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).

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.

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.

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.

Normal Function

The HMGCL gene provides instructions for making an enzyme called 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMG-CoA lyase). This enzyme is found in mitochondria, which are the energy-producing centers inside cells. HMG-CoA lyase plays a critical role in breaking down proteins and fats from the diet. Specifically, it is responsible for processing leucine, a protein building block (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.

Health Conditions Related to Genetic Changes

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

More than 25 mutations in the HMGCL gene have been identified in people with 3-hydroxymethyl-3-methylglutaryl-CoA lyase deficiency (also called HMG-CoA lyase deficiency). Most of these mutations change single amino acids in the HMG-CoA lyase enzyme. For example, the most common mutation in the Saudi Arabian population replaces the amino acid arginine with the amino acid glutamine at position 41 (written as Arg41Gln or R41Q). Other HMGCL mutations result in the production of an abnormally short enzyme that is missing critical segments.

If a mutation 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, chemical byproducts called organic acids can build up and make the blood too acidic (metabolic acidosis). A shortage of ketones can cause blood glucose levels to become dangerously low (hypoglycemia). The effects of metabolic acidosis and hypoglycemia can damage cells, particularly in the brain, resulting in serious illness in children with HMG-CoA lyase deficiency.

Other Names for This Gene

• 3-hydroxy-3-methylglutarate-CoA lyase
• 3-hydroxy-3-methylglutaryl-Coenzyme A lyase
• 3-hydroxymethyl-3-methylglutaryl-CoA lyase
• 3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase
• HL
• HMG-CoA lyase
• HMGCL_HUMAN

Genomic Location

HMG-CoA lyase deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• HMG-CoA lyase deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking HMGCL gene to their baby. Only babies with two nonworking HMGCL genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the HMGCL gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the HMGCL gene, they have a 1 in 4 chance of having a child with HMG-CoA lyase deficiency.
  • Carriers for HMG-CoA lyase deficiency often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with HMG-CoA lyase deficiency.
  • Parents who already have a child with HMG-CoA lyase deficiency still have a 1 in 4 chance of having another child with HMG-CoA lyase deficiency. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of HMG-CoA lyase deficiency vary widely. They often appear within the first few days or months of life. They may also appear later in childhood, and rarely, in adulthood.

Signs of the condition may include the following:

• Vomiting
• Diarrhea
• Dehydration
• Sleeping longer or more often (lethargy)
• Floppy arms and legs (hypotonia)
• Low blood sugar levels (hypoglycemia)
• Behavior changes
• Gets upset easily
• Low number of red blood cells (anemia)
• Seizures

Newborn screening for HMG-CoA lyase deficiency is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of certain substances (called acylcarnitines) are in your baby’s blood. The body makes these substances when it breaks down food. Babies with high levels of these substances might have HMG-CoA lyase deficiency.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for HMG-CoA lyase deficiency is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing. An out-of-range result can mean that your baby has one of several possible conditions. It is important to do follow-up testing to correctly identify the condition causing your baby’s result.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition may happen. Screening samples collected too early (before your baby is 24 hours old) may affect the results of screening.

Some babies may have a false-positive result for HMG-CoA lyase deficiency because their mother has high acylcarnitine levels. These babies do not have and will not develop HMG-CoA lyase deficiency. More testing on both mom and baby will determine who has high acylcarnitine levels.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Frequent feedings to avoid long periods without food
• Following strict emergency guidelines when sick
• L-carnitine supplements
• Special diet in some cases

Children who receive early and ongoing treatment for HMG-CoA lyase deficiency can have healthy growth and development.

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.