Pyruvate dehydrogenase deficiency ...; Complex deficiency pyruvate dehydrogenase; Lactic acidosis pyruvate dehydrogenase deficiency (Pyruvate dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency) - Genes PDHA1, PDHB, PDHX PDP1 and DLAT

The pyruvate dehydrogenase deficiency (Pyruvate dehydrogenase deficiency), also called lactic acidosis pyruvate dehydrogenase deficiency, a genetic disorder characterized by the accumulation of lactic acid in the body and a variety of neurological problems.

Signs and symptoms associated with the disease usually manifest shortly after birth and may vary among affected individuals. Affected manifest delay in their mental and organic development, with muscular hypotonia, incoordination and difficulty in walking, seizures and episodes of lactic acidosis. Lactic acidosis, which can be potentially fatal, can cause nausea, vomiting, severe breathing problems and abnormal heart rhythm. Some affected individuals have structural abnormalities of the brain, such as underdevelopment of the corpus callosum, cerebral cortex atrophy, or tissue damage in parts of the brain. Because of the serious health effects, many affected individuals do not survive beyond infancy, although some may live into adolescence or adulthood.

This process is due to mutations in the PDHA1, PDHB, PDHX PDP1 and DLAT genes. These genes encode components of pyruvate dehydrogenase complex. This complex has an important role in pathways that convert energy from food into a form that cells can metabolize. The pyruvate dehydrogenase complex pyruvate converts molecule, formed by the decomposition of carbohydrates, acetyl-CoA. This conversion is essential to start the series of chemical reactions that produce energy for cells. The pyruvate dehydrogenase complex is composed of multiple copies of several enzymes called E1, E2, and E3, each of which performs part of the chemical reaction that converts pyruvate into acetyl-CoA. In addition, other proteins within the complex ensure proper operation. One of these proteins, the binding protein E3, provides the correct structure for the complex to perform its function. Other proteins associated control the complex activity: pyruvate dehydrogenase phosphatase active complex, while inhibits pyruvate dehydrogenase kinase complex.

Mutations in the gene PDHA1, located on the short arm of the X chromosome (Xp22.1) are the most common cause of pyruvate dehydrogenase deficiency, which represents approximately 80% percent of cases. This gene encodes the alpha subunit protein E1 of pyruvate dehydrogenase, which forms part of the pyruvate dehydrogenase complex. This enzyme is composed of four subunits , two alpha subunits (encoded by the gene PDHA1) and two beta subunits (encoded by the gene PDHB). They have identified dozens of mutations in the gene PDHA1 in people with pyruvate dehydrogenase deficiency. These mutations have been divided into two groups: one group includes mutations that add or remove nucleotides in the PDHA1 gene, while the other includes mutations that change amino acids in the alpha E1 protein or result in a signal early stop encoding the protein. All of them give rise to a deficiency of alpha E1 protein or a abnormal protein malfunction. E1 alpha decreased functional activity causes less pyruvate dehydrogenase complex. As a consequence, pyruvate is accumulated and converted to lactic acid, causing lactic acidosis. Moreover, cellular energy production is decreased. The brain, which is especially dependent on this form of energy is severely affected, leading to neurological problems associated with the disease.

Meanwhile, mutations in the gene PDHB, located on the short arm of chromosome 3 (3p21.1-p14.2), are a very uncommon cause of pyruvate dehydrogenase deficiency. This gene encodes the beta subunit E1 component of pyruvate dehydrogenase protein. Mutations in this gene change amino acids in the beta protein E1, leading to an abnormal protein encoding beta E1 that can not function properly. The abnormal protein is not able to interact with alpha E1 (encoded by the gene PDHA1) to form the E1 enzyme, or other factors required for the enzyme. Accordingly, a decrease of functional beta E1 causes a reduction of the activity of pyruvate dehydrogenase complex.

In a few individuals affected, mutations have been identified in the PDHX gene, located on the short arm of chromosome 11 (11p13). This gene encodes the E3 - binding protein, which is also part of the pyruvate dehydrogenase complex. The E3 binding protein binds to the complex and provides the correct structure for the complex to perform its function. Gene mutations PDHX associated with pyruvate dehydrogenase deficiency result in a complete absence of the E3 binding protein. The loss of this protein alters the binding of the enzyme to the E3 pyruvate dehydrogenase complex, reducing the activity of the complex.

The PDP1 (pyruvate dehydrogenase phosphatase activity -PDP1- subunit 1) gene, located on the long arm of chromosome 8 (8q22.1), encodes pyruvate dehydrogenase protein phosphatase 1. Mutations in the gene PDP1 are a rare cause of disease. The most frequent mutation eliminates an amino acid pyruvate dehydrogenase protein phosphatase 1, which is believed to change its shape. The abnormal protein can not remove the phosphate group of pyruvate dehydrogenase complex, reducing the activity of the complex.

Finally, the DLAT gene, located on the long arm of chromosome 11 (11q23.1), encodes the enzyme E2 (also known as dihydrolipoamide acetyltransferase), which is part of the pyruvate dehydrogenase complex. At least 2 DLAT gene mutations have been identified in individuals with pyruvate dehydrogenase deficiency. Mutations in this gene are a rare cause of this disease. These mutations result in abnormal coding E2 enzyme, causing a reduction of the activity of pyruvate dehydrogenase complex.

Pyruvate dehydrogenase deficiency may have different patterns of inheritance. When the disease is due to mutations in the gene PDHA1 is inherited with a recessive X - linked pattern in males, an altered copy of the gene in each cell is sufficient to express the disease. In women (who have two X chromosomes), a mutation usually has to occur in both copies of the gene expressing the disease. However, pyruvate dehydrogenase deficiency, an altered copy of PDHA1 gene is sufficient to cause disease, because the X chromosome with the normal copy of the gene is deactivated PDHA1 through a process called X-inactivation. Women with pyruvate dehydrogenase deficiency caused by mutation of the gene are biased PDHA1 X-inactivation, resulting in inactivation of the X chromosome with the normal gene copy PDHA1 in most cells in the body. This skewed X-chromosome inactivation causes the mutated gene is expressed in PDHA1 more than half of the cells. When the disease is due to mutations in other genes associated (PDHB, PDHX PDP1 and DLAT), is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations that altered to express . The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with pyruvate dehydrogenase deficiency, by complete PCR amplification of the exons of the genes PDHA1, PDHB, PDHX PDP1 and DLAT, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).