Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system.

Researchers have identified at least three types of pyruvate carboxylase deficiency, which are distinguished by the severity of their signs and symptoms. Type A, which has been identified mostly in people from North America, has severe symptoms that begin in infancy. Characteristic features include developmental delay and a buildup of lactic acid in the blood (lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. In some cases, episodes of lactic acidosis are triggered by an illness or periods without food (fasting). Children with pyruvate carboxylase deficiency type A typically survive only into infancy or early childhood.

Pyruvate carboxylase deficiency type B has life-threatening signs and symptoms that become apparent shortly after birth. This form of the condition has been reported mostly in Europe, particularly France. Affected infants have severe lactic acidosis, a buildup of ammonia in the blood (hyperammonemia), and liver failure. They experience neurological problems including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with this form of the condition usually survive for less than 3 months after birth.

A milder form of pyruvate carboxylase deficiency, sometimes called type C, has also been described. This type is characterized by slightly increased levels of lactic acid in the blood and minimal signs and symptoms affecting the nervous system.

Mutations in the PC gene cause pyruvate carboxylase deficiency. This gene provides instructions for making an enzyme called pyruvate carboxylase. This enzyme is active in mitochondria, which are the energy-producing centers within cells. It is involved in several important cellular functions, including the generation of glucose, a simple sugar that is the body's main energy source. Pyruvate carboxylase also plays a role in the formation of the protective sheath that surrounds certain nerve cells (myelin) and the production of brain chemicals called neurotransmitters that allow nerve cells to communicate with one another.

Mutations in the PC gene reduce the amount of pyruvate carboxylase in cells or disrupt the enzyme's activity. The missing or altered enzyme cannot carry out its essential role in generating glucose, which impairs the body's ability to make energy in mitochondria. Additionally, a loss of pyruvate carboxylase allows compounds such as lactic acid and ammonia to build up and damage organs and tissues. Researchers suggest that the loss of pyruvate carboxylase function in the nervous system, particularly the role of the enzyme in myelin formation and neurotransmitter production, also contributes to the neurologic features of pyruvate carboxylase deficiency.

Normal Function

The PC gene provides instructions for making an enzyme called pyruvate carboxylase. This enzyme is active in mitochondria, which are the energy-producing centers within cells.

Pyruvate carboxylase is responsible for a chemical reaction that converts a molecule called pyruvate to another molecule called oxaloacetate. This reaction is essential for several different cellular functions. In the kidneys and liver, it is the first step in a process called gluconeogenesis. Gluconeogenesis generates glucose, a simple sugar that is the body's main energy source. This chemical reaction also occurs in the pancreas, where it helps regulate the secretion of a hormone called insulin. Insulin controls the amount of glucose in the blood that is passed into cells for conversion to energy.

In fat-storing (adipose) tissue, pyruvate carboxylase is involved in the formation of certain fats (lipogenesis). This enzyme also plays an important role in the nervous system, where it replenishes the building blocks needed to make brain chemicals called neurotransmitters. Additionally, pyruvate carboxylase is necessary for the formation of myelin, which is the fatty covering that insulates and protects certain nerve cells.

Health Conditions Related to Genetic Changes

Pyruvate carboxylase deficiency

More than 30 mutations in the PC gene have been identified in people with pyruvate carboxylase deficiency. This condition causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system.

Most PC gene mutations change a single protein building block (amino acid) in pyruvate carboxylase, which reduces the amount of this enzyme in cells or disrupts its ability to effectively convert pyruvate to oxaloacetate. Other genetic changes lead to the production of an abnormally short version of the enzyme that is completely nonfunctional.

If pyruvate carboxylase is missing or altered, it cannot carry out its role in generating glucose. Any disruption in gluconeogenesis impairs the body's ability to make energy in mitochondria. Additionally, a loss of pyruvate carboxylase allows lactic acid and ammonia, among other compounds, to build up and damage organs and tissues. Researchers suggest that the loss of pyruvate carboxylase function in the nervous system, particularly the role of the enzyme in myelin formation and neurotransmitter production, also contributes to the neurologic features of pyruvate carboxylase deficiency.

Other Names for This Gene

• PCB
• PYC_HUMAN
• Pyruvic carboxylase

Genomic Location

Pyruvate carboxylase deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• Pyruvate carboxylase deficiency is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking PC gene to their baby. Only babies with two nonworking PC genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the PC 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 PC gene, they have a 1 in 4 chance of having a child with Pyruvate carboxylase deficiency.
  • Carriers for Pyruvate carboxylase 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 Pyruvate carboxylase deficiency.
  • Parents who already have a child with Pyruvate carboxylase deficiency still have a 1 in 4 chance of having another child with Pyruvate carboxylase 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 Pyruvate carboxylase deficiency type A and type B often appear shortly after birth (within a few days of birth). Babies with Pyruvate carboxylase deficiency type C may not show signs until childhood.

Signs of the condition may include the following:

• Growing slowly or gaining weight slowly (failure to thrive)
• Low blood sugar levels (hypoglycemia)
• High blood ammonia levels (hyperammonemia)
• Vomiting
• Rapid breathing (tachypnea)
• Low muscle tone (hypotonia)
• Trouble feeding
• Unusual eye movements (nystagmus)
• Seizures
• Developmental delay
• Birth defects of the brain or brain injuries that happen before the baby is born
• Loss of the white matter in the brain

Newborn screening for Pyruvate carboxylase deficiency I requires collecting a small amount of blood from your baby’s heel. Screening measures how much of a substance called citrulline is in your baby’s blood. Babies with high levels of citrulline might have Pyruvate carboxylase deficiency.

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

If your baby’s blood spot screening result for pyruvate carboxylase 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 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 very soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Screening samples collected too early (before the baby is 24 hours old) may affect the results of screening. Babies with other conditions that have elevated citrulline may also be detected through this screening. An example of another condition that may be detected is Citrullinemia, Type I.

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 how to best care for your baby. Currently, the treatment options available cannot stop the progression of the condition. Health care providers will develop a plan that is tailored to the needs of each child.

Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A appears to be much more common in some Algonkian Indian tribes in eastern Canada.