3-methylcrotonyl-CoA carboxylase deficiency (also known as 3-MCC deficiency) is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have a shortage of an enzyme that helps break down proteins containing a particular building block (amino acid) called leucine.

Infants with 3-MCC deficiency appear normal at birth but usually develop signs and symptoms in infancy or early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Many of these complications can be prevented with early detection and lifelong management with a low-protein diet and appropriate supplements. Some people with gene mutations that cause 3-MCC deficiency never experience any signs or symptoms of the condition.

The characteristic features of 3-MCC deficiency are similar to those of Reye syndrome, a severe disorder that develops 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 MCCC1 or MCCC2 gene can cause 3-MCC deficiency. These two genes provide instructions for making different parts (subunits) of an enzyme called 3-methylcrotonyl-coenzyme A carboxylase (3-MCC). This enzyme plays a critical role in breaking down proteins obtained from the diet. Specifically, 3-MCC is responsible for the fourth step in processing leucine, an amino acid that is part of many proteins.

Mutations in the MCCC1 or MCCC2 gene reduce or eliminate the activity of 3-MCC, preventing the body from processing leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, which can damage the brain. This damage underlies the signs and symptoms of 3-MCC deficiency.

Normal Function

The MCCC1 gene provides instructions for making one part (the alpha subunit) of an enzyme called 3-methylcrotonoyl-CoA carboxylase or 3-MCC. Alpha subunits join with smaller beta subunits made from the MCCC2 gene; six of these pairings together form a functioning enzyme. The alpha subunit also includes a region for binding to the B vitamin biotin, which is required for the enzyme's function.

The 3-MCC enzyme is found in mitochondria, which are the energy-producing centers inside cells. This enzyme plays a critical role in breaking down proteins obtained from the diet. Specifically, it is responsible for the fourth step in the breakdown of leucine, an amino acid that is a building block of many proteins. This step converts a molecule called 3-methylcrotonyl-CoA to a molecule called 3-methylglutaconyl-CoA. Additional chemical reactions convert 3-methylglutaconyl-CoA into molecules that are later used for energy.

Health Conditions Related to Genetic Changes

3-methylcrotonyl-CoA carboxylase deficiency

At least 30 mutations in the MCCC1 gene have been identified in people with 3-methylcrotonyl-CoA carboxylase deficiency (also known as 3-MCC deficiency). Most of these mutations change single amino acids in 3-MCC, but a few mutations lead to the production of an abnormally short version of the enzyme. Mutations in the MCCC1 gene severely reduce or eliminate the activity of 3-MCC. As a result, leucine cannot be broken down properly, and byproducts of leucine processing build up to toxic levels in the body. These toxic substances can damage the brain, causing the characteristic signs and symptoms of 3-MCC deficiency.

Other Names for This Gene

• 3-methylcrotonyl-CoA carboxylase 1
• 3-methylcrotonyl-CoA carboxylase biotin-containing subunit
• MCCA
• MCCA_HUMAN
• MCCase subunit alpha
• methylcrotonoyl-CoA carboxylase 1 (alpha)

Genomic Location

Normal Function

The MCCC2 gene provides instructions for making one part (the beta subunit) of an enzyme called 3-methylcrotonoyl-CoA carboxylase or 3-MCC. Beta subunits join with larger alpha subunits made from the MCCC1 gene; six of these pairings together form a functioning enzyme.

The 3-MCC enzyme is found in mitochondria, which are the energy-producing centers inside cells. This enzyme plays a critical role in breaking down proteins obtained from the diet. Specifically, it is responsible for the fourth step in the breakdown of leucine, an amino acid that is a building block of many proteins. This step converts a molecule called 3-methylcrotonyl-CoA to a molecule called 3-methylglutaconyl-CoA. Additional chemical reactions convert 3-methylglutaconyl-CoA into molecules that are later used for energy.

Health Conditions Related to Genetic Changes

3-methylcrotonyl-CoA carboxylase deficiency

More than 40 mutations in the MCCC2 gene have been identified in people with 3-methylcrotonyl-CoA carboxylase deficiency (also known as 3-MCC deficiency). Most of these mutations change single amino acids in 3-MCC, which severely reduces the activity of the enzyme. Other mutations prevent the production of any functional enzyme. As a result, leucine cannot be broken down properly, and byproducts of leucine processing build up to toxic levels in the body. These toxic substances can damage the brain, causing the characteristic signs and symptoms of 3-MCC deficiency.

Other Names for This Gene

• 3-methylcrotonyl-CoA carboxylase non-biotin-containing subunit
• MCCase subunit beta
• MCCB
• MCCB_HUMAN
• methylcrotonoyl-CoA carboxylase 2 (beta)
• non-biotin containing subunit of 3-methylcrotonyl-CoA carboxylase

Genomic Location

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

• 3-MCC deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene that causes methylmalonic acidemia (MCCC1 or MCCC2) to their baby. Only babies with two matching nonworking genes—for example, one nonworking MCCC1 from the mom and one nonworking MCCC1 from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking MCCC1 from the mom and one nonworking MCCC2 from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the MCCC1 or MCCC2 gene are called carriers.
  • Carriers do not have the condition and will not 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 MCCC1 or MCCC2 gene, they have a 1 in 4 chance of having a child with 3-MCC deficiency.
  • Carriers for 3-MCC 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-MCC deficiency.
  • Parents who already have a child with 3-MCC deficiency still have a 1 in 4 chance of having another child with 3-MCC 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-MCC deficiency often appear within the first few months of life but may also appear later in childhood. Some babies with this condition never show any signs.

Signs of the condition may include the following:

• Poor appetite
• Sleeping longer or more often
• Tiredness
• Behavior changes
• Gets upset easily
• Floppy arms and legs (hypotonia)
• Vomiting
• Muscle tightness (spasticity)
• Delayed growth
• Delayed development

Newborn screening for 3-MCC 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. The body produces these substances when it breaks down food. Babies with high levels of these substances might have 3-MCC deficiency.

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

If your baby’s blood spot screening result for 3-MCC 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 may develop health problems if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition may happen. Babies who are born early (premature) may have out-of-range results.

Some babies may have a false-positive result for 3-MCC deficiency because their mother unknowingly has the condition. These babies do not have and will not develop the condition. 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.

Treatment options can include the following:

• Frequent feedings to avoid long periods without food
• L-carnitine supplements

Children who receive early and ongoing treatment for 3-MCC deficiency can have healthy growth and development.