3-hydroxyacyl-CoA dehydrogenase deficiency is an inherited condition that prevents the body from converting certain fats to energy, particularly during prolonged periods without food (fasting).

Initial signs and symptoms of this disorder typically occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, and lack of energy (lethargy). Affected individuals can also have muscle weakness (hypotonia), liver problems, low blood glucose (hypoglycemia), and abnormally high levels of insulin (hyperinsulinism). Insulin controls the amount of glucose that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-CoA dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden death. This condition may explain some cases of sudden infant death syndrome (SIDS), which is defined as unexplained death in babies younger than 1 year.

Problems related to 3-hydroxyacyl-CoA dehydrogenase 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 HADH gene cause 3-hydroxyacyl-CoA dehydrogenase deficiency. The HADH gene provides instructions for making an enzyme called 3-hydroxyacyl-CoA dehydrogenase.

Normally, through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to break down (metabolize) fats and convert them to energy. The 3-hydroxyacyl-CoA dehydrogenase enzyme is required for a step that metabolizes groups of fats called medium-chain fatty acids and short-chain fatty acids.

Mutations in the HADH gene lead to a shortage of 3-hydroxyacyl-CoA dehydrogenase. Medium-chain and short-chain fatty acids cannot be metabolized properly without sufficient levels of this enzyme. As a result, these fatty acids are not converted to energy, which can lead to characteristic features of 3-hydroxyacyl-CoA dehydrogenase deficiency, such as lethargy and hypoglycemia. Medium-chain and short-chain fatty acids that are not broken down can build up in tissues and damage the liver, heart, and muscles, causing serious complications.

Conditions that disrupt the metabolism of fatty acids, including 3-hydroxyacyl-CoA dehydrogenase deficiency, are known as fatty acid oxidation disorders.

Normal Function

The HADH gene provides instructions for making an enzyme called 3-hydroxyacyl-CoA dehydrogenase that is important for converting certain fats to energy. This enzyme is involved in a process called fatty acid oxidation, in which several enzymes work in a step-wise fashion to break down (metabolize) fats and convert them to energy. The role of 3-hydroxyacyl-CoA dehydrogenase is to metabolize groups of fats called medium-chain fatty acids and short-chain fatty acids. These fatty acids are found in foods such as milk and certain oils and are produced when larger fatty acids are metabolized.

3-hydroxyacyl-CoA dehydrogenase functions in mitochondria, the energy-producing centers within cells. This enzyme is especially important for the normal functioning of the heart, liver, kidneys, muscles, and pancreas. The pancreas makes enzymes that help digest food, and it also produces insulin, which controls how much sugar (glucose) is passed from the blood into cells for conversion to energy.

3-hydroxyacyl-CoA dehydrogenase is essential in the process that converts medium-chain and short-chain fatty acids to ketones, the major source of energy used by the heart and muscles. During prolonged periods without food (fasting) or when energy demands are increased, ketones are also important for the liver and other tissues.

Health Conditions Related to Genetic Changes

3-hydroxyacyl-CoA dehydrogenase deficiency

At least three mutations in the HADH gene have been found to cause 3-hydroxyacyl-CoA dehydrogenase deficiency. These mutations change single protein building blocks (amino acids) used to make the 3-hydroxyacyl-CoA dehydrogenase enzyme. These changes probably alter the 3-dimensional shape of the enzyme, which impairs its normal function.

With a shortage (deficiency) of functional 3-hydroxyacyl-CoA dehydrogenase, medium-chain and short-chain fatty acids are not metabolized properly. As a result, these fatty acids are not converted to energy, which can lead to signs and symptoms of 3-hydroxyacyl-CoA dehydrogenase deficiency such as lack of energy (lethargy) and low blood glucose (hypoglycemia). Medium-chain and short-chain fatty acids that are not broken down can build up in tissues and damage the liver, heart, and muscles, causing serious complications.

Congenital hyperinsulinism

MedlinePlus Genetics provides information about Congenital hyperinsulinism

Other disorders

Mutations in the HADH gene have been reported in a small number of people with familial hyperinsulinism. This disorder is characterized by abnormally high levels of insulin (hyperinsulinism) and unusually low blood glucose (hypoglycemia).

Researchers have identified at least five HADH gene mutations that cause familial hyperinsulinism. These mutations severely reduce 3-hydroxyacyl-CoA dehydrogenase activity, either by impairing the enzyme's function or by decreasing the amount of this enzyme in cells. Researchers believe that inadequate 3-hydroxyacyl-CoA dehydrogenase activity in the pancreas leads to excessive insulin secretion and hypoglycemia in people with familial hyperinsulinism. It is unclear why the HADH gene mutations that cause familial hyperinsulinism seem to affect only the pancreas.

Other Names for This Gene

• HAD
• HADH1
• HADHSC
• HCDH_HUMAN
• HHF4
• hydroxyacyl-Coenzyme A dehydrogenase
• L-3-hydroxyacyl-Coenzyme A dehydrogenase
• L-3-hydroxyacyl-Coenzyme A dehydrogenase, short chain
• M/SCHAD
• medium and short chain L-3-hydroxyacyl-coenzyme A dehydrogenase
• MGC8392
• SCHAD
• short chain 3-hydroxyacyl-CoA dehydrogenase

Genomic Location

3-Hydroxyacyl-CoA dehydrogenase deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• 3-Hydroxyacyl-CoA dehydrogenase deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking HADH gene to their baby. Only babies with two nonworking HADH genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the HADH 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 HADH gene, they have a 1 in 4 chance of having a child with 3-hydroxyacyl-CoA dehydrogenase deficiency.
  • Carriers for 3-hydroxyacyl-CoA dehydrogenase 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 3-hydroxyacyl-CoA dehydrogenase deficiency.
  • Parents who already have a child with 3-hydroxyacyl-CoA dehydrogenase deficiency still have a 1 in 4 chance of having another child with 3-hydroxyacyl-CoA dehydrogenase 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 3-hydroxyacyl-CoA dehydrogenase deficiency often appear shortly after birth (1 month to 2 years of age). 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:

• Poor appetite
• Vomiting
• Diarrhea
• Muscle weakness (hypotonia)
• Tiredness or lack of energy (lethargy)
• Breathing problems
• Seizures

Newborn screening for 3-hydroxyacyl-CoA dehydrogenase 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 3-hydroxyacyl-CoA dehydrogenase deficiency.

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

If your baby’s blood spot screening result for 3-hydroxyacyl-CoA dehydrogenase 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 test
• 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 do not happen often. Because this condition is very rare, it is not known what can lead to false-positive results, or how often they occur.

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
• Medications to help lower insulin to a normal level (in some cases)

Even with treatment, some children may still have high insulin levels, low blood sugar levels, or problems with their heart or liver.