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.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released August 20, 2005; last updated October 4, 2018; expires October 4, 2021


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, patients are completely asymptomatic and show no abnormalities in standard metabolic tests. Therefore, diagnosing 3-hydroxy-3-methylglutaryl-CoA synthase deficiency has been thought to be difficult, and despite the life-threatening nature of the disease, it may remain unrecognized in at least some patients. The author explains that the disease should be easy to recognize when adequate samples are obtained in the acute crisis. The diagnosis is confirmed through sequence analysis of the HMGCS2 gene on chromosome 1p12.

Key points


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 HMG-CoA synthase can lead to hypoglycemia, coma, and probably death at times of fasting, but has no known adverse effects outside fasting periods.


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


• Treatment is restricted to avoidance of prolonged fasting periods; no other (drug) treatment is indicated.

Historical note and terminology

A genetic deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (protein abbreviation HMCS2, 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 a number of additional patients (Morris et al 1998; Aledo et al 2001; Aledo et al 2006; Bouchard et al 2001; Zschocke et al 2002; Wolf et al 2003). 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 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; Mascaro et al 1995; 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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