NORD gratefully acknowledges Richard E Frye, MD, PhD, FAAP, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center, for assistance in the preparation of this report.
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.
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 o. 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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