Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a condition that prevents the body from converting certain fats into energy, particularly during periods without food (fasting).

There are three forms of VLCAD deficiency, and they are defined by when the signs and symptoms of the condition begin. The early-onset form is the most severe and begins in infancy. Signs and symptoms can include lack of energy (lethargy) and muscle weakness. People with VCLAD deficiency can have low blood sugar (glucose), known as hypoglycemia. Affected individuals are also at risk for serious complications such, as liver abnormalities and life-threatening heart problems.

Individuals with childhood-onset VLCAD deficiency typically experience an enlarged liver (hepatomegaly) and low blood glucose. This form is sometimes referred to as the hepatic or hypoketotic hypoglycemic form because of these signs. Additional signs and symptoms include other liver problems or muscle weakness.

The adult-onset form, which begins in adolescence or adulthood, usually involves muscle pain and the breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a large amount of a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). Myoglobinuria causes the urine to be red or brown.

In both children and adults, problems related to VLCAD deficiency can be triggered by periods of fasting, illness, exercise, and exposure to hot or cold temperatures. In children, this disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome occur in children who take aspirin during these viral infections.

Variants (also called mutations) in the ACADVL gene cause VLCAD deficiency. This gene provides instructions for making an enzyme called very long-chain acyl-CoA dehydrogenase, which is required to break down (metabolize) a group of fats called very long-chain fatty acids. These fatty acids are found in foods and the body's fat tissues. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.

Variants in the ACADVL gene lead to a shortage (deficiency) of the VLCAD enzyme within cells. When cells do not have enough of this enzyme, very long-chain fatty acids are not broken down properly. As a result, these fats are not converted to energy, which can lead to signs and symptoms of the disorder such as lethargy and hypoglycemia. Very long-chain fatty acids or partially metabolized fatty acids may also build up in tissues and damage the heart, liver, and muscles. This abnormal buildup causes the other signs and symptoms of VLCAD deficiency.

Normal Function

The ACADVL gene provides instructions for making an enzyme called very long-chain acyl-CoA dehydrogenase (VLCAD). This enzyme functions within mitochondria, the energy-producing centers in cells. Very long-chain acyl-CoA dehydrogenase is essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them to energy.

Very long-chain acyl-CoA dehydrogenase is required to break down a group of fats called very long-chain fatty acids. These fatty acids are found in food and body fat. Fatty acids are a major source of energy for the heart and muscles. During periods without food (fasting), fatty acids are also an important energy source for the liver and other tissues.

Health Conditions Related to Genetic Changes

Very long-chain acyl-CoA dehydrogenase deficiency

Variants (also known as mutations) in the ACADVL gene have been found to cause very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Many of these variants change single protein building blocks (amino acids) in the VLCAD enzyme. Other variants delete part of the ACADVL gene or create a premature stop signal in the instructions for making VLCAD. These variants lead to a change in the enzyme's structure, severely reducing or eliminating its activity. As a result, very little functional enzyme is produced.

With a shortage (deficiency) of functional VLCAD enzyme, very-long chain fatty acids are not broken down properly. As a result, these fats are not converted to energy, which can lead to signs and symptoms of this disorder such as the lack of energy (lethargy) and low blood glucose (hypoglycemia). Very long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the heart, liver, and muscles. This abnormal buildup causes the other signs and symptoms of VLCAD deficiency.

Other Names for This Gene

• ACAD6
• ACADV_HUMAN
• acyl-CoA dehydrogenase, very long chain
• acyl-coenzyme A dehydrogenase, very long chain
• LCACD
• VLCAD

Genomic Location

VLCAD deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• VLCAD deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking ACADVL gene to their baby. Only babies with two nonworking ACADVL genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ACADVL 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 ACADVL gene, they have a 1 in 4 chance of having a child with VLCAD deficiency.
  • Carriers for VLCAD 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 VLCAD deficiency.
  • Parents who already have a child with VLCAD deficiency still have a 1 in 4 chance of having another child with VLCAD 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 VLCAD deficiency can vary widely and may appear anytime from a few months of age to adulthood. Common illnesses, like a cold or flu, or a long time without food can trigger symptoms

Signs of the condition may include the following:

• Weakness
• Tiredness or lack of energy (lethargy)
• Enlarged liver (hepatomegaly)
• Heart problems (can be life-threatening)
• Low blood sugar (hypoglycemia)

Newborn screening for VLCAD 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. Your body produces these substances when it makes energy from fats. Babies with high levels of these substances might have VLCAD deficiency.

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

If your baby’s blood spot screening result for VLCAD 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.

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

• Blood and/or urine tests
• Echocardiogram and/or other heart tests
• Genetic testing using a blood sample
• Small skin 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 are not common, but they can happen if your baby received carnitine.

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:

• Regular and frequent meals and snacks
• Diet high in carbohydrates and low in fat
• Medium chain triglyceride (MCT) oil to help give the body fats it can break down
• L-carnitine supplements to help the body break down fats
• People with VLCAD deficiency must be very careful if they get sick and have vomiting or diarrhea, or do not want to eat. They may need emergency care to prevent low blood sugar levels.

Children who receive early and ongoing treatment for VLCAD deficiency can have healthy growth and development.