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3-hydroxy-3-methylglutaryl-CoA lyase deficiency
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA lyase deficiency) is a rare inherited metabolic disorder where the body cannot properly process the amino acid leucine or produce ketones, leading to severe episodes of hypoglycemia and metabolic acidosis, often appearing in infancy.

Overview

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 called leucine. Additionally, the disorder prevents the body from making ketones, which are compounds that are used for energy during periods without food (fasting).

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.

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.

Symptoms

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 (glucose) 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.

Causes & Risk Factors

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.

Learn more about the gene associated with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

  • HMGCL

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.

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

Frequently Asked Questions

Dietary management is crucial and involves a strict low-leucine diet, as the body cannot properly process this amino acid. This means limiting protein intake, especially from high-leucine foods like meat, dairy, and eggs. Additionally, frequent small meals and snacks are necessary to prevent prolonged fasting, which can trigger episodes due to the inability to produce ketones for energy. A specialized medical formula and supplements may be prescribed to ensure adequate nutrition while managing leucine intake. Dietary plans must be carefully managed by a metabolic dietitian.
Critical warning signs of a crisis include sudden, severe vomiting and diarrhea, extreme tiredness (lethargy), poor feeding, weak muscle tone (hypotonia), and unusual breathing patterns. These can rapidly progress to dangerously low blood sugar (hypoglycemia), metabolic acidosis, convulsions, or coma. Emergency medical help should be sought immediately if any of these symptoms appear, especially during an infection, prolonged fasting, or other stress, as prompt treatment is vital to prevent life-threatening complications.
With early diagnosis and strict adherence to dietary and medical management, many individuals with HMG-CoA lyase deficiency can lead relatively healthy lives. However, there can be a risk of developmental delays, intellectual disability, or neurological problems if episodes are frequent or severe, particularly in early life. Regular monitoring by a metabolic specialist, dietitian, and other healthcare providers is essential to manage the condition and minimize long-term complications.
HMG-CoA lyase deficiency is often suspected in infants presenting with symptoms like severe hypoglycemia and metabolic acidosis. Diagnosis typically involves blood and urine tests to detect abnormal levels of specific organic acids and acylcarnitines, which accumulate due to the enzyme deficiency. Genetic testing to identify mutations in the HMGCL gene confirms the diagnosis. In some regions, it may also be detected through newborn screening programs.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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