3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: case report of a child with rare HMGCL gene variants

Abstract Objectives 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessive organic aciduria. Most patients present within the first year of life with metabolic decompensation, which can cause neurological damage or death if untreated. Case presentation A 20-month-old previously healthy boy was admitted to the hospital after a nocturnal seizure. Upon admission, the child was unconscious and laboratory analysis revealed severe hypoglycemia and metabolic acidosis without ketonuria. Hypoglycemia was corrected with a bolus of 10 % glucose followed by continuous glucose-electrolyte infusion. Status epilepticus was treated with midazolam and phenobarbital. Magnetic resonance imaging (MRI) performed on the second hospital day, revealed bilateral and symmetric T2 hyperintense lesions in the cortex, supratentorial white matter, basal ganglia and central pons, along with slight white matter volume reduction. Urinary organic acids indicated HMGCLD. HMG-CoA lyase activity in immortalized lymphocytes was significantly decreased. Sanger sequencing of the HMGCL gene identified a heterozygous sequence variant, c.796T>C, p.(Cys266Arg). MLPA analysis showed a reduced gene dosage for exons 3 and 4 of HMGCL , consistent with a heterozygous deletion. Upon diagnosis, a low-protein diet was recommended, as well as oral l -carnitine therapy with a high-calorie supplement drink at night. Initially, the child had slightly impaired psychomotor development, which normalized by age 3.5. He was without metabolic crises or seizures since diagnosis. Conclusions In any child presenting with hypoketotic hypoglycemia and metabolic acidosis of unknown etiology, HMGCLD should be considered. Given the rarity of HMGCLD and its sporadic cases across Europe, management should involve a well-experienced multidisciplinary team.