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 individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.

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), 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 requires especially large amounts of energy, is severely affected, resulting in the neurological problems associated with pyruvate dehydrogenase deficiency.

Normal Function

The DLAT gene provides instructions for making the E2 enzyme (also known as dihydrolipoamide acetyltransferase), which is part of a large group of proteins called the pyruvate dehydrogenase complex. This complex comprises multiple copies of three enzymes, including E2, and several related proteins. The E2 enzyme is the core to which the other proteins attach to form the complex.

The pyruvate dehydrogenase complex plays an important role in the pathways that convert the energy from food into a form that cells can use. This complex converts a molecule called pyruvate, which is formed from the breakdown of carbohydrates, into another molecule called acetyl-CoA. The E2 enzyme performs one part of this chemical reaction. The conversion of pyruvate is essential to begin the series of chemical reactions that produces adenosine triphosphate (ATP), the cell's main energy source.

Health Conditions Related to Genetic Changes

Pyruvate dehydrogenase deficiency

At least two mutations in the DLAT gene have been identified in individuals with pyruvate dehydrogenase deficiency; mutation of the DLAT gene is a very rare cause of this condition. Pyruvate dehydrogenase deficiency is characterized by a potentially life-threatening buildup of a chemical called lactic acid in the body (lactic acidosis), delayed development, and neurological problems.

Mutations in the DLAT gene lead to an abnormal E2 enzyme and reduced activity of the pyruvate dehydrogenase complex, although the mechanism is unclear. With decreased activity of this complex, pyruvate builds up and is converted, in another chemical reaction, to lactic acid, causing lactic acidosis. 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.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• 70 kDa mitochondrial autoantigen of primary biliary cirrhosis
• dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex
• dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial
• DLTA
• E2 component of pyruvate dehydrogenase complex
• M2 antigen complex 70 kDa subunit
• ODP2_HUMAN
• PBC
• PDC-E2
• PDCE2
• pyruvate dehydrogenase complex component E2

Genomic Location

Normal Function

The PDHA1 gene provides instructions for making a protein called E1 alpha. The E1 alpha protein is a piece (a subunit) of a larger protein: two E1 alpha proteins combine with two copies of another protein called E1 beta (produced from the PDHB gene) to form the E1 enzyme. This enzyme, also known as pyruvate dehydrogenase, is a component of a group of proteins called the pyruvate dehydrogenase complex.

The pyruvate dehydrogenase complex plays an important role in the pathways that convert the energy from food into a form that cells can use. This complex converts a molecule called pyruvate, which is formed from the breakdown of carbohydrates, into another molecule called acetyl-CoA. The E1 enzyme performs one part of this chemical reaction. The conversion of pyruvate is essential to begin the series of chemical reactions that produces adenosine triphosphate (ATP), the cell's main energy source.

Health Conditions Related to Genetic Changes

Pyruvate dehydrogenase deficiency

Mutations in the PDHA1 gene are the most common cause of pyruvate dehydrogenase deficiency, accounting for approximately 80 percent of cases of this condition. Pyruvate dehydrogenase deficiency is characterized by a potentially life-threatening buildup of a chemical called lactic acid in the body (lactic acidosis), delayed development, and neurological problems. Dozens of PDHA1 gene mutations have been identified in affected individuals. These mutations have been divided into two groups. One group includes mutations that add or remove DNA building blocks (nucleotides) to the PDHA1 gene (called insertion and deletion mutations, respectively). These types of mutations occur more commonly in affected females than males. The other group includes mutations that change single protein building blocks (amino acids) in the E1 alpha protein or result in a premature stop signal in the instructions for making the protein (called missense and nonsense mutations, respectively). These types of mutations occur in affected males more often than females.

Mutations in the PDHA1 gene associated with pyruvate dehydrogenase deficiency lead to a reduction in the amount of E1 alpha protein or result in an abnormal protein that cannot function properly. The abnormal protein may not be able to interact with E1 beta to form the E1 enzyme or with other factors needed for the E1 enzyme to perform its chemical reaction. A decrease in functional E1 alpha results in reduced pyruvate dehydrogenase complex activity. With decreased function of this complex, pyruvate builds up and is converted, in another chemical reaction, to lactic acid, causing lactic acidosis. 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.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• ODPA_HUMAN
• PDHA
• PDHCE1A
• PDHE1-A type I
• PHE1A
• pyruvate dehydrogenase (lipoamide) alpha 1
• pyruvate dehydrogenase alpha 1
• pyruvate dehydrogenase complex, E1-alpha polypeptide 1
• pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial

Genomic Location

Normal Function

The PDHB gene provides instructions for making a protein called E1 beta. E1 beta is a piece (a subunit) of a larger protein: two E1 beta proteins combine with two copies of another protein, called E1 alpha (produced from the PDHA1 gene), to form the E1 enzyme. This enzyme, also known as pyruvate dehydrogenase, is a component of a group of proteins called the pyruvate dehydrogenase complex.

The pyruvate dehydrogenase complex plays an important role in the pathways that convert the energy from food into a form that cells can use. This complex converts a molecule called pyruvate, which is formed from the breakdown of carbohydrates, into another molecule called acetyl-CoA. The E1 enzyme performs one part of this chemical reaction. The conversion of pyruvate is essential to begin the series of chemical reactions that produces adenosine triphosphate (ATP), the cell's main energy source.

