normal between episodes. - Labs show a high anion gap metabolic acidosis, ketonuria and sometimes hyperammonemia or hypoglycemia (the latter less typical).

**Diagnosis** - Urine organic acids show 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate and tiglylglycine. - The blood acylcarnitine profile shows elevated C5:1 (tiglylcarnitine) and C5-OH. - Confirm with ACAT1 genetic testing or an enzyme assay.

**Treatment** - Acute episodes: IV dextrose (to suppress lipolysis and ketogenesis), fluids and bicarbonate as needed. - Long term: avoid fasting, with moderate protein restriction (isoleucine) and carnitine supplementation as needed.

**High-yield board points** - Ketoacidosis with a normal or modest glucose level in a child should make you think of a ketolysis defect (T2 or SCOT deficiency) in addition to DKA. - Contrast with SCOT deficiency, which causes persistent ketosis even when the patient is well. T2 deficiency causes episodic ketosis. - Contrast with the MSUD, propionic acidemia and methylmalonic acidemia branches of branched-chain amino acid metabolism. - Ketolysis defects are not hypoketotic. Fatty acid oxidation defects (e.g., MCAD deficiency) cause hypoketotic hypoglycemia, which is the opposite pattern.