HMGCS2D
Introduction
Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies (ketogenesis).
What is HMGCS2D?
Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is a rare inherited ketogenesis disorder that affects the step in metabolism immediately downstream of fatty‑acid oxidation. When the body has exhausted its stores of available sugars, especially during times of stress, illness, fasting or intense exercise, it must turn to fats and subsequently to ketone bodies to produce energy. Individuals with HMGCS2D may have difficulty producing this energy.
Genetics
HMGCS2D results from biallelic pathogenic variants in the HMGCS2 gene that are inherited from both parents. Carriers of a single pathogenic variant are asymptomatic. If both parents are carriers, each pregnancy carries a 25 % risk that the child will be affected by HMGCS2D.
Signs and Symptoms of HMGCS2D
Patients typically present with an acute metabolic decompensation, most often within the first year of life but after the neonatal period. Usually, patients show episodes of (mostly) hypoketotic hypoglycemia, hepatomegaly and acute encephalopathy, closely resembling disorders of fatty‑acid oxidation. During a metabolic crisis, urine organic acids may reveal dicarboxylic aciduria, often (but not always) in the absence of ketonuria.
How to Diagnose HMGCS2D
Patients with suspected HMGCS2D should undergo blood acylcarnitine profiling by tandem mass spectrometry and urine organic‑acid analysis by GC‑MS, which help to differentiate HMGCS2D from fatty‑acid oxidation disorders affecting earlier metabolic steps. HMGCS2D is confirmed by positive molecular testing for pathogenic HMGCS2 variants.
HMGCS2D Treatment
The mainstay of therapy for HMGCS2D is preventive: the need for ketogenesis must be avoided.
Therefore, prolonged fasting should be avoided and increased energy requirements must be met through regular carbohydrate intake. During acute decompensations, any hypoglycemia should be corrected promptly, followed by a continuous high‑rate intravenous glucose infusion with appropriate electrolyte supplementation.
Investigational Therapies and Fatty Acid Oxidation Research
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