Pyruvate Carboxylase Deficiency

Pyruvate Carboxylase Deficiency

National Organization for Rare Disorders, Inc.

Important

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.

Synonyms

  • Ataxia with Lactic Acidosis, Type II
  • PC Deficiency

Disorder Subdivisions

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

General Discussion

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.

Symptoms

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.

Causes

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

Affected Populations

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.

Standard Therapies

Diagnosis

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.

Investigational Therapies

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 National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

JOURNAL ARTICLES

De Meirleir L. Defects of pyrvate metabolism and the Krebs cycle J Child Neurol 2002;Suppl 3:3S26-33; discussion 3S33-4.



Garcia-Cazorla A, Rabier D, Touati G, et al. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol 2006;59(1);121-7.



Higgins JJ, Glasgow AM, Lusk M: MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol 1994 ; 9(4): 436-9.



Mochel F, Delonlay P, Touati G. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab 2005; 84(4): 305-12.



Nyhan WL, Khanna A, Barshop BA. Pyruvate carboxylase deficiency--insights from liver transplantation. Mol Genet Metab 2002; 77(1-2): 143-9.



Schiff M, Levrat V, Acquaviva C, et al, A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation. Mol Genet Metab 2006;87(2):175-7.



Stacpoole PW, Barnes CL, Hurbanis MD: Treatment of congenital lactic acidosis with dichloroacetate [see comments]. Arch Dis Child 1997; 77(6): 535-41.



Ullrich K, Schmidt H, van Teeffelen-Heithoff A: Glycogen storage disease type I and III and pyruvate carboxylase deficiency: results of long-term treatment with uncooked cornstarch. Acta Paediatr Scand 1988 ; 77(4): 531-6.



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.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



United Mitochondrial Disease Foundation

8085 Saltsburg Road Suite 201

Pittsburgh, PA 15239

United States

Tel: (412)793-8077

Fax: (412)793-6477

Tel: (888)317-8633

Email: info@umdf.org

Internet: http://www.umdf.org



Lactic Acidosis Support Trust

1A Whitley Close

Middlewich

Cheshire, CW10 0NQ

United Kingdom

Tel: 0160683719

Fax: 01606837198



NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison

Bldg 31, Rm 9A06

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Tel: (301)496-3583

Email: NDDIC@info.niddk.nih.gov

Internet: http://www2.niddk.nih.gov/



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



MitoAction

14 Pembroke Street

Medford, MA 02155

Tel: (888)648-6228

Fax: (888)648-6228

Email: info@mitoaction.org

Internet: http://www.MitoAction.org



Childhood Liver Disease Research and Education Network

c/o Joan M. Hines, Research Administrator

Children's Hospital Colorado

13123 E 16th Ave. B290

Aurora, CO 80045

Tel: (720)777-2598

Fax: (720)777-7351

Email: joan.hines@childrenscolorado.org

Internet: http://www.childrennetwork.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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