Use of sodium D, L-3-hydroxybutyrate as adjunct therapy in two siblings with HMG-CoA lyase deficiency

Abstract

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare autosomal recessive mitochondrial disease characterised by recurrent life-threatening metabolic crises generally presenting in neonates or infancy during catabolic stress triggered by prolonged fasting or intercurrent illness. Acute decompensations with lethargy, vomiting, hypoketotic hypoglycemia and metabolic acidosis may evolve into Reye-like syndrome if untreated, with acute liver failure, hyperammonemic encephalopathy, dilated cardiomyopathy, and death in 20% of cases. Long-term health complications include psychomotor retardation, white matter abnormalities, epilepsy, hepatic steatosis, pancreatitis, cardiomyopathy, and arrythmia. The mitochondrial enzyme catalyses the cleavage of HMG-CoA to acetyl-CoA and acetoacetate, the common final step of ketogenesis and leucine degradation, resulting in diagnostic urinary organic acid pattern (elevated 3-hydroxy-3-methylglutaric, 3-methylgutaconic, 3-methylglutaric, and 3-hydroxyisovaleric acids) with the absence of ketonuria, when deficient. Therapeutic interventions include dietary protein or leucine and fat restriction, carnitine supplementation, avoidance of fasting, and use of carbohydrate-based high caloric intake when unwell. We describe the clinical course and diagnostic work-up in two affected siblings, with the proband presenting with severe neonatal onset disease with metabolic acidosis, non-ketotic hypoglycaemia, hyperammonemia and white matter changes on brain MRI. High-risk screening for a younger sibling led to pre-emptive management with good outcomes. Sodium D, L-3-hydroxybutyrate (S-DL-3OHB) was used in both siblings as an adjunct therapy to prevent cerebral dysfunction and cardiomyopathy, with the rationale that decreased ketogenesis in this disorder may impact the major energy source for the brain and heart during starvation. S-DL-3OHB therapy is a well-tolerated and effective therapeutic option for this disorder.