Pyruvate carboxylase deficiency

Reviewed August 2006

What is pyruvate carboxylase deficiency?

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system.

Researchers have identified at least three types of pyruvate carboxylase deficiency, which are distinguished by the severity of their signs and symptoms. Type A, which has been identified mostly in people from North America, has moderately severe symptoms that begin in infancy. Characteristic features include developmental delay and a buildup of lactic acid in the blood (lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. In some cases, episodes of lactic acidosis are triggered by an illness or periods without food (fasting). Children with pyruvate carboxylase deficiency type A typically survive only into early childhood.

Pyruvate carboxylase deficiency type B has life-threatening signs and symptoms that become apparent shortly after birth. This form of the condition has been reported mostly in Europe, particularly France. Affected infants have severe lactic acidosis, a buildup of ammonia in the blood (hyperammonemia), and liver failure. They experience neurological problems including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with this form of the condition usually survive for less than 3 months after birth.

A milder form of pyruvate carboxylase deficiency, sometimes called type C, has also been described. This type is characterized by slightly increased levels of lactic acid in the blood and minimal signs and symptoms affecting the nervous system.

How common is pyruvate carboxylase deficiency?

Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. This disorder appears to be much more common in some Algonkian Indian tribes in eastern Canada.

What genes are related to pyruvate carboxylase deficiency?

Mutations in the PC gene cause pyruvate carboxylase deficiency.

The PC gene provides instructions for making an enzyme called pyruvate carboxylase. This enzyme is active in mitochondria, which are the energy-producing centers within cells. It is involved in several important cellular functions including the generation of glucose, a simple sugar that is the body's main energy source. Pyruvate carboxylase also plays a role in the formation of the protective sheath that surrounds certain nerve cells (myelin) and the production of brain chemicals called neurotransmitters.

Mutations in the PC gene reduce the amount of pyruvate carboxylase in cells or disrupt the enzyme's activity. The missing or altered enzyme cannot carry out its essential role in generating glucose, which impairs the body's ability to make energy in mitochondria. Additionally, a loss of pyruvate carboxylase allows potentially toxic compounds such as lactic acid and ammonia to build up and damage organs and tissues. Researchers suggest that the loss of pyruvate carboxylase function in the nervous system, particularly the role of the enzyme in myelin formation and neurotransmitter production, also contributes to the neurologic features of pyruvate carboxylase deficiency.

Related Gene(s)

Changes in this gene are associated with pyruvate carboxylase deficiency.

How do people inherit pyruvate carboxylase deficiency?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of pyruvate carboxylase deficiency?

These resources address the diagnosis or management of pyruvate carboxylase deficiency and may include treatment providers.

Gene Review: Pyruvate Carboxylase Deficiency (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pdc)
Gene Tests: Pyruvate Carboxylase Deficiency (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/214456)

You might also find information on the diagnosis or management of pyruvate carboxylase deficiency in Educational resources (http://ghr.nlm.nih.gov/condition/pyruvate-carboxylase-deficiency/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/pyruvate-carboxylase-deficiency/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about pyruvate carboxylase deficiency?

You may find the following resources about pyruvate carboxylase deficiency helpful. These materials are written for the general public.

MedlinePlus - Health information
- Health Topic: Metabolic Disorders (http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html)
- Health Topic: Neurologic Diseases (http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html)
- Health Topic: Newborn Screening (http://www.nlm.nih.gov/medlineplus/newbornscreening.html)
Educational resources - Information pages
- Merck Manual Home Edition for Patients and Caregivers (http://www.merckmanuals.com/home/childrens_health_issues/hereditary_metabolic_disorders/disorders_of_carbohydrate_metabolism.html)
- Orphanet (http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=3008)
Patient support - For patients and families
- Children Living with Inherited Metabolic Diseases (CLIMB) (UK) (http://www.climb.org.uk/)
- National Organization for Rare Disorders (http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/873/viewAbstract)
- Resource list from the University of Kansas Medical Center (http://www.kumc.edu/gec/support/metaboli.html)
- United Mitochondrial Disease Foundation (http://www.umdf.org/site/c.8qKOJ0MvF7LUG/b.7929671/k.BDF0/Home.htm)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pdc)
Gene Tests - Genetic tests ordered by healthcare professionals (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/214456)
ACT Sheets - Newborn screening follow up
- Increased citrulline (http://www.ncbi.nlm.nih.gov/books/NBK55827/bin/Citrullinemia.pdf)
ClinicalTrials.gov - Linking patients to medical research (http://clinicaltrials.gov/ct2/results?cond=%22pyruvate%20carboxylase%20deficiency%22%20OR%20%22Pyruvate%20Metabolism%2C%20Inborn%20Errors%22)
PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=(pyruvate%20carboxylase%20deficiency%5BTIAB%5D)%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%203600%20days%22%5Bdp%5D)
OMIM - Genetic disorder catalog (http://omim.org/entry/266150)

What other names do people use for pyruvate carboxylase deficiency?

Ataxia with Lactic Acidosis, Type II
PC deficiency
Pyruvate Carboxylase Deficiency Disease

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about pyruvate carboxylase deficiency?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding pyruvate carboxylase deficiency?

acidity ; acidosis ; acids ; ammonia ; ataxia ; autosomal ; autosomal recessive ; carboxylase ; cell ; coma ; compound ; deficiency ; developmental delay ; enzyme ; fasting ; gene ; glucose ; hyperammonemia ; hypotonia ; incidence ; lactic acid ; lactic acidosis ; liver failure ; mitochondria ; muscle tone ; mutation ; nerve cell ; nervous system ; neurologic ; neurological ; neurotransmitters ; newborn screening ; recessive ; screening ; seizure ; sign ; simple sugar ; symptom ; tissue ; toxic

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

Brun N, Robitaille Y, Grignon A, Robinson BH, Mitchell GA, Lambert M. Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am J Med Genet. 1999 May 21;84(2):94-101. (http://www.ncbi.nlm.nih.gov/pubmed/10323732?dopt=Abstract)
Carbone MA, Applegarth DA, Robinson BH. Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings. Hum Mutat. 2002 Jul;20(1):48-56. (http://www.ncbi.nlm.nih.gov/pubmed/12112657?dopt=Abstract)
Carbone MA, MacKay N, Ling M, Cole DE, Douglas C, Rigat B, Feigenbaum A, Clarke JT, Haworth JC, Greenberg CR, Seargeant L, Robinson BH. Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet. 1998 Jun;62(6):1312-9. (http://www.ncbi.nlm.nih.gov/pubmed/9585612?dopt=Abstract)
García-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P, Saudubray JM. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol. 2006 Jan;59(1):121-7. (http://www.ncbi.nlm.nih.gov/pubmed/16278852?dopt=Abstract)
Schiff M, Levrat V, Acquaviva C, Vianey-Saban C, Rolland MO, Guffon N. A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation. Mol Genet Metab. 2006 Feb;87(2):175-7. Epub 2005 Dec 1. (http://www.ncbi.nlm.nih.gov/pubmed/16325442?dopt=Abstract)
Wexler ID, Kerr DS, Du Y, Kaung MM, Stephenson W, Lusk MM, Wappner RS, Higgins JJ. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediatr Res. 1998 May;43(5):579-84. (http://www.ncbi.nlm.nih.gov/pubmed/9585002?dopt=Abstract)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.



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