It is a mitochondrial enzyme that catalyzes the second and rate-limiting reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting, by addition of a third acetyl group to acetoacetyl-CoA, producing HMG-CoA.

[5] Mutations in this gene are associated with mitochondrial HMG-CoA synthase deficiency (also known as HMGCS2D), affecting ketone body synthesis.

[7] Affected patients are unable to perform ketogenesis during starvation and times of higher energy need such as fever and vigorous exercise.

Commonly found is damage to heart muscles and the brain, along with hypoglycemia (not always present)[8] and elevated blood fatty acid concentration.

[9] Urine organic acid analysis can be used to detect likely cases, which can be further confirmed using DNA sequencing.