Pyruvate carboxylase deficiency

Definition

Pyruvate carboxylase deficiency (PCD) is a rare non-sex linked (autosomal) disorder that results from an insufficient amount of the enzyme pyruvate carboxylase. This disorder is inherited as a recessive trait and it is known to be caused by more than one different mutation in the same gene (allelic variants).

Description

There are two recognized types of pyruvate carboxylase deficiency, neonatal PCD (type B) and infantile onset PCD (type A). Neonatal PCD is associated with a complete, or near complete, inability to produce pyruvate carboxylase. Infantile onset PCD is associated with a chemical change in the pyruvate carboxylase enzyme that prevents this slightly different chemical from functioning as efficiently as the normal pyruvate carboxylase enzyme.

In order for the cells of the body to function properly, they must have energy. This energy comes in the form of the chemical ATP. ATP is primarily produced by breaking down carbohydrates and blood sugar (glucose) molecules. To begin the process of converting glucose and carbohydrates into usable energy, these molecules are first converted into pyruvate molecules. Once pyruvate molecules have been formed, one of two things will happen: if more energy is required by the cell, the molecules will be further broken down into ATP; or, if no additional energy is needed by the cell, the pyruvate molecules will be put back together to reform a glucose molecule.

These transformations of pyruvate are accomplished primarily by two enzymes: pyruvate dehydrogenase (PDH), an enzyme that begins the breakdown of the pyruvate into ATP, and pyruvate carboxylase, an enzyme that begins the chemical process to reform glucose molecules. The reformation of glucose from pyruvate is a vital step in cellular metabolism. It allows carbohydrate molecules to be converted into a more readily usable form (glucose). Glucose is not only easier to breakdown into the energy required by the cells, but it is also more able to be transported through the bloodstream than most other fuel sources. This is particularly important because certain cells (primarily those of the brain and nervous system) cannot breakdown larger molecules; they must get their energy directly from glucose.

Pyruvate carboxylase is, in effect, part of the "off switch" for the production of ATP from pyruvate. After a cell has received the amount of ATP it requires, it is the job of pyruvate carboxylase to re-convert the excess pyruvate molecules in that cell back into glucose molecules for storage or transport to another part of the body where they may be needed. Any molecules that are not put back together will degrade into lactic acid. This lactic acid will either be released into the bloodstream or it will buildup in the tissues. The buildup of lactic acid in the muscle tissues and red blood cells is normal during strenuous exercise. However, the accumulation of lactic acid in other tissues without exercise or without oxygen deprivation is symptomatic of an underlying problem in the normal metabolism of the cells.

People with PCD have either a complete inability or a severely limited ability to produce pyruvate carboxylase. Since these individuals cannot produce the amounts of this enzyme required to form glucose from pyruvate, this pyruvate is converted instead into lactic acid, which builds up in the cells. Additionally, since glucose cannot be adequately formed within the body of a pyruvate carboxylase deficient individual, all the glucose required by the body must be ingested. This causes a glucose shortage that leads to low blood sugar (hypoglycemia) and a progressive degeneration of the tissues, with the most profound effects observed in the brain and central nervous system, since these tissues are the most reliant on the use of glucose for energy.

Pyruvate carboxylase is also important in the process that removes excess nitrogen from the body (the urea cycle). Since pyruvate carboxylase deficient individuals do not have sufficient quantities of pyruvate carboxylase, they develop a build-up of nitrogen, in the form of ammonia, in the bloodstream and the tissues.

Genetic profile

The gene that is responsible for the production of pyruvate carboxylase has been localized to a small region of chromosome 11. There are at least three mutations in this gene that lead to type B PCD. There is only one known mutation that leads to type A PCD.

Both types of PCD are transmitted via a recessive trait which means that both parents must be carriers of the mutation in order for it to occur in their children. In the case of parents with one child affected with PCD, the likelihood that a second child will be affected with PCD is 25%.

Demographics

PCD is estimated to occur in approximately one in every 250,000 live births, although only 39 cases had been described in the literature prior to 2001.

