HMG-CoA lyase deficiency

Jorn Oliver Sass Dr rer nat (Dr. Sass of Bonn-Rhein Sieg University of Applied Sciences has no relevant financial relationships to disclose.)
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 March 30, 1995; last updated January 31, 2019; expires January 31, 2022

This article includes discussion of HMG-CoA lyase deficiency, 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, 3-Hydroxy-3-methylglutaric aciduria, and HMGCL deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


HMG-CoA lyase deficiency is an inborn error of metabolism resulting in impaired ketogenesis. The catabolism of leucine is also affected, and several metabolites accumulate that probably have toxic potential. The disease is characterized by life-threatening metabolic derangements with hypoketotic hypoglycemia and metabolic acidosis, often manifesting within the early neonatal period; the remainder of patients typically present within the first year of life. As with many other organic acidurias, in HMG-CoA lyase deficiency early diagnosis and early initiation of appropriate treatment appear important for a good outcome.

Key points


• Deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase (HMG-CoA lyase) is an organic aciduria with impaired ketogenesis and leucine catabolism.


• HMG-CoA lyase deficiency is characterized by life-threatening metabolic derangement with hypoketotic hypoglycemia and metabolic acidosis.


• HMG-CoA lyase deficiency is an autosomal recessive disorder due to mutations in the HMGCL gene.


• Complications can probably be minimized by early diagnosis and appropriate treatment, including avoidance of prolonged fasting.

Historical note and terminology

3-hydroxy-3-methylglutaryl coenzyme A lyase (HMG-CoA lyase) catalyzes the final step of ketogenesis and leucine metabolism, the cleavage of HMG-CoA yielding acetyl-CoA and acetoacetate (Sass 2012; Fukao et al 2014; Sass et al 2018). Inborn deficiency of HMG-CoA lyase results in 3-hydroxy-3-methylglutaric aciduria. The first patient reported with HMG-CoA lyase deficiency was a boy who presented at 7 months of age with diarrhea and vomiting that were associated with lethargy, pallor, dehydration and events of cyanosis and apnea (Faull et al 1976a). Metabolic acidosis and hypoglycemia were noted and Reye syndrome was suspected. Urine samples obtained after clinical onset showed a pattern of organic acids with highly elevated concentrations of 3-hydroxy-iso-valeric, 3-methylglutaric, 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids. The patient recovered completely after intensive care and several days of intravenous fluids. Several aspects of his metabolic disease (including confirmation of HMG-CoA lyase deficiency in skin fibroblasts and in leukocytes) and his further development have been addressed in a number of subsequent reports (Faull et al 1976b; Wysocki et al 1976; Wysocki and Hahnel 1976a; Wysocki and Hahnel 1976b; Wysocki and Hahnel 1978; Wysocki and Hahnel 1986; Shilkin et al 1981). At the age of 10 years he has been considered healthy on a self-regulated diet high in potatoes and citrus cordials. However, the boy lacked attention at school, required special teaching and has broken both arms a total of 9 times. Occasional attacks with lethargy, pallor, nausea and vomiting occur and are managed by supplementing glucose intake (Wysocki and Hahnel 1986).

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