Ketone body metabolism disorders (HMG-CoA lyase, SCOT, beta-ketothiolase)

Ketone bodies are made in the liver during fasting and used by brain and muscle. A defect can sit on either side, and the two sides look opposite at the bedside.

• Autosomal recessive, HMGCL. The enzyme sits at the junction of leucine catabolism and ketone body synthesis, so the disorder is both an organic acidemia and a ketogenesis defect
• Presents in infancy with hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, vomiting and lethargy, usually triggered by fasting or intercurrent illness
• Hepatomegaly, and a Reye-like picture that is often the initial working diagnosis
• Urine organic acids show 3-hydroxy-3-methylglutaric acid, the specific marker, along with 3-methylglutaconic and 3-hydroxyisovaleric acids
• Notably no ketosis despite hypoglycemia, which is what makes it mimic a fatty acid oxidation defect. Acylcarnitines separate them
• Relatively common in Saudi Arabia and Portugal

• Autosomal recessive, OXCT1 (succinyl-CoA:3-oxoacid CoA transferase), the first committed step of ketone utilisation
• Severe ketoacidotic crises, often starting in the neonatal period or infancy, precipitated by fasting or illness
• In severe cases there is permanent ketosis, present even when well and fed, which is close to pathognomonic
• Urine organic acids show ketosis without a specific abnormal metabolite, so the diagnosis rests on the clinical pattern plus OXCT1 sequencing
• Development is normal between crises

• Autosomal recessive, ACAT1 (mitochondrial acetoacetyl-CoA thiolase, also called T2 deficiency)
• Sits in both isoleucine catabolism and ketolysis, so it behaves as an organic acidemia and a ketone utilisation defect
• Intermittent severe ketoacidotic episodes with normal health in between; the first episode is typically between 6 and 24 months
• Urine organic acids show 2-methyl-3-hydroxybutyric acid and tiglylglycine, which is the specific pattern
• Detectable on newborn screening through elevated C5:1 and C5-OH acylcarnitines

Shared across all three:

• Avoid fasting, with an age-appropriate maximum fasting interval and a written sick-day plan. This is the single most important intervention
• Emergency regimen with intravenous dextrose at the first sign of illness or poor intake, before decompensation
• Treat acidosis; give bicarbonate for severe acidosis in the ketolysis defects
• Mild protein restriction in HMG-CoA lyase and beta-ketothiolase deficiency, both of which involve branched-chain amino acid catabolism
• Carnitine supplementation where deficiency is documented
• Long-term outcome is good when crises are prevented, and poor when they are not, because the damage is done by the metabolic crises themselves