<scp>HMG</scp>‐<scp>CoA</scp> Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease

Mitochondrial HMG-CoA synthase-2 (HMGCS2) deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, hepatomegaly, and encephalopathy with onset between 3 and 36 months of age. Approximately 50 cases were reported worldwide. We describe two patients with HMGCS2 deficiency. Patient 1 presented on day of life 7 with a sepsis-like condition, coma, metabolic acidosis, and marked elevation of ammonium level at 1081 μmol/L. Metabolic screening demonstrated elevated valine and leucine/isoleucine concentrations, resembling maple syrup urine disease (MSUD). The patient received a blood exchange transfusion, which lowered the ammonium level to 92 μmol/L. Urine organic acid analysis did not confirm MSUD. At 1 year and 4 months, the patient experienced acute decompensation again. Exome sequencing revealed a homozygous <i>HMGCS2</i> variant, c.1502G>C (p.Arg501Pro). Patient 2, an older sibling of Patient 1, was healthy but diagnosed through genetic testing. Both patients exhibited abnormal biochemical profiles, including dicarboxylic aciduria and increased urinary excretion of 4-hydroxy-6-methyl-2-pyrone (4-HMP) after 8 h of fasting, suggesting that a clinically asymptomatic patient, like Patient 2, may eventually develop acute decompensation. Therefore, preemptive treatment with fasting avoidance with or without l-carnitine during intercurrent illness should be advised. The present cases were the second and third patients of p.Arg501Pro homozygosity. The elevated branched-chain amino acids in the metabolic screening (without including alloisoleucine) and the described organic acid profile can be found during the catabolic state, resembling MSUD, and severe hyperammonemia is an uncommon phenotype and an exception to neonatal decompensation in HMGCS2 deficiency. Our findings demonstrated intrafamilial variability and expanded the clinical and biochemical spectrum of HMGCS2 deficiency.