3-hydroxy-3-methylglutaryl-CoA Lyase Deficiency

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/3-hydroxy-3-methylglutaryl-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 compounds that are used for energy during periods without food (fasting).

genetic conditions

1. Introduction

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.

2. Frequency

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.

3. Causes

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.

4. Inheritance

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.

5. Other Names for This Condition

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

References

Bischof F, Nägele T, Wanders RJ, Trefz FK, Melms A.3-hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult withleukoencephalopathy. Ann Neurol. 2004 Nov;56(5):727-30.
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. JBiol Chem. 2003 Aug 1;278(31):29016-23.
Gibson KM, Breuer J, Nyhan WL. 3-Hydroxy-3-methylglutaryl-coenzyme A lyasedeficiency: review of 18 reported patients. Eur J Pediatr. 1988 Dec;148(3):180-6.Review.
Mitchell GA, Ozand PT, Robert MF, Ashmarina L, Roberts J, Gibson KM, WandersRJ, Wang S, Chevalier I, Plöchl E, Miziorko H. HMG CoA lyase deficiency:identification of five causal point mutations in codons 41 and 42, including afrequent Saudi Arabian mutation, R41Q. Am J Hum Genet. 1998 Feb;62(2):295-300.
Pie J, Casals N, Puisac B, Hegardt FG. Molecular basis of3-hydroxy-3-methylglutaric aciduria. J Physiol Biochem. 2003 Dec;59(4):311-21.
Pié J, López-Viñas E, Puisac B, Menao S, Pié A, Casale C, Ramos FJ, HegardtFG, Gómez-Puertas P, Casals N. Molecular genetics of HMG-CoA lyase deficiency.Mol Genet Metab. 2007 Nov;92(3):198-209.
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.

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Subjects: Genetics & Heredity

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Catherine Yang

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Entry Collection: MedlinePlus

Update Date: 23 Dec 2020

Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The gene associated with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

4. Inheritance

5. Other Names for This Condition

References