Health Conditions Related to Genetic Changes

Pyruvate dehydrogenase deficiency

Mutations in the PDHB gene are a very rare cause of pyruvate dehydrogenase deficiency. This condition is characterized by a potentially life-threatening buildup of a chemical called lactic acid in the body (lactic acidosis), delayed development, and neurological problems. These mutations change single protein building blocks (amino acids) in the E1 beta protein, resulting in an abnormal E1 beta protein that cannot function properly. The abnormal protein may not be able to interact with E1 alpha to form the E1 enzyme or with other factors needed for the E1 enzyme to perform its chemical reaction. A decrease of functional E1 beta leads 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, causing lactic acidosis. 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.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• ODPB_HUMAN
• PDHBD
• PDHE1-B
• PDHE1B
• PHE1B
• pyruvate dehydrogenase (lipoamide) beta
• pyruvate dehydrogenase E1 component subunit beta, mitochondrial
• pyruvate dehydrogenase, E1 beta polypeptide

Genomic Location

Normal Function

The PDHX gene provides instructions for making a protein called E3 binding protein, which is part of a large group of proteins known as the pyruvate dehydrogenase complex. This complex is made up of several enzymes, including one called E3, and other proteins. E3 binding protein attaches E3 to the complex and provides the correct structure for the complex to perform its function.

The pyruvate dehydrogenase complex plays an important role in the pathways that convert the energy from food into a form that cells can use. This enzyme 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 produces adenosine triphosphate (ATP), the cell's main energy source.

Health Conditions Related to Genetic Changes

Pyruvate dehydrogenase deficiency

Mutations in the PDHX gene cause pyruvate dehydrogenase deficiency in a small number of people. This condition is characterized by a potentially life-threatening buildup of a chemical called lactic acid in the body (lactic acidosis), delayed development, and neurological problems. PDHX gene mutations associated with pyruvate dehydrogenase deficiency result in the complete absence of E3 binding protein. Loss of this protein impairs the binding of the E3 enzyme to the pyruvate dehydrogenase complex, which leads to a reduction of the complex's activity. With decreased function of this complex, pyruvate builds up and is converted, in another chemical reaction, to lactic acid, causing lactic acidosis. 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.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• dihydrolipoamide dehydrogenase-binding protein of pyruvate dehydrogenase complex
• DLDBP
• E3BP
• lipoyl-containing pyruvate dehydrogenase complex component X
• ODPX_HUMAN
• OPDX
• proX
• pyruvate dehydrogenase complex, component X
• pyruvate dehydrogenase complex, E3-binding protein subunit
• pyruvate dehydrogenase complex, lipoyl-containing component X
• pyruvate dehydrogenase protein X component, mitochondrial

Genomic Location

Normal Function

The PDP1 gene provides instructions for making a protein called pyruvate dehydrogenase phosphatase 1, which is part of a large group of proteins called the pyruvate dehydrogenase complex. The pyruvate dehydrogenase phosphatase 1 protein turns on (activates) the complex by removing a phosphate group (a cluster of oxygen and phosphorus atoms) from the complex.

The pyruvate dehydrogenase complex plays an important role in the pathways that convert the energy from food into a form that cells can use. This enzyme 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 produces adenosine triphosphate (ATP), the cell's main energy source.

Health Conditions Related to Genetic Changes

Pyruvate dehydrogenase deficiency

At least one mutation in the PDP1 gene has been identified in individuals with pyruvate dehydrogenase deficiency; mutation of the PDP1 gene is a very rare cause of this condition. Pyruvate dehydrogenase deficiency is characterized by a potentially life-threatening buildup of a chemical called lactic acid in the body (lactic acidosis), delayed development, and neurological problems.

The identified mutation removes one protein building block (amino acid) of the pyruvate dehydrogenase phosphatase 1 protein, which is thought to change its shape. The abnormal protein cannot remove the phosphate group from the pyruvate dehydrogenase complex, which reduces the activity of the complex. With decreased activity of this complex, pyruvate builds up and is converted, in another chemical reaction, to lactic acid, causing lactic acidosis. 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.

Other Names for This Gene

• PDH
• PDP
• PDP 1
• PDP1_HUMAN
• PDPC
• PDPC 1
• PPM2C
• protein phosphatase 2C, magnesium-dependent, catalytic subunit
• pyruvate dehydrogenase (Lipoamide) phosphatase-phosphatase
• pyruvate dehydrogenase [acetyl-transferring]]-phosphatase 1, mitochondrial
• pyruvate dehyrogenase phosphatase catalytic subunit 1

Genomic Location

Pyruvate dehydrogenase deficiency can have different inheritance patterns. When the condition is caused by mutations in the PDHA1 gene, it is inherited in an X-linked pattern. The PDHA1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males, who have only one X chromosome, a mutation in the only copy of the gene in each cell is sufficient to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In females, who have two copies of the X chromosome, one altered copy of the PDHA1 gene in each cell can lead to less severe features of the condition or may cause no signs or symptoms at all. However, many females with one altered copy of this gene have pyruvate dehydrogenase deficiency similar to affected males because the X chromosome with the normal copy of the PDHA1 gene is turned off through a process called X-inactivation. Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body cells. Sometimes X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.

Research shows that females with pyruvate dehydrogenase deficiency caused by mutation of the PDHA1 gene often have skewed X-inactivation, which results in the inactivation of the X chromosome with the normal copy of the PDHA1 gene in most cells of the body. This skewed X-inactivation causes the chromosome with the mutated PDHA1 gene to be expressed in more than half of cells.

When caused by mutations in other genes, pyruvate dehydrogenase deficiency 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.

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