3-Hydroxy-3-Methylglutaric Aciduria · HMG

Description

3-Hydroxy-3-methylglutaric aciduria, HMG, is an autosomal recessive disorder of leucine catabolism and ketogenesis. The enzyme 3-hydroxy-3-methylglutaryl-CoA lyase, encoded by HMGCL on chromosome 1, catalyzes the final step of leucine catabolism and the same final step of mitochondrial ketogenesis from acetyl-CoA. Pathogenic variants in HMGCL reduce or abolish enzyme activity. 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid accumulate in urine. Because ketone body production is blocked at the same step, affected children cannot generate ketones during fasting; the metabolic crisis is hypoketotic hypoglycemia rather than ketoacidosis.

The classical presentation is acute decompensation in the first year of life, often the first six months, triggered by fasting, infection, or weaning from frequent feeds. Vomiting, lethargy, hypotonia, hepatomegaly, and severe hypoglycemia without appropriate ketonemia develop, and the picture can be mistaken for Reye syndrome. Hyperammonemia and metabolic acidosis are often present. Untreated, mortality at first crisis is significant, and survivors of severe crises can have residual neurological injury. A subset of children present later in childhood with milder episodic features.

Detection is by newborn screening on the dried blood spot, using tandem mass spectrometry to identify elevated 3-hydroxyisovalerylcarnitine, C5-OH, often accompanied by elevated 3-methylglutarylcarnitine, C6DC. C5-OH is shared with isovaleric acidemia, 3-MCC, holocarboxylase synthetase deficiency, biotinidase deficiency, and beta-ketothiolase deficiency. Confirmation uses urine organic acids showing the characteristic profile, plasma acylcarnitines, and HMGCL sequencing. HMG is rare worldwide. The largest reported clusters are from Saudi Arabia and the Iberian peninsula, attributed to founder variants and consanguinity, and most published cohort data come from those populations.

Treatments to date

There is no FDA-approved disease-specific drug therapy for HMG. Standard of care is preventive. Families avoid prolonged fasting and follow age-appropriate feeding intervals. Sick-day protocols provide oral carbohydrate at home and prompt intravenous dextrose at the emergency department when oral intake fails. A modestly fat-restricted, modestly protein-restricted diet is used in some centers; the degree of restriction varies. L-carnitine supplementation is used when secondary carnitine depletion is documented. An emergency letter and a medical alert identifier travel with the child.

Acute decompensations are managed with intravenous dextrose at high infusion rates, correction of acidosis, fluid resuscitation, and ammonia scavengers when hyperammonemia is present. Hemofiltration or hemodialysis is reserved for severe acidosis or refractory hyperammonemia. Long-term outcomes are good when crises are prevented from the neonatal period. The benefit of newborn screening is largest for HMG because prevention of the first hypoketotic hypoglycemic episode prevents the principal source of morbidity and mortality. Disease-specific therapies including substrate reduction and gene-based approaches are in preclinical development.