Mitochondrial trifunctional protein deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting).

Signs and symptoms of mitochondrial trifunctional protein deficiency may begin during infancy or later in life. Features that occur during infancy include feeding difficulties, lack of energy (lethargy), low blood glucose (hypoglycemia), weak muscle tone (hypotonia), and liver problems. Infants with this disorder are also at high risk for serious heart problems, breathing difficulties, coma, and sudden death. Signs and symptoms of mitochondrial trifunctional protein deficiency that may begin after infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and a loss of sensation in the extremities (peripheral neuropathy).

Problems related to mitochondrial trifunctional protein 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 HADHA and HADHB genes cause mitochondrial trifunctional protein deficiency. These genes each provide instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. As the name suggests, mitochondrial trifunctional protein contains three enzymes that each perform a different function. This enzyme complex is required to break down (metabolize) a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils. These fatty acids are stored in 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 HADHA or HADHB genes that cause mitochondrial trifunctional protein deficiency disrupt all three functions of this enzyme complex. Without enough of this enzyme complex, long-chain fatty acids from food and body fat cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may also build up and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of mitochondrial trifunctional protein deficiency.

Normal Function

The HADHA gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. Mitochondrial trifunctional protein is made of eight parts (subunits). Four alpha subunits are produced from the HADHA gene, and four beta subunits are produced from the HADHB gene. As the name suggests, mitochondrial trifunctional protein contains three enzymes that each perform a different function. The alpha subunits contain two of the enzymes, known as long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 2-enoyl-CoA hydratase. The beta subunits contain the third enzyme. These enzymes are essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them to energy.

Mitochondrial trifunctional protein is required to metabolize a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils. These fatty acids are stored in 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.

Health Conditions Related to Genetic Changes

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Researchers have identified several HADHA gene mutations that cause long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. These mutations decrease the long-chain 3-hydroxyacyl-CoA dehydrogenase enzyme activity of mitochondrial trifunctional protein. (The protein's other enzyme activities remain normal or nearly normal.) Many of the HADHA mutations change one of the protein building blocks (amino acids) used to make the alpha subunit. The most common mutation replaces the amino acid glutamic acid with the amino acid glutamine at position 474 in the alpha subunit. This mutation is written as Glu474Gln or E474Q. The Glu474Gln mutation and other amino acid replacements probably alter the structure of the alpha subunit, preventing it from functioning normally. Other HADHA mutations result in an abnormally short, nonfunctional version of the alpha subunit.

With a shortage (deficiency) of functional alpha subunits, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to some features of LCHAD deficiency, such as lack of energy (lethargy) and low blood glucose (hypoglycemia). Long-chain fatty acids or partially metabolized fatty acids may also build up and damage the liver, heart, muscles, and light-sensitive tissue at the back of the eye (retina). This abnormal buildup causes the other signs and symptoms of LCHAD deficiency.

Mitochondrial trifunctional protein deficiency

Researchers have identified several HADHA gene mutations that cause mitochondrial trifunctional protein deficiency. These mutations reduce all three enzyme activities of mitochondrial trifunctional protein. Some of these mutations result in abnormally short, nonfunctional alpha subunits and lead to decreased levels of mitochondrial trifunctional protein. Other mutations replace one amino acid with another amino acid in the alpha subunit, which probably alters the subunit's structure and disrupts all three functions of the enzyme complex.

When mitochondrial trifunctional protein activity is lost, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of mitochondrial trifunctional protein deficiency.

Other disorders

In a small number of cases, HADHA mutations appear to increase a woman's risk of developing two serious liver disorders during pregnancy, known as acute fatty liver of pregnancy (AFLP) and HELLP syndrome. AFLP begins with abdominal pain and can rapidly progress to liver failure. HELLP stands for hemolysis (the breakdown of red blood cells), elevated liver enzyme levels, and low platelets (cells involved with blood clotting).

A woman is more likely to have AFLP or HELLP syndrome if she has a mutation in one copy of the HADHA gene and the fetus she carries has two copies of a HADHA mutation, particularly the Glu474Gln mutation. Little is known about the relationship between HADHA mutations and liver problems in the mother during pregnancy. One possibility is that partially metabolized long-chain fatty acids produced by the fetus or placenta accumulate in the mother and are toxic to her liver. In very rare cases of maternal liver disease, the mother has one copy of an altered HADHA gene and the fetus is not affected. In these cases, the role of the mother's HADHA mutation in liver disease is unclear.

