55 Kenosia Avenue
Danbury, CT 06810
Phone: 203.744.0100
Toll Free: 1.800.999.6673

PEPCK Deficiency

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1992, 1999, 2006, 2007

Synonyms of PEPCK Deficiency

Disorder Subdivisions

General Discussion

PEPCK deficiency is an extremely rare disorder of carbohydrate metabolism inherited as an autosomal recessive trait. A deficiency of the enzyme phosphoenolpyruvate carboxykinase (PEPCK), which is a key enzyme in the conversion of proteins and fat to glucose (gluconeogenesis), causes an excess of acid in the circulating blood (acidemia). Characteristics of this disorder are low blood sugar (hypoglycemia), loss of muscle tone, liver enlargement and impairment, and failure to gain weight and grow normally.


There are two forms of PEPCK deficiency: cytosolic and mitochondrial. Both forms represent an inherited deficiency in the enzyme phosphoenolpyruvate carboxykinase. This enzyme is key in the process of converting proteins and fat to glucose (gluconeogenesis).

Symptoms of this disorder include the presence of excess acid in the circulating blood (lactic acidemia); loss of muscle tone (hypotonia); abnormal enlargement of the liver (hepatomegaly); inability to gain appropriate weight and grow normally (failure to thrive); and an abnormally low blood sugar (glucose) level (hypoglycemia). Glucose is essential as the body's source of energy, and for the functioning of many organs and systems in the body, especially the central nervous system.

At or shortly after birth, the infant with PEPCK deficiency may have an enlarged liver, apnea, and a moderate delay in motor functions. Poor appetite, vomiting, coma, convulsions, and seizures may be present. Liver impairment produces increased liver enzymes, alanine, glycine, and glutamine levels. At least one case reported to date has involved atrophy of the optic nerve.

The course of this disorder can be very rapid.


PEPCK deficiencies, in both forms, are very rare disorders that are inherited as autosomal recessive traits. The abnormal gene that is responsible for the cytosolic (soluble) form of PEPCK deficiency has been traced to gene map locus 20q13.31.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 20q13.31" refers to band 13.31 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait 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, therefore, 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 a few 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

PEPCK deficiency is extremely rare. One overview suggests that only 10 cases have been reported in the medical literature.

Related Disorders

Symptoms of the following disorders can be similar to those of PEPCK deficiency disorder. Comparisons may be useful for a differential diagnosis:

Fructose-1,6-bisphosphatase deficiency
Fructose 1,6-bisphosphatase (FBPase) (also termed fructose 1,6-diphosphatase) is a key enzyme in gluconeogenesis. It permits glucose production from sources such as amino acids (eg, alanine and glycine), glycerol, or lactate.

Korsakoff's syndrome is a deficiency of vitamin B-1 (thiamine) which causes cardiovascular, central and peripheral nervous system disturbances. The disease results from either inadequate dietary intake of B-2 or from impaired absorption or utilization of vitamin B-1. It is common in the orient where excessive milling of rice reduces its thiamine content. (For more information on this disorder, choose "Korsakoff" as your search term in the Rare Disease Database.)

Leigh's disease is a rare genetic metabolic disorder characterized by lesions of the brain, spinal chord, optic nerve and in some cases, an enlarged heart. Symptoms during infancy may include low body weight, slow growth, tremors, skin changes and interrupted breathing patterns. Progressive neurological disturbances, mental retardation, slurred speech and loss of motor coordination (ataxia) may occur in cases beginning during or after infancy. (For more information on this disorder, choose "Leigh" as your search term in the Rare Disease Database.)

Pyruvate carboxylase deficiency is a rare metabolic disorder in which there is a deficiency of the enzyme pyruvate carboxylase. This disorder causes an excess presence of acid in the circulating blood (lactic acidemia), neurologic deterioration, vomiting, irritability, inactivity, loss of muscle tone, abnormal eye movements, and seizures. The course of this disorder is progressive. It is inherited through an autosomal recessive trait. (For more information on this disorder, choose "Pyruvate Carboxylase " as your search term in the Rare Disease Database.)

Pyruvate dehydrogenase deficiency is a rare disorder of carbohydrate metabolism inherited through an autosomal recessive trait. Symptoms are caused by a deficiency of the enzyme pyruvate dehydrogenase resulting in persistent or recurrent metabolic acidosis (acidemia). The disorder is manifested by mental retardation and other neurological symptoms. (For more information on this disorder, choose "Pyruvate Dehydrogenase" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis of PEPCK deficiency can be made shortly after birth by biochemical analysis of fibroblast cells.

Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.

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 NIH Clinical Center 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:

PEPCK Deficiency Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:


Sutyherland C. PEPCK Deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:486.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:182.

Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:2288; 2290.

Clarke JTR. A Clinical Guide to Inherited Metabolic Diseases. 1st ed. Cambridge University Press, Cambridge, UK; 1996:108.

Van den Berghe G. Disorders of gluconeogenesis. J Inher Metab Dis. 1996;19:470-77.

Modaressi S. Christ B. Bratke J, Zahn S, Heise T, Jungermann K. Molecular cloning, sequencing and expression of the cDNA of the mitochondrial form of phosphoenolpyruvate carboxykinase from human liver. Biochem J. 1996;315:807-14.

Leonard JV, Hyland K, Furukawa N, Clayton PT. Mitochondrial phosphoenolpyruvate carboxykinase deficiency. Eur J Pediatr. 1991;150:198-99.

Cao H, van der Veer, Ban MR, Hanley AJG, et al. Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus. J Clin Endocr Metab. 2004;89:898-903.

Yu H, Thun R, Chandrasekharappa S, Trent JM, Zhang J, Meisler MH. Human PCK1 encoding phosphoenolpyruvate carboxykinase is located on chromosome 20q13.2. Genomics. 1993;15:219-21.

Vidnes J, Sovik O. Gluconeogenesis in infancy and childhood. III. Deficiency of the extramitochondrial form of hepatic phosphoenolpyruvate carboxykinase in a case of persistent neonatal hyperglycaemia. Acta Paediatr Scand. 1976;15:219-21.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Phosphoenolpyruvate Carboxykinase 1, Soluble; PCK1. Entry Number; 261-680: Last Edit Date; 4/12/2005.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Phosphoenolpyruvate Carboxykinase 2, Mitochondrial; PCK2. Entry Number; 261650: Last Edit Date;7/13/2004.

Phosphoenolpyruvate carboxykinase (PEPCK) deficiency. Orphanet. Update 20/08/2006. 1p.

King MW. Gluconeogenesis. Indiana State University. Last modified: 22-Mar-2006. 9pp.

Report last updated: 2007/09/23 00:00:00 GMT+0