Isovaleric acidemia is a rare disorder in which the body is unable to properly break down a particular protein building block (amino acid). The condition is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems.

Normally, the body breaks down proteins from food into smaller parts called amino acids. Amino acids can be further processed to provide energy for growth and development. People with isovaleric acidemia have inadequate levels of an enzyme that helps break down a particular amino acid called leucine.

Health problems related to isovaleric acidemia range from very mild to life-threatening. In severe cases, the features of isovaleric acidemia become apparent within a few days after birth. The initial symptoms include poor feeding, vomiting, seizures, and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including seizures, coma, and possibly death. A characteristic sign of isovaleric acidemia is a distinctive odor of sweaty feet during acute illness. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals.

In other cases, the signs and symptoms of isovaleric acidemia appear during childhood and may come and go over time. Children with this condition may fail to gain weight and grow at the expected rate (failure to thrive) and often have delayed development. In these children, episodes of more serious health problems can be triggered by prolonged periods without food (fasting), infections, or eating an increased amount of protein-rich foods.

Some people with gene mutations that cause isovaleric acidemia are asymptomatic, which means they never experience any signs or symptoms of the condition.

Mutations in the IVD gene cause isovaleric acidemia. The IVD gene provides instructions for making an enzyme that plays an essential role in breaking down proteins from the diet. Specifically, this enzyme helps process the amino acid leucine, which is part of many proteins. If a mutation in the IVD gene reduces or eliminates the activity of this enzyme, the body is unable to break down leucine properly. As a result, an organic acid called isovaleric acid and related compounds build up to harmful levels in the body. This buildup damages the brain and nervous system, causing serious health problems.

Normal Function

The IVD gene provides instructions for making an enzyme called isovaleryl-CoA dehydrogenase. This enzyme plays an essential role in processing proteins obtained from the diet. Normally, the body breaks down proteins from food into smaller parts called amino acids. Amino acids can be further processed to provide energy for growth and development. In cells throughout the body, isovaleryl-CoA dehydrogenase is found within specialized structures called mitochondria. Mitochondria convert energy from food to a form that cells can use.

Isovaleryl-CoA dehydrogenase helps process a particular amino acid called leucine. Specifically, this enzyme is responsible for the third step in the breakdown of leucine. This step is a chemical reaction that converts a molecule called isovaleryl-CoA to another molecule, 3-methylcrotonyl-CoA. Additional chemical reactions convert 3-methylcrotonyl-CoA into molecules that are used for energy.

Health Conditions Related to Genetic Changes

Isovaleric acidemia

Nearly 100 mutations in the IVD gene have been identified in people with isovaleric acidemia. Some of these mutations disrupt the normal function of the enzyme, while other mutations prevent the cell from producing any functional enzyme. As a result, the body is unable to break down leucine properly. Defects in leucine processing allow several potentially harmful substances, including a compound called isovaleric acid, to build up to toxic levels in the body. An accumulation of isovaleric acid causes people with isovaleric acidemia to have a characteristic odor of sweaty feet. The buildup of isovaleric acid and related compounds also damages the brain and nervous system, leading to poor feeding, lack of energy (lethargy), seizures, and the other signs and symptoms of isovaleric acidemia.

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Other Names for This Gene

• ACAD2
• isovaleryl CoA dehydrogenase
• IVD_HUMAN

Genomic Location

Isovaleric acidemia is a genetic condition. Babies inherit it from their biological (birth) parents.

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

• Poor feeding
• Vomiting
• Lack of energy
• Low muscle tone
• Tremor
• Odor of sweaty feet

Isovaleric acidemia (IVA) is diagnosed based on the symptoms, clinical exam, and blood and urine testing. The results of genetic testing may help confirm the diagnosis.
IVA can also be diagnosed on the newborn screen. However, some people found to have IVA on a newborn screen may never develop symptoms.

Newborn screening for isovaleric acidemia 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 breaks down food. Babies with high levels of these substances might have isovaleric acidemia.

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

If your baby’s blood spot screening result for isovaleric acidemia 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.

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:

• Frequent feedings to avoid long periods without food
• Glycine supplements
• L-carnitine supplements
• Diet of special formulas or foods in some cases

Children who receive early and ongoing treatment for isovaleric acidemia can have healthy growth and development.