HMG-CoA lyase

**Function and location** - Mitochondrial enzyme (gene HMGCL, chromosome 1p36). A peroxisomal isoform also exists. - Reaction: HMG-CoA → acetoacetate + acetyl-CoA. - Roles: (1) final step of ketone body synthesis in hepatic mitochondria, and (2) final step of leucine degradation (leucine is a purely ketogenic amino acid).

**Ketogenesis pathway (liver mitochondria)** - 2 acetyl-CoA → acetoacetyl-CoA (thiolase) - Acetoacetyl-CoA + acetyl-CoA → HMG-CoA (**HMG-CoA synthase**, the rate-limiting step) - HMG-CoA → acetoacetate + acetyl-CoA (**HMG-CoA lyase**) - Acetoacetate → β-hydroxybutyrate (β-hydroxybutyrate dehydrogenase) or spontaneously → acetone

**Don't confuse with:** - **HMG-CoA reductase**: cytosolic, rate-limiting enzyme of cholesterol synthesis, inhibited by statins. - **HMG-CoA synthase**: mitochondrial isoform (ketogenesis) vs cytosolic isoform (cholesterol synthesis).

**HMG-CoA lyase deficiency** - Autosomal recessive inborn error of ketogenesis and leucine catabolism. It is more common in Saudi Arabia, Portugal, and Spain. - Pathophysiology: Fasting normally depends on ketones for fuel as glucose runs out. Without HMG-CoA lyase, ketones can't be made, so glucose use rises and hypoglycemia follows. HMG-CoA accumulates and is diverted to 3-hydroxy-3-methylglutarate, 3-methylglutaconate, and 3-hydroxyisovalerate. - Presentation: Usually in the first year of life, often during fasting or illness. Findings include vomiting, lethargy, hypotonia, seizures, and coma. Hepatomegaly can occur, and Reye-like episodes are possible. - Labs: - **Hypoketotic hypoglycemia** (an inappropriately low ketone level for the degree of hypoglycemia) - Metabolic acidosis (anion gap), caused by organic acid accumulation - Hyperammonemia and elevated liver enzymes - Urine organic acids: ↑ 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric, and 3-hydroxyisovaleric acids - Acylcarnitine profile: ↑ 3-hydroxyisovalerylcarnitine (C5-OH) and 3-methylglutarylcarnitine (C6DC) - Diagnosis: Urine organic acids, acylcarnitine profile, and enzyme assay or HMGCL gene sequencing. - Treatment: Avoid fasting and give frequent feeds. Restrict dietary protein, especially leucine, and fat. Give IV dextrose during acute episodes, correct the acidosis, and supplement carnitine.

**Differential for hypoketotic hypoglycemia** - Fatty acid oxidation defects (e.g., MCAD deficiency). These also cause hypoketosis, but urine shows dicarboxylic acids and no 3-hydroxy-3-methylglutaric acid. - HMG-CoA lyase deficiency and HMG-CoA synthase deficiency (HMGCS2) impair ketogenesis directly. - Hyperinsulinism.

**High-yield takeaways** - Leucine is exclusively ketogenic, and lysine is the other exclusively ketogenic amino acid. - Hypoketotic hypoglycemia plus 3-hydroxy-3-methylglutaric aciduria points to HMG-CoA lyase deficiency.