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

Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood glucose (hypoglycemia). In rare cases, symptoms of this disorder are not recognized early in life, and the condition is not diagnosed until adulthood. People with MCAD deficiency are at risk of serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death.

Problems related to MCAD deficiency can be triggered by periods of fasting or by illnesses such as viral infections. 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 are associated with the use of aspirin during these viral infections.

Mutations in the ACADM gene cause MCAD deficiency. This gene provides instructions for making an enzyme called medium-chain acyl-CoA dehydrogenase, which is required to break down (metabolize) a group of fats called medium-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.

Mutations in the ACADM gene lead to a shortage (deficiency) of the MCAD enzyme within cells. Without sufficient amounts of this enzyme, medium-chain fatty acids are not metabolized properly. As a result, these fats are not converted to energy, which can lead to the characteristic signs and symptoms of this disorder such as lethargy and hypoglycemia. Medium-chain fatty acids or partially metabolized fatty acids may also build up in tissues and damage the liver and brain. This abnormal buildup causes the other signs and symptoms of MCAD deficiency.

Normal Function

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

MCAD is required to metabolize a group of fats called medium-chain fatty acids. These fatty acids are found in foods and body fat and are produced when larger fatty acids are metabolized. 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

Medium-chain acyl-CoA dehydrogenase deficiency

More than 80 mutations in the ACADM gene have been found to cause medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Many of these mutations change single protein building blocks (amino acids) in the MCAD enzyme. The most common change replaces the amino acid lysine with the amino acid glutamic acid at position 304 in the enzyme (written as Lys304Glu or K304E). This mutation and other amino acid substitutions alter the enzyme's structure, severely reducing or eliminating its activity. Other types of mutations lead to an abnormally small and unstable enzyme that cannot function.

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

Other Names for This Gene

• ACAD1
• ACADM_HUMAN
• acyl-CoA dehydrogenase, C-4 to C-12 straight chain
• MCAD
• MCADH

Genomic Location

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

• MCAD deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking ACADM gene to their baby. Only babies with two nonworking ACADM genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ACADM 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 ACADM gene, they have a 1 in 4 chance of having a child with MCAD deficiency.
  • Carriers for MCAD 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 MCAD deficiency.
  • Parents who already have a child with MCAD deficiency still have a 1 in 4 chance of having another child with MCAD 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 MCAD deficiency often appear shortly after birth (1 month to 2 years of age). Common illnesses like a cold or flu or prolonged periods without food can trigger symptoms.

Signs of the condition may include the following:

• Weakness
• Tiredness or lack of energy (lethargy)
• Breathing problems
• Vomiting
• Seizures
• Low blood sugar (hypoglycemia)

A diagnosis of MCADD requires an evaluation of a person's symptoms as well as the interpretation of several tests. Initial testing may include:

• Plasma acylcarnitine
• Urine organic acid
• Urine acylglycine

Further testing to confirm the diagnosis may include molecular genetic testing of the ACADM gene or biochemical genetic testing.

MCADD is included in many newborn screening programs, so a newborn with MCADD who does not yet exhibit symptoms may be diagnosed early. If a newborn screening result for MCADD is not in the normal range ("positive"), additional testing can then be ordered.

Newborn screening for MCAD 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 MCAD deficiency.

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

If your baby’s blood spot screening result for MCAD 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
• 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 soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. However, certain medications, like carnitine supplements or some seizure medications (valproate), may affect the results of screening.

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
• L-carnitine supplements to help the body break down fats
• People with MCAD 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 continuing treatment for MCAD deficiency can have healthy growth and development.

In the United States, the estimated incidence of MCAD deficiency is 1 in 17,000 people. The condition is more common in people of northern European ancestry than in other ethnic groups.