Pyruvate Carboxylase Deficiency

Disease Overview

Pyruvate carboxylase deficiency (PC deficiency) is a rare genetic disorder present at or shortly after birth and characterized by failure to thrive, developmental delay, recurrent seizures and 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.

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Synonyms

• ataxia with lactic acidosis, type II
• PC deficiency

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Subdivisions

• pyruvate carboxylase deficiency type A
• pyruvate carboxylase deficiency type B
• pyruvate carboxylase deficiency type C

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Signs & Symptoms

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, abnormal signs and reflexes reflecting damage to 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. This type is the rarest and the most treatable. Only 13 patients have been reported as of 2024

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Causes

PC deficiency is caused by changes (variants) 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 synthesis of the protective sheath around 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 a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.

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Affected populations

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.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be like those of pyruvate carboxylase deficiency. Comparison may be useful for a differential diagnosis.

Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin in infancy. 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 syndrome progresses, symptoms may also include generalized weakness, hypotonia and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome. Most individuals with Leigh syndrome 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 people, Leigh syndrome is inherited in an autosomal recessive pattern. However, X-linked recessive and mitochondrial inheritance have also been described. (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 of the three enzymes in the pyruvate dehydrogenase complex (PDC). The age of onset and severity of disease depends on the activity level of the PDC enzymes. Individuals with PDCD beginning prenatally or postnatally in early infancy usually die in early childhood. Those who develop PDCD later in childhood may have intellectual disability and other neurological symptoms and usually survive into adulthood. Most individuals with PDCD have a variant in the PDHA1 gene located on the X chromosome. Some affected individuals have rarer forms of the disorder that follow autosomal recessive inheritance. Some individuals have a thiamine responsive form of this disorder. (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 recycle 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 be recycled by the body. Biotinidase deficiency is inherited as an autosomal recessive genetic condition. Most affected infants show a widespread red skin rash (eczema), seizures and hypotonia. Older children may also have other developmental delays, lactic acidosis, hearing loss, recurrent infections, optic nerve damage (optic atrophy) and hair loss (alopecia). Daily treatment with biotin is an effective treatment. (For more information about this disorder, choose “biotinidase” as your search term in the Rare Disease Database.)

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Diagnosis

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 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 variants is available to confirm the diagnosis.

Carrier testing and prenatal diagnosis may be possible by molecular genetic testing if the specific PC gene variants have been identified in an affected family member.

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Standard Therapies

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 benefited three PC type C patients by presumably providing a source of acetyl-CoA and propionyl-CoA. Triheptanoin also may show promise in reversing neurological affects, but further studies are needed to address this suggestion. One PC type A patient also benefited from triheptanoin with reversal of hepatic failure and biochemical abnormalites, but life expectancy was not prolonged in this single reported patient.

There is no proven disease modifying therapy currently available to correct or improve neurological symptoms.

Genetic counseling is recommended for families with a child with pyruvate carboxylase deficiency.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov

All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

Bernhardt I, Van Dorp L, Dixon M, et al. Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin. JIMD Rep. 2023;65(1):10-16. Published 2023 Dec 28. doi:10.1002/jmd2.12405

Wang D, De Vivo D. Pyruvate Carboxylase Deficiency. 2009 Jun 2 [Updated 2018 Mar 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6852/ Accessed May 21, 2024.

Frye RE, Benke PJ. Pyruvate Carboxylase Deficiency. Medscape. Updated: Aug 19, 2022. https://emedicine.medscape.com/article/125014-overview Accessed May 21, 2024.

Pyruvate Carboxylase Deficiency. Online Mendelian Inheritance in Man (OMIM). Entry No. 266150; Last Updated 8/17/2023. Available at https://omim.org/entry/266150 Accessed May 21, 2024.

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Programs & Resources

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