NORD gratefully acknowledges Robert Callus, NORD Editorial Intern from the University of Notre Dame, and Darryl De Vivo, MD, Department of Pediatric Neurology, Columbia University, Neurological Institute of New York, for assistance in the preparation of this report.
Pyruvate carboxylase deficiency (PC deficiency) is a rare genetic disorder present at birth characterized by failure to thrive, developmental delay, recurrent seizures and a failure of the body to produce the necessary fuels for energy and neurotransmitters important for brain function. In its most severe form, PC deficiency leads to progressive damage to the tissue and organs, especially in the nervous system. PC deficiency is inherited as an autosomal recessive genetic condition.
Three types of PC deficiency have been described and are called type A, type B and type C.
PC deficiency type A (infantile form) begins in infancy and symptoms include developmental delay, intellectual disability, mixed acid-base disturbance with mild to moderate elevations in lactic acid and ketone bodies in the blood (lactic acidosis/ketoacidosis), abdominal pain, vomiting, tiredness and muscle weakness. Children with this type of PC deficiency usually die in infancy or early childhood, but some survive to adulthood.
PC deficiency type B (severe neonatal form) usually begins at or shortly after birth. Lactic acidosis, ketoacidosis and elevated ammonia (hyperammonemia) are characteristic. Liver failure, decreased muscle tone (hypotonia), intellectual disability, abnormal eye movements, irregular signs and reflexes due to damage of upper motor neurons (pyramidal tract signs), seizures and coma are common. Children with this type of pyruvate carboxylase deficiency usually die within the first three months of life, but two longer-term survivors have been described.
PC deficiency type C is characterized by normal or mildly delayed development and normal life expectancy. Lactic acidosis is mild and intermittent.
PC deficiency is caused by changes (mutations) in the pyruvate carboxylase (PC) 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 oxaloacetate. Brain energy is essential for the production of the protective sheath around some nerve cells (myelin) and the production of neurotransmitters in the brain.
PC 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 inherits 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 altered 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 inherit normal genes from both parents is 25%. The risk is the same for males and females.
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.
PC 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 native tribes of North America and type B occurs more often in Europe, especially in France, but also in Germany and England.
PC deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis.
PC deficiency is diagnosed by physical symptoms and laboratory studies. Levels of ammonia, pyruvate, lactate, acetoacetate and beta-hydroxybutyrate in the blood are high. Testing can be performed on samples of skin cells to determine if the pyruvate carboxylase enzyme activity is abnormally low. When deficient, the PC enzyme activity is usually less than 5% of normal activity. Molecular genetic testing for PC gene mutations is available to confirm the diagnosis.
Carrier testing and prenatal diagnosis may be possible by molecular genetic testing if the specific PC gene mutations have been identified in an affected family member.
Treatment of PC deficiency is aimed at providing alternative sources of energy for the body and alternative means of metabolizing pyruvate (anaplerotic therapy). A diet that is low in fat and high in carbohydrates and protein is recommended. Intravenous fluids, hydration and correction of the metabolic acidosis can aid in individual flare-ups for disease management. Thiamine, lipoic acid, dichloroacetate, aspartic acid, and citrate can sometimes help to reduce the levels of pyruvate and lactate. 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 an anaplerotic source of acetyl-CoA and propionyl-CoA. Triheptanoin also may show promise in reversing neurological manifestations but further studies are essential to address this suggestion. Life expectancy was not prolonged in this single reported case.
There is no proven 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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Wang D, De Vivo D. Pyruvate Carboxylase Deficiency. 2009 Jun 2 [Updated 2018 Mar 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6852/ Accessed Jan 13, 2030.
Frye RE, Benke PJ. Pyruvate Carboxylase Deficiency.Medscape. Updated: Aug 09, 2016. https://emedicine.medscape.com/article/125014-overview Accessed Jan 13, 2020.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 266150; Last Updated10/29/2018. Available at https://omim.org/entry/266150 Accessed Jan 13, 2020.
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