Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Johannes Zschocke MD PhD (Dr. Zschocke of the Medical University of Innsbruck has no relevant financial relationships to disclose.)
Jennifer Friedman MD, editor. (

Dr. Friedman of the University of California San Diego has no relevant financial relationships to disclose.

Originally released August 20, 2005; last updated February 21, 2021; expires February 21, 2024


Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, the rate-limiting enzyme in hepatic ketogenesis, causes potentially life-threatening hypoglycemic hypoketotic coma during fasting periods. In the normal, nonfasting state, most patients are asymptomatic and show no abnormalities in standard metabolic tests. Cases with acute severe metabolic acidosis, fatty liver, and dyslipidemia without hypoglycemia have been reported. The author explains that the disease should be easy to recognize when adequate samples are obtained for metabolic analyses in the acute crisis. The diagnosis is confirmed through sequence analysis of the HMGCS2 gene on chromosome 1p12.

Key points


• Mitochondrial HMG-CoA synthase is required for the generation of ketone bodies that provide chemical energy to the brain and other organs at times of fasting.


• The genetic deficiency of mitochondrial HMG-CoA synthase can lead to hypoketotic hypoglycemia, coma, and death at times of fasting and metabolic stress. Some patients may show acute severe metabolic acidosis, fatty liver, and dyslipidemia sometimes without hypoglycemia.


• There are usually no known adverse effects outside catabolic periods.


• The diagnosis is based on biochemical findings during fasting periods and molecular genetics analysis.


• Treatment is mostly based on the avoidance of prolonged fasting periods; no other (drug) treatment is necessary in most patients.

Historical note and terminology

A genetic deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2, EC as a cause of fasting hypoketotic coma in a child was first recognized in 1997 (Thompson et al 1997) and has since been reported in more than 30 patients (Pitt et al 2015; Conboy et al 2018; Puisac et al 2018; Lee et al 2019; Liu et al 2019). Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase has to be distinguished from its cytosolic isoform, which catalyzes the rate-limiting first step of cholesterol biosynthesis and is encoded by a different gene. The HMGCS2 gene for mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase is located on chromosome 1p12. The full cDNA sequence and gene structure were identified by 1997 (Boukaftane et al 1994; Boukaftane and Mitchell 1997). The crystal structure of human mitochondrial HMG-CoA synthase was published in 2010 (Shafqat et al 2010). Guidelines for the diagnosis of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency were published in 2002 (Zschocke et al 2002).

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