Carnitine-acylcarnitine translocase (CACT) deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods without food (fasting). Signs and symptoms of this disorder usually begin soon after birth and may include breathing problems, seizures, and an irregular heartbeat (arrhythmia). Affected individuals typically have low blood glucose (hypoglycemia) and a low level of ketones, which are produced during the breakdown of fats and used for energy. Together these signs are called hypoketotic hypoglycemia. People with CACT deficiency also usually have excess ammonia in the blood (hyperammonemia), an enlarged liver (hepatomegaly), and a weakened heart muscle (cardiomyopathy).

Many infants with CACT deficiency do not survive the newborn period. Some affected individuals have a less severe form of the condition and do not develop signs and symptoms until early childhood. These individuals are at risk for liver failure, nervous system damage, coma, and sudden death.

Mutations in the SLC25A20 gene cause CACT deficiency. This gene provides instructions for making a protein called carnitine-acylcarnitine translocase (CACT). This protein is essential for fatty acid oxidation, a multistep process that breaks down (metabolizes) fats and converts them into energy. Fatty acid oxidation takes place within mitochondria, which are the energy-producing centers in cells. A group of fats called long-chain fatty acids must be attached to a substance known as carnitine to enter mitochondria. Once these fatty acids are joined with carnitine, the CACT protein transports them into mitochondria. 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.

Although mutations in the SLC25A20 gene change the structure of the CACT protein in different ways, they all lead to a shortage (deficiency) of the transporter. Without enough functional CACT protein, long-chain fatty acids cannot be transported into mitochondria. As a result, these fatty acids are not converted to energy. Reduced energy production can lead to some of the features of CACT deficiency, such as hypoketotic hypoglycemia. Fatty acids and long-chain acylcarnitines (fatty acids still attached to carnitine) may also build up in cells and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of the disorder.

Normal Function

The SLC25A20 gene provides instructions for making a protein called carnitine-acylcarnitine translocase (CACT). This protein is essential for fatty acid oxidation, a multistep process that breaks down (metabolizes) fats and converts them into energy. Fatty acid oxidation takes place within mitochondria, which are the energy-producing centers in cells. A group of fats called long-chain fatty acids must be attached to a substance known as carnitine to enter mitochondria. Once these fatty acids are joined with carnitine, the CACT protein transports them into mitochondria. Carnitine is then removed from the long-chain fatty acid and transported back out of mitochondria by the CACT protein. 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.

Health Conditions Related to Genetic Changes

Carnitine-acylcarnitine translocase deficiency

At least 27 mutations in the SLC25A20 gene have been found to cause carnitine-acylcarnitine translocase (CACT) deficiency. Although these mutations change the structure of the CACT protein in different ways, they all lead to a shortage (deficiency) of the protein. Without enough functional CACT protein, long-chain fatty acids cannot be transported into mitochondria. As a result, these fatty acids are not converted to energy. Reduced energy production can lead to some of the features of CACT deficiency, such as low blood glucose (hypoglycemia) and low levels of the products of fat breakdown (hypoketosis). Fatty acids and long-chain acylcarnitines (fatty acids still attached to carnitine) may also build up in cells and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of the disorder.

Other Names for This Gene

• CAC
• CACT
• carnitine-acylcarnitine carrier
• carnitine/acylcarnitine translocase
• MCAT_HUMAN
• solute carrier family 25 (carnitine/acylcarnitine translocase), member 20

Genomic Location

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

• CACT deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking SLC25A20 gene to their baby. Only babies with two nonworking SLC25A20 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the SLC25A20 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 SLC25A20 gene, they have a 1 in 4 chance of having a child with CACT deficiency.
  • Carriers for CACT 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 CACT deficiency.
  • Parents who already have a child with CACT deficiency still have a 1 in 4 chance of having another child with CACT 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.

• Excess ammonia in the blood (hyperammonemia)
• Enlarged liver (hepatomegaly)
• Heart abnormalities (cardiomyopathy) and abnormal heart rhythm (arrhythmias)
• Muscle weakness
• Neurological problems
• Seizures
• Developmental delay

Newborn screening for CACT 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 CACT deficiency.

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

If your baby’s blood spot screening result for CACT 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
• Small skin sample

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

False-positive newborn screening results for this condition can happen. Some situations can affect screening results for CACT deficiency:

• Screening samples were collected too early (before the baby is 24 hours old)
• Babies who were given carnitine may have false positive results for this condition.

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 supplements to provide fats the body can break down
• L-carnitine supplements to help the body break down fats (in some cases)

Children who receive early and ongoing treatment for CACT deficiency can help prevent or control symptoms. Even with treatment, some children may still experience heart, liver, or lung problems.

Prompt and careful treatment may help prevent or control symptoms in children with mild carnitine-acylcarnitine translocase deficiency. Outcomes seem to correlate better with the absence of cardiac disease. Diagnosis before the occurrence of clinical symptoms and very early treatment, together with good dietary compliance, could lead to a better prognosis, especially in milder clinical cases. However, some children continue to have metabolic crises and other health problems despite treatment. Even with treatment, there is a risk of death, especially in newborns with symptoms.