miércoles, 11 de julio de 2012

Pyruvate dehydrogenase deficiency - Genetics Home Reference

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Pyruvate dehydrogenase deficiency - Genetics Home Reference




Genetics Home Reference: your guide to understanding genetic conditions





Pyruvate dehydrogenase deficiency

Reviewed July 2012

What is pyruvate dehydrogenase deficiency?

Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills, such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many people with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.

How common is pyruvate dehydrogenase deficiency?

Pyruvate dehydrogenase deficiency is a rare condition; however, its prevalence is unknown.

What genes are related to pyruvate dehydrogenase deficiency?

The genes involved in pyruvate dehydrogenase deficiency each provide instructions for making a protein that is a component of a group of proteins called the pyruvate dehydrogenase complex. This complex plays an important role in the pathways that convert the energy from food into a form that cells can use. The pyruvate dehydrogenase complex converts a molecule called pyruvate, which is formed from the breakdown of carbohydrates, into another molecule called acetyl-CoA. This conversion is essential to begin the series of chemical reactions that produce energy for cells.
The pyruvate dehydrogenase complex is made up of multiple copies of several enzymes called E1, E2, and E3, each of which performs part of the chemical reaction that converts pyruvate to acetyl-CoA. In addition, other proteins included in the complex ensure its proper function. One of these proteins, E3 binding protein, attaches E3 to the complex and provides the correct structure for the complex to perform its function. Other associated proteins control the activity of the complex: pyruvate dehydrogenase phosphatase turns on (activates) the complex, while pyruvate dehydrogenase kinase turns off (inhibits) the complex.
The E1 enzyme, also called pyruvate dehydrogenase, is composed of four parts (subunits): two alpha subunits (called E1 alpha) and two beta subunits (called E1 beta). Mutations in the gene that provides instructions for making E1 alpha, the PDHA1 gene, are the most common cause of pyruvate dehydrogenase deficiency, accounting for approximately 80 percent of cases. These mutations lead to a shortage of E1 alpha protein or result in an abnormal protein that cannot function properly. A decrease in functional E1 alpha leads to reduced activity of the pyruvate dehydrogenase complex.
Other components of the pyruvate dehydrogenase complex are also involved in pyruvate dehydrogenase deficiency. Mutations in the genes that provide instructions for E1 beta (the PDHB gene), the E2 enzyme (the DLAT gene), the E3 enzyme (the DLD gene), E3 binding protein (the PDHX gene), and pyruvate dehydrogenase phosphatase (the PDP1 gene) have been identified in people with this condition. Although it is unclear how mutations in each of these genes affect the complex, reduced functioning of one component of the complex appears to impair the activity of the whole complex. As with PDHA1 gene mutations, changes in these other genes lead to a reduction of pyruvate dehydrogenase complex activity.
With decreased function of this complex, pyruvate builds up and is converted, in another chemical reaction, to lactic acid. The excess lactic acid causes lactic acidosis in affected individuals. In addition, the production of cellular energy is diminished. The brain, which is especially dependent on this form of energy, is severely affected, resulting in the neurological problems associated with pyruvate dehydrogenase deficiency.
Read more about the DLAT, DLD, PDHA1, PDHB, PDHX, and PDP1 genes.

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