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Genetics Home Reference: your guide to understanding genetic conditions
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3-hydroxy-3-methylglutaryl-CoA lyase deficiency

(often shortened to HMG-CoA lyase deficiency)
Reviewed October 2008

What is HMG-CoA lyase deficiency?

3-hydroxy-3-methylglutaryl-CoA lyase deficiency (also known as HMG-CoA lyase deficiency) is an uncommon inherited disorder in which the body cannot process a particular protein building block (amino acid) called leucine. Additionally, the disorder prevents the body from making ketones, which are used for energy during periods without food (fasting).

The signs and symptoms of HMG-CoA lyase deficiency usually appear within the first year of life. The condition causes episodes of vomiting, diarrhea, dehydration, extreme tiredness (lethargy), and weak muscle tone (hypotonia). During an episode, blood sugar levels can become dangerously low (hypoglycemia), and a buildup of harmful compounds can cause the blood to become too acidic (metabolic acidosis). If untreated, the disorder can lead to breathing problems, convulsions, coma, and death. Episodes are often triggered by an infection, fasting, strenuous exercise, or other types of stress.

HMG-CoA lyase deficiency is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

How common is HMG-CoA lyase deficiency?

HMG-CoA lyase deficiency is a rare condition; it has been reported in fewer than 100 individuals worldwide. Most people diagnosed with this disorder have been from Saudi Arabia, Portugal, or Spain.

What genes are related to HMG-CoA lyase deficiency?

Mutations in the HMGCL gene cause HMG-CoA lyase deficiency. The HMGCL gene provides instructions for making an enzyme known as 3-hydroxymethyl-3-methylglutaryl-coenzyme A lyase (HMG-CoA lyase). This enzyme plays a critical role in breaking down dietary proteins and fats for energy. Specifically, it is responsible for processing leucine, an amino acid that is part of many proteins. HMG-CoA lyase also produces ketones during the breakdown of fats. Ketones are compounds that certain organs and tissues, particularly the brain, use for energy when the simple sugar glucose is not available. For example, ketones are important sources of energy during periods of fasting.

If a mutation in the HMGCL gene reduces or eliminates the activity of HMG-CoA lyase, the body is unable to process leucine or make ketones properly. When leucine is not processed normally, a buildup of chemical byproducts called organic acids can result in metabolic acidosis. A shortage of ketones often leads to hypoglycemia. Metabolic acidosis and hypoglycemia can damage cells, particularly in the brain, resulting in serious illness in children with HMG-CoA lyase deficiency.

Related Gene(s)

Changes in this gene are associated with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

  • HMGCL

How do people inherit HMG-CoA lyase deficiency?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of HMG-CoA lyase deficiency?

These resources address the diagnosis or management of HMG-CoA lyase deficiency and may include treatment providers.

  • Baby's First Test (http://www.babysfirsttest.org/newborn-screening/conditions/3-hydroxy-3-methylglutaric-aciduria)
  • Gene Review: Organic Acidemias Overview (http://www.ncbi.nlm.nih.gov/books/NBK1134)
  • Genetic Testing Registry: Deficiency of hydroxymethylglutaryl-CoA lyase (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268601)

You might also find information on the diagnosis or management of HMG-CoA lyase deficiency in Educational resources (http://www.ghr.nlm.nih.gov/condition/3-hydroxy-3-methylglutaryl-coa-lyase-deficiency/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/3-hydroxy-3-methylglutaryl-coa-lyase-deficiency/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about HMG-CoA lyase deficiency?

You may find the following resources about HMG-CoA lyase deficiency helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for HMG-CoA lyase deficiency?

  • Deficiency of hydroxymethylglutaryl-CoA lyase
  • 3HMG
  • HMG
  • 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency
  • Hydroxymethylglutaric aciduria
  • 3-OH 3-CH3 glutaric aciduria
  • 3-OH 3-methyl glutaric aciduria

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about HMG-CoA lyase deficiency?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding HMG-CoA lyase deficiency?

acidosis ; acids ; aciduria ; amino acid ; autosomal ; autosomal recessive ; breakdown ; catabolism ; cell ; CoA ; coenzyme A ; coma ; deficiency ; dehydration ; enzyme ; fasting ; gene ; glucose ; hypoglycemia ; hypotonia ; infection ; inherited ; ketogenesis ; lethargy ; leucine ; methyl ; muscle tone ; mutation ; newborn screening ; OH ; protein ; recessive ; screening ; simple sugar ; stress ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Bischof F, Nägele T, Wanders RJ, Trefz FK, Melms A. 3-hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult with leukoencephalopathy. Ann Neurol. 2004 Nov;56(5):727-30. (http://www.ncbi.nlm.nih.gov/pubmed/15505778?dopt=Abstract)
  • Casals N, Gómez-Puertas P, Pié J, Mir C, Roca R, Puisac B, Aledo R, Clotet J, Menao S, Serra D, Asins G, Till J, Elias-Jones AC, Cresto JC, Chamoles NA, Abdenur JE, Mayatepek E, Besley G, Valencia A, Hegardt FG. Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. J Biol Chem. 2003 Aug 1;278(31):29016-23. Epub 2003 May 13. (http://www.ncbi.nlm.nih.gov/pubmed/12746442?dopt=Abstract)
  • Gibson KM, Breuer J, Nyhan WL. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr. 1988 Dec;148(3):180-6. Review. (http://www.ncbi.nlm.nih.gov/pubmed/3063529?dopt=Abstract)
  • Mitchell GA, Ozand PT, Robert MF, Ashmarina L, Roberts J, Gibson KM, Wanders RJ, Wang S, Chevalier I, Plöchl E, Miziorko H. HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. Am J Hum Genet. 1998 Feb;62(2):295-300. (http://www.ncbi.nlm.nih.gov/pubmed/9463337?dopt=Abstract)
  • Pie J, Casals N, Puisac B, Hegardt FG. Molecular basis of 3-hydroxy-3-methylglutaric aciduria. J Physiol Biochem. 2003 Dec;59(4):311-21. (http://www.ncbi.nlm.nih.gov/pubmed/15164951?dopt=Abstract)
  • Pié J, López-Viñas E, Puisac B, Menao S, Pié A, Casale C, Ramos FJ, Hegardt FG, Gómez-Puertas P, Casals N. Molecular genetics of HMG-CoA lyase deficiency. Mol Genet Metab. 2007 Nov;92(3):198-209. Epub 2007 Aug 9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17692550?dopt=Abstract)
  • Yalçinkaya C, Dinçer A, Gündüz E, Fiçicioğlu C, Koçer N, Aydin A. MRI and MRS in HMG-CoA lyase deficiency. Pediatr Neurol. 1999 May;20(5):375-80. Review. (http://www.ncbi.nlm.nih.gov/pubmed/10371384?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: October 2008
Published: October 20, 2014