Propionic acidemia is an inherited disorder in which the body is unable to process certain parts of proteins and lipids (fats) properly. It 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.

In most cases, the features of propionic acidemia become apparent within a few days after birth. The initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including heart abnormalities, seizures, coma, and possibly death.

Less commonly, the signs and symptoms of propionic acidemia appear during childhood and may come and go over time. Some affected children experience intellectual disability or delayed development. In children with this later-onset form of the condition, episodes of more serious health problems can be triggered by prolonged periods without food (fasting), fever, or infections.

Mutations in the PCCA and PCCB genes cause propionic acidemia. These genes provide instructions for making two parts (subunits) of an enzyme called propionyl-CoA carboxylase, which plays a role in the normal breakdown of proteins. Specifically, this enzyme helps process several amino acids, which are the building blocks of proteins. Propionyl-CoA carboxylase also helps break down certain types of fat and cholesterol in the body. Mutations in the PCCA or PCCB gene disrupt the function of the enzyme and prevent the normal breakdown of these molecules. As a result, a substance called propionyl-CoA and other potentially harmful compounds can build up to toxic levels in the body. This buildup damages the brain and nervous system, causing the serious health problems associated with propionic acidemia.

Normal Function

The PCCA gene provides instructions for making part of an enzyme called propionyl-CoA carboxylase, specifically, the alpha subunit of this enzyme. Six alpha subunits come together with six beta subunits (produced from the PCCB gene) to form a functioning enzyme. The alpha subunit also includes a region for binding to the B vitamin biotin.

Propionyl-CoA carboxylase plays a role in the normal processing of proteins. It carries out a particular step in the breakdown of several protein building blocks (amino acids) called isoleucine, methionine, threonine, and valine. Propionyl-CoA carboxylase also helps break down certain types of lipids (fats) and cholesterol. First, several chemical reactions convert the amino acids, lipids, or cholesterol to a molecule called propionyl-CoA. Using biotin, propionyl-CoA carboxylase then converts propionyl-CoA to a molecule called methylmalonyl-CoA. Additional enzymes break down methylmalonyl-CoA into other molecules that are used for energy.

Health Conditions Related to Genetic Changes

Propionic acidemia

More than 120 mutations in the PCCA gene have been identified in people with propionic acidemia, a condition that causes severe health problems appearing shortly after birth. These mutations include changes in single DNA building blocks (nucleotides) and insertions or deletions of genetic material in the PCCA gene. PCCA mutations prevent the production of functional propionyl-CoA carboxylase or reduce the enzyme's activity. The altered or missing enzyme is unable to process certain parts of proteins and lipids properly. As a result, propionyl-CoA and other potentially harmful compounds can build up to toxic levels in the body. This buildup damages the brain and nervous system, causing the serious health problems associated with propionic acidemia.

Other Names for This Gene

• PCCA_HUMAN
• PCCase alpha subunit
• propionyl CoA carboxylase, alpha polypeptide
• propionyl Coenzyme A carboxylase, alpha polypeptide
• propionyl-CoA carboxylase alpha subunit
• propionyl-CoA:carbon dioxide ligase alpha subunit

Genomic Location

Normal Function

The PCCB gene provides instructions for making part of an enzyme called propionyl-CoA carboxylase, specifically, the beta subunit of this enzyme. Six beta subunits come together with six alpha subunits (produced from the PCCA gene) to form a functioning enzyme.

Propionyl-CoA carboxylase plays a role in the normal processing of proteins. It carries out a particular step in the breakdown of several protein building blocks (amino acids) called isoleucine, methionine, threonine, and valine. Propionyl-CoA carboxylase also helps break down certain types of lipids (fats) and cholesterol. First, several chemical reactions convert the amino acids, lipids, or cholesterol to a molecule called propionyl-CoA. Using the B vitamin biotin, propionyl-CoA carboxylase then converts propionyl-CoA to a molecule called methylmalonyl-CoA. Additional enzymes break down methylmalonyl-CoA into other molecules that are used for energy.

Health Conditions Related to Genetic Changes

Propionic acidemia

More than 100 mutations in the PCCB gene have been identified in people with propionic acidemia, a condition that causes severe health problems appearing shortly after birth. These mutations include changes in single DNA building blocks (nucleotides) and insertions or deletions of genetic material in the PCCB gene. PCCB mutations prevent the production of functional propionyl-CoA carboxylase or reduce the enzyme's activity. The altered or missing enzyme prevents certain parts of proteins and lipids from being broken down properly. As a result, propionyl-CoA and other potentially toxic compounds can build up to toxic levels in the body. This buildup damages the brain and nervous system, causing the serious health problems associated with propionic acidemia.

Other Names for This Gene

• PCCase beta subunit
• PCCB_HUMAN
• propanoyl-CoA:carbon dioxide ligase beta subunit
• propionyl CoA carboxylase, beta polypeptide
• propionyl-CoA carboxylase beta subunit
• propionyl-CoA carboxylase, beta subunit

Genomic Location

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

• Propionic acidemia is an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene that causes propionic acidemia (PCCA or PCCB) to their baby. Only babies with two matching nonworking genes—for example, one nonworking PCCA from the mom and one nonworking PCCA from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking PCCA from the mom and one nonworking PCCB from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the PCCA or PCCB 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 PCCA or PCCB gene, they have a 1 in 4 chance of having a child with propionic acidemia.
  • Carriers for propionic 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 propionic acidemia.
  • Parents who already have a child with propionic acidemia still have a 1 in 4 chance of having another child with propionic 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.

Propionic acidemia causes episodes of illness called decompensation events caused by the build-up of toxic substances in the blood. Decompensation events are serious bouts of illness that can cause brain damage if not treated quickly.

Symptoms of a decompensation event usually occur a few days after birth and may include:

• Poor feeding and loss of appetite
• Vomiting
• Weak muscle tone (hypotonia)
• Lack of energy (lethargy)
• Seizures
• Coma

Other complications may include:

• Thickened heart muscle (cardiomyopathy)
• Enlarged liver
• Intellectual and motor disability
• Movement disorders
• Poor growth
• Anemia

In the late-onset form, symptoms appear in childhood and are similar to the neonatal-onset form, but may come and go over time.

• Biochemical testing for abnormal levels of specific chemicals
• Genetic testing for mutations in either the PCCA or PCCB gene

Newborn screening for propionic 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 fats. A specific organic acid (called methylcitric acid) may also be measured. Babies with high levels of these substances might have propionic acidemia.

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

If your baby’s blood spot screening result for propionic 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 urine tests
• 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 very serious health problems in the first few days of life if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Some situations can affect screening results:

• Babies born early (premature)
• Babies who received carnitine
• Babies with high levels of bilirubin in their blood (hyperbilirubinemia)
• Babies whose mothers have low levels of vitamin B-12 (B-12 deficiency)

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:

• Diet low in certain proteins and fats
• Special formulas and foods
• Regular and frequent meals and snacks
• Biotin and carnitine supplementation in some cases
• Antibiotics in some cases

Early and ongoing treatment for propionic acidemia can help reduce and prevent some of the early signs and symptoms. Even with treatment, some children might still have developmental delays or learning difficulties.

Propionic acidemia affects about 1 in 100,000 people in the United States. The condition appears to be more common in several populations worldwide, including the Inuit population of Greenland, some Amish communities, and Saudi Arabians.