Pyruvate Carboxylase Deficiency
Pyruvate Carboxylase Deficiency
National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Pyruvate Carboxylase Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.
Related Disorders List
Information on the following diseases can be found in the Related Disorders section of this report:
- Leigh Disease
- Pyruvate Dehydrogenase Deficiency Complex
- Biotinidase Deficiency
Pyruvate carboxylase deficiency is a rare genetic disorder characterized by a failure of the body to produce the necessary fuels for energy and neurotransmitters important for brain function. In its most severe form PCD leads to progressive damage to the tissue and organs, especially in the nervous system. Pyruvate carboxylase deficiency is inherited as an autosomal recessive genetic condition.
Three types of pyruvate carboxylase deficiency have been described and are called type A , type B and type C.
Pyruvate carboxylase deficiency type A begins in the infancy and symptoms include developmental delay, mild to moderate elevations in lactic acid in the blood (lactic acidosis), abdominal pain, vomiting, tiredness and muscle weakness. Children with this type of pyruvate carboxylase deficiency usually live until childhood.
Pyruvate carboxylase deficiency type B usually begins at, or shortly after, birth. Elevation in lactic acid (lactic acidosis) and ammonia (hyperammonemia) is pronounced. Liver failure, weak muscle tone (hypotonia), abnormal eye movements, seizures and coma are common. Children with this type of pyruvate carboxylase deficiency usually die within several months of life.
Pyruvate carboxylase deficiency type C is believed to be a benign form of the disease. Elevation in which lactic acid is mild and periodic. Effects on the nervous system are mild and life expectancy is normal.
Pyruvate carboxylase deficiency is caused by abnormalites (mutations) in the pyruvate carboxylase gene resulting in a missing or decreased amount of pyruvate carboxylase enzyme. This enzyme functions in the energy producing centers of cells (mitochondria) to make glucose. It is also involved in the production of the protective sheath around some nerve cells (myelin) and the production of neurotransmitters in the brain.
Pyruvate carboxylase deficiency is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder
Pyruvate carboxylase deficiency is a very rare disorder that affects males and females in equal numbers. The frequency of this condition has been estimated to be 1 in 250,000 births. Type A occurs more often in North America and type B occurs more often in Europe, especially in France.
Symptoms of the following disorders can be similar to those of pyruvate carboxylase deficiency. Comparison may be useful for a differential diagnosis.
Leigh disease is a rare genetic neurometabolic disorder characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh disease usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh disease progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function.
Several different enzyme defects can cause Leigh disease. Most affected individuals have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh disease is inherited as an autosomal recessive genetic condition but X-linked and mitochondrial inheritance have also been noted. (For more information about this disorder, choose "Leigh" as your search term in the Rare Disease Database.)
Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one or more enzymes in the pyruvate dehydrogenase complex. The age of onset and severity of disease depends on the activity level of the PDC enzymes. Individuals with PDCD beginning prenatally or in infancy usually die in early childhood. Those who develop PDCD later in childhood may have mental retardation and other neurological symptoms and usually survive into adulthood. Approximately 25% of individuals with PDCD have an abnormality in the PHE1A gene located on the X chromosome. Approximately 75% of affected individuals have a form of the disorder that follows autosomal recessive inheritance. (For more information about this disorder, choose "pyruvate dehydrogenase" as your search term in the Rare Disease Database.)
Biotinidase deficiency is a treatable, metabolic disorder that is the result of a low concentration or absence of the biotinidase enzyme. The body is not able to properly process the vitamin, biotin, which is sometimes referred to as Vitamin H. Biotin is an essential vitamin in the metabolic process and biotinidase allows biotin to become available for use by the body. Biotinidase deficiency is inherited as an autosomal recessive genetic condition.
Most affected infants show signs of lactic acid in the urine (aciduria), a widespread, red, skin rash (eczema), seizures, poor muscle tone (hypotonia), developmental delays, and hair loss (alopecia). Daily treatment with biotin is an effective treatment.
Pyruvate carboxylase deficiency is diagnosed by physical symptoms and laboratory studies. Levels of pyruvate and lactate in the blood are high. Testing can be performed on samples of blood or skin cells to determine if the function of the pyruvate carboxylase enzyme is abnormal. Pyruvate carboxylase deficiency type B is associated with no enzyme activity and type A is associated with enzyme activity that is less than 2% of normal levels.
Prenatal diagnosis is possible by measurement of pyruvate carboxylase enzyme levels on cultured amniotic fluid cells obtained from amniocentesis or on cultured chorionic villus cells obtained from chorionic villus sampling.
Treatment of pyruvate carboxylase deficiency is aimed at providing alternative sources of energy for the body and alternative means of metabolizing pyruvate. A diet that is low in fat and high in carbohydrates and protein is recommended. Thiamine, lipoic acid, dichloroacetate and citrate can sometimes help to reduce the level of pyruvate and lactic acid. Biotin can sometimes improve the function of the pyruvate carboxylase enzyme. Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing a source of acetyl-CoA and anaplerotic propionyl-CoA. However, life expectancy was not prolonged.
There is no therapy currently available to correct or improve the neurological symptoms.
Genetic counseling is recommended for families that have a child with pyruvate carboxylase deficiency.
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FROM THE INTERNET
Frye RE, Benke PJ. Pyruvate Carboxylase Deficiency. eMedicine. Last Updated 4/29/05.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 266150; Last Updated 3/22/06.
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