Beta-ketothiolase deficiency is an inherited disorder in which the body cannot effectively process a protein building block (amino acid) called isoleucine. This disorder also impairs the body's ability to process ketones, which are molecules produced during the breakdown of fats.

The signs and symptoms of beta-ketothiolase deficiency typically appear between the ages of 6 months and 24 months. Affected children experience episodes of vomiting, dehydration, difficulty breathing, extreme tiredness (lethargy), and, occasionally, seizures. These episodes, which are called ketoacidotic attacks, sometimes lead to coma. Ketoacidotic attacks are frequently triggered by infections or periods without food (fasting), and increased intake of protein-rich foods can also play a role.

Mutations in the ACAT1 gene cause beta-ketothiolase deficiency. This gene provides instructions for making an enzyme that is found in the energy-producing centers within cells (mitochondria). This enzyme plays an essential role in breaking down proteins and fats from the diet. Specifically, the ACAT1 enzyme helps process isoleucine, which is a building block of many proteins, and ketones, which are produced during the breakdown of fats.

Mutations in the ACAT1 gene reduce or eliminate the activity of the ACAT1 enzyme. A shortage of this enzyme prevents the body from processing proteins and fats properly. As a result, related compounds can build up to toxic levels in the blood. These substances may cause the blood to become too acidic (ketoacidosis) and can damage the body's tissues and organs, particularly in the nervous system.

Normal Function

The ACAT1 gene provides instructions for making an enzyme that is found in the energy-producing centers within cells (mitochondria). This enzyme plays an essential role in breaking down proteins and fats from the diet. Specifically, it helps process isoleucine, an amino acid that is a building block of many proteins. This enzyme is also involved in processing ketones, which are molecules that are produced when fats are broken down in the body.

During the breakdown of proteins, the ACAT1 enzyme is responsible for a step in processing isoleucine. It converts a molecule called 2-methyl-acetoacetyl-CoA into two smaller molecules, propionyl-CoA and acetyl-CoA, that can be used to produce energy.

The ACAT1 enzyme carries out the last step in ketone breakdown (ketolysis) during the processing of fats. The enzyme converts a molecule called acetoacetyl-CoA into two molecules of acetyl-CoA, which can be used to produce energy. In the liver, the enzyme also carries out this chemical reaction in reverse, which is a step in building new ketones (ketogenesis).

Health Conditions Related to Genetic Changes

Beta-ketothiolase deficiency

More than 100 mutations in the ACAT1 gene have been identified in people with beta-ketothiolase deficiency. The condition usually appears before age 2 and causes episodes (called ketoacidotic attacks) of vomiting, dehydration and other health problems, which can lead to coma. Some of the genetic changes that cause beta-ketothiolase deficiency disrupt the normal function of the enzyme, while other mutations prevent cells from producing any functional enzyme.

A shortage of the ACAT1 enzyme prevents the body from processing proteins and fats properly. As a result, chemical byproducts called organic acids can build up to toxic levels in the blood. These substances may cause the blood to become too acidic (ketoacidosis) and can damage the body's tissues and organs, particularly in the nervous system. This damage likely underlies the episodes associated with beta-ketothiolase deficiency.

Other Names for This Gene

• ACAT
• acetoacetyl Coenzyme A thiolase
• acetyl-Coenzyme A acetyltransferase 1
• acetyl-Coenzyme A acetyltransferase 1 (acetoacetyl Coenzyme A thiolase)
• MAT
• methylacetoacetyl-Coenzyme A thiolase
• T2
• THIL
• THIL_HUMAN

Genomic Location

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

• Beta-ketothiolase deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking ACAT1 gene to their baby. Only babies with two nonworking ACAT1 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ACAT1 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 ACAT1 gene, they have a 1 in 4 chance of having a child with beta-ketothiolase deficiency.
  • Carriers for beta-ketothiolase 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 beta-ketothiolase deficiency.
  • Parents who already have a child with beta-ketothiolase deficiency still have a 1 in 4 chance of having another child with beta-ketothiolase 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 beta-ketothiolase deficiency often appear when a baby is about 1 year old. However, they can start as early as six months old or as late as 2 years old.

Signs of the condition may include the following:

• Poor appetite
• Dehydration
• Sleeping longer or more often (lethargy)
• Vomiting
• Breathing trouble
• Diarrhea
• Fever

Newborn screening for beta-ketothiolase 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 makes these substances when it breaks down food. Babies with high levels of these substances might have beta-ketothiolase deficiency.

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

If your baby’s blood spot screening result for beta-ketothiolase 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. An out-of-range result can mean that your baby has one of several possible conditions. It is important to do follow-up testing to correctly identify the condition causing your baby’s result.

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. Babies who are born early (premature) may have out-of-range results.

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

• Low-protein diet
• Frequent feedings to avoid long periods without food
• L-carnitine supplements
• Bicitra (a medical supplement to balance acid levels in the blood)

Children who receive early and ongoing treatment for beta-ketothiolase deficiency can have healthy growth and development.