Other Names for This Gene

• ECHA_HUMAN
• GBP
• hydroxyacyl dehydrogenase, subunit A
• hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit
• hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit
• LCEH
• LCHAD
• long-chain hydroxyacyl-CoA dehydrogenase
• mitochondrial trifunctional protein, alpha subunit
• MTPA

Genomic Location

Normal Function

The HADHB gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. Mitochondrial trifunctional protein is made of eight parts (subunits). Four alpha subunits are produced from the HADHA gene, and four beta subunits are produced from the HADHB gene. As the name suggests, mitochondrial trifunctional protein contains three enzymes that each perform a different function. The beta subunits contain one of the enzymes, known as long-chain 3-keto-acyl-CoA thiolase. The alpha subunits contain the other two enzymes. These enzymes are essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them to energy.

Mitochondrial trifunctional protein is required to metabolize a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils. These fatty acids are stored in 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.

Health Conditions Related to Genetic Changes

Mitochondrial trifunctional protein deficiency

Researchers have identified at least 26 mutations in the HADHB gene that cause mitochondrial trifunctional protein deficiency. These mutations reduce all three enzyme activities of mitochondrial trifunctional protein. Most mutations change one of the protein building blocks (amino acids) used to make the beta subunit. A change in amino acids probably alters the subunit's structure, which disrupts all three activities of the enzyme complex. Some mutations produce abnormally short, nonfunctional beta subunits and lead to decreased levels of mitochondrial trifunctional protein.

With a loss of mitochondrial trifunctional protein activity, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder, such as a lack of energy (lethargy) and low blood glucose (hypoglycemia). Long-chain fatty acids or partially metabolized fatty acids may also build up and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of mitochondrial trifunctional protein deficiency.

Other disorders

A few mutations in the HADHB gene have been found to decrease only the long-chain 3-keto-acyl-CoA thiolase enzyme activity of mitochondrial trifunctional protein. These mutations change single amino acids used to make the beta subunit. The signs and symptoms of isolated long-chain 3-keto-acyl-CoA thiolase deficiency are similar to those of mitochondrial trifunctional protein deficiency. These features include feeding difficulties, lethargy, hypoglycemia, weak muscle tone (hypotonia), and liver problems. Infants with this disorder are also at high risk for serious heart problems, breathing difficulties, coma, and sudden death.

HADHB mutations appear to increase a woman's risk of developing two serious liver disorders during pregnancy, known as acute fatty liver of pregnancy (AFLP) and HELLP syndrome. AFLP begins with abdominal pain and can rapidly progress to liver failure. HELLP stands for hemolysis (the breakdown of red blood cells), elevated liver enzyme levels, and low platelets (cells involved with blood clotting). A small percentage of women who have a mutation in one copy of the HADHB gene and carry a fetus with mutations in both copies of the HADHB gene develop one of these maternal liver diseases. Little is known about the relationship between HADHB mutations and liver problems in the mother during pregnancy. One possibility is that partially metabolized long-chain fatty acids produced by the fetus or placenta accumulate in the mother and are toxic to the liver.

Other Names for This Gene

• ECHB_HUMAN
• HADH
• hydroxyacyl dehydrogenase, subunit B
• hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), beta subunit
• hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), beta subunit
• MTPB
• TFPB
• TP-beta

Genomic Location

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

• Mitochondrial trifunctional protein deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene that causes mitochondrial trifunctional protein deficiency (HADHA or HADHB) to their baby. Only babies with two nonworking genes—for example, one nonworking HADHA from the mom and one nonworking HADHA from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking HADHA from the mom and one nonworking HADHB from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the HADHA or HADHB 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 HADHA or HADHB gene, they have a 1 in 4 chance of having a child with mitochondrial trifunctional protein deficiency.
  • Carriers for mitochondrial trifunctional protein 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 mitochondrial trifunctional protein deficiency.
  • Parents who already have a child with mitochondrial trifunctional protein deficiency still have a 1 in 4 chance of having another child with mitochondrial trifunctional protein 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 mitochondrial trifunctional protein deficiency can vary widely and may appear anytime from a few months of age to childhood. They can be triggered by common illnesses (like a cold or flu) or a long time without food.

Signs of the condition may include the following:

• Problems feeding
• Weak muscle tone (hypotonia)
• Tiredness or lack of energy (lethargy)
• No reflexes or pain response
• Enlarged liver (hepatomegaly)
• Heart problems (cardiomyopathy)
• Low blood sugar (hypoglycemia)

Newborn screening for mitochondrial trifunctional protein 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 mitochondrial trifunctional protein deficiency.

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

If your baby’s blood spot screening result for mitochondrial trifunctional protein 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.

Some babies may have a false-positive result for mitochondrial trifunctional protein deficiency because their mother has high carnitine levels. These babies do not have and will not develop mitochondrial trifunctional protein deficiency. More testing on both mom and baby will determine who has high carnitine 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:

• 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 mitochondrial trifunctional protein 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 mitochondrial trifunctional protein deficiency can have healthy growth and development.