3-hydroxy-3-methylglutaric aciduria

3-Hydroxy-3-methylglutaric aciduria (HMG-CoA lyase deficiency) is a rare inherited metabolic disorder caused by deficiency of the enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase). This enzyme plays a critical role in the breakdown of the amino acid leucine and in ketogenesis — the body's process of producing ketone bodies, which serve as an alternative energy source during fasting or illness. Without functional HMG-CoA lyase, toxic organic acids accumulate in the blood and urine, and the body cannot produce ketone bodies when needed. The condition is also known as HMG-CoA lyase deficiency or 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Symptoms typically present in the first year of life, often triggered by fasting, illness, or metabolic stress. Affected individuals may experience episodes of metabolic crisis characterized by vomiting, lethargy, hypoglycemia (low blood sugar), metabolic acidosis, and hyperammonemia. Without prompt treatment, these crises can lead to seizures, coma, and potentially death. Between episodes, many patients can be relatively well, though some develop chronic neurological complications including developmental delay, intellectual disability, and white matter abnormalities on brain imaging. The liver is commonly affected, with hepatomegaly (enlarged liver) and elevated liver enzymes frequently observed. Cardiomyopathy has also been reported in some cases. Treatment focuses on preventing metabolic crises through dietary management, including avoidance of prolonged fasting and restriction of leucine intake (a low-protein diet supplemented with leucine-free amino acid formulas). During acute episodes, emergency management with intravenous glucose and correction of metabolic acidosis is essential. L-carnitine supplementation is commonly used to help clear accumulated toxic metabolites. With early diagnosis — increasingly possible through newborn screening using tandem mass spectrometry — and careful metabolic management, outcomes have improved significantly, though the long-term prognosis varies among individuals.

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