Type A PCD is also called North American PCD because it occurs almost exclusively in Algonquin language-speaking Native North Americans. In the Micmac, Cree, and Ojibwa tribes of Canada, it is estimated that as high as one in 10 individuals are carriers of the mutation that causes type A PCD. This suggests a founder effect in these populations. A founder effect is a genetic term that means a single individual brought a mutation into a subpopulation at a time when the subpopulation was quite small. As a result, a large majority of the members of the subpopulation carry the mutation derived through direct ancestry to this one individual.

Type B PCD is also called French PCD because it has a much higher incidence among the French than among any other subpopulation.

Signs and symptoms

Type A, or infantile onset, PCD may be fatal prior to birth, or it may not present any symptoms until approximately three months of age. These individuals will show severe physical and mental delay. Additionally, children affected with type A PCD have a progressive degeneration of the entire brain and nervous system (necrotizing encephalomyelopathy) that eventually leads to death.

Type B, or neonatal, PCD is generally fatal prior to birth. In the rare instances of a liveborn child affected with type B PCD, severe growth delay (extremely low birth weight) and severe mental impairment are to be expected. Children born with type B PCD will fail to thrive and generally do not survive past the first three months of life.

Diagnosis

PCD is diagnosed primarily through blood tests to determine the blood concentrations of lactate and pyruvate. Extremely high levels of both of these chemicals in the blood indicate that a congenital problem in cellular metabolism is most likely present. PCD is often differentiated from other cellular metabolic disorders by the extreme speed with which glucose levels in the blood drop during fasting (fasting hypoglycemia) and the abnormally low levels of the chemical aspartic acid in the blood.

PCD can be tested prenatally by measuring the activity of pyruvate carboxylase in chorionic villi samples.

Treatment and management

Administration of aspartic acid has been successful in decreasing the pyruvate and lactate concentrations in the blood of some PCD affected individuals. But, this treatment does not repair the damage to the pyruvate carboxylase enzyme, so progressive degeneration of the nervous system is slowed only slightly and the outcome is still death.

Biotin (a B-complex vitamin) is a coenzyme to pyruvate carboxylase. It has been shown that type B PCD is responsive to treatment with biotin while type A is not. Therefore, in the rare instance of a liveborn child with type B PCD, life may be extended through the administration of biotin.

Prognosis

Without prenatal administration of enzyme replacement therapy (which is currently not available), in which the developing fetus is given an artificial form of pyruvate carboxylase, individuals affected with either type A or type B PCD will die either prior to birth or, generally, within the first six months of life. Without prenatal enzyme replacement therapy, most children affected with PCD are born with such brain and nervous system dysfunction that a decision has to be made about treatment to sustain life.

Resources

BOOKS

Al-Essa, M. A., and P. T. Ozand. Manual of Metabolic Disease. Riyadh, Saudi Arabia: King Faisal Specialist Hospital and Research Centre, 1998.

PERIODICALS

Brun, N., et al. "Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form." American Journal of Medical Genetics (May 1999): 94–101.

Van Costner, R. N., S. Janssens, and J. P. Mission. "Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples." Prenatal Diagnosis (October 1998): 1041–4.

ORGANIZATIONS

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

United Mitochondrial Disease Foundation. PO Box 1151, Monroeville, PA 15146-1151. (412) 793-8077. Fax: (412) 793-6477. <http://www.umdf.org>.

WEBSITES

Frye, Richard E., et al. "Pyruvate carboxylase deficiency." eMedicine November 6, 2001 [cited February 27, 2001]. <http://www.emedicine.com/ped/topic1967.htm>.

Kuang, Wanli, Patricia Sun, Katrina Traber, and Hilary Weiss. "Pyruvate Carboxylase Deficiency." American Medical Association at New York University School of Medicine. 1999 [cited February 27, 2001]. <http://endeavor.med.nyu.edu/student-org/ama/docs/mgb1999-2000/ab12.htm>.

"Pyruvate Carboxylase Deficiency." Online Mendelian Inheritance in Man (OMIM). September 10, 2002 [cited February 27, 2001]. <http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?266150>.

Paul A. Johnson