Genes or Chromosomes Affected by the Pyruvate Dehydrogenase Deficiency
The main culprit for the pyruvate dehydrogenase deficiency is the mutations in the PDHA1 gene that is inherited in an X-linked pattern. The PDHA1 gene contains instructions for the making of the protein E1 alpha. However, E1 alpha is part of a larger protein, where two E1 alpha proteins combine with two other proteins known as E1 beta to create the E1 enzyme. The E1 beta protein comes from the PDHB gene. The E1 enzyme is also known as the pyruvate dehydrogenase and is part of a set of proteins that make up the pyruvate dehydrogenase complex. Additionally, the pyruvate dehydrogenase complex is essential to the pathways that help convert food into energy usable by the cells. For instance, the complex breaks down carbohydrates into acetyl-CoA, thus making the pyruvate complex the starting point for converting carbohydrates into adenosine triphosphate.
The PDHA1 gene is part of the X chromosome. On the one hand, if a mutation happens in a male, it is sufficient to cause pyruvate dehydrogenase deficiency as males only have one X chromosome. X-linked inheritance, however, does not allow fathers to pass X-linked traits to their sons. Therefore, pyruvate dehydrogenase deficiency is not hereditary from father to son. Females, on the other hand, have two copies of the X chromosome. Suppose one copy of the PDHA1 gene is altered (mutated), it is enough to cause pyruvate dehydrogenase deficiency. The difference is that there would be neither signs nor symptoms. However, through X-inactivation, females with mutated copies of the PDHA1 gene will have the condition accompanied by all of its signs and symptoms. Such is the case because X-inactivation will turn off the unaltered copy of the gene.
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All these happen in the early phases of embryonic development where, in the somatic cells, one of the two X chromosomes is permanently inactivated. The X-inactivation ensures that both sexes, especially males, have only one active copy of the X chromosome in each cell. Normally, X-inactivation is a random process. As a result, half of the body cells each have an active copy of the X chromosome. Sometimes, however, X-inactivation is not random, and one chromosome is active in more than half of the body cells. This condition is known as skewed X-inactivation.
There is a higher correlation between females with pyruvate dehydrogenase deficiency resulting from mutations in the PDHA1 gene and skewed X-inactivation. The impact skewed inactivation has is that in more than half of the body cells, the mutated copy of the PDHA1 gene is expressed. The outcome is that the individual, shortly after birth, will build up lactic acid in their bodies. This build-up is potentially life-threatening, whose symptoms include vomiting, nausea, arrhythmia, abnormal heartbeat, and severe breathing problems. Pyruvate dehydrogenase deficiency also creates neurological problems, especially degeneration and development problems in cognitive function and motor skills. Additionally, some individuals will develop abnormal brain structures like underdeveloped corpus callosum, atrophy, and lesions in the cerebral cortex. Even then, pyruvate dehydrogenase deficiency is largely classified as a rare condition with unknown prevalence.
Specific Mutations Inherent in the Disorder
As briefly described in the previous section, the genes that result in pyruvate dehydrogenase deficiency contain the instructions to make the pyruvate dehydrogenase complex, which is important in making the E1 enzyme that helps convert food into adenosine triphosphate (ATP), the energy form usable by the cells. The pyruvate dehydrogenase complex, however, is built from multiple copies of several enzymes. These are E1, E2, and E3, each with a role to play in the chemical reaction that carbohydrates to acetyl-CoA. Apart from the enzymes, other proteins are required to ensure the proper functioning of the pyruvate dehydrogenase complex. The E3 protein, for instance, is a binding protein that attaches the E3 enzyme to the pyruvate dehydrogenase complex and ensures that it is following the proper structure. Other proteins help to control the activity of the complex. For instance, the pyruvate dehydrogenase phosphatase activates the complex, while pyruvate dehydrogenase kinase inhibits it.
Mutations can happen in each of the components of the pyruvate dehydrogenase complex, depending on mutations of their respective genes, activation, and inheritance. For instance, the E1 enzyme, also known as pyruvate dehydrogenase, is made up of four subunits: two E1 alpha and E1 beta subunits, respectively. Mutations in the PDHA1 gene, which contains the instructions for making E1 alpha, are the most common cause of pyruvate dehydrogenase deficiency. As its name suggests, the mutations result in a deficiency of pyruvate hydrogenase (E1), a deficiency that results in the formation of an abnormal protein. In other words, the decrease in functionality in E1 alpha reduces the activity of the pyruvate dehydrogenase complex. The dysfunction carries over as the pyruvate in the complex build-up in the body. However, another chemical reaction converts pyruvate into lactic acid. It is the accumulation of lactic acid that causes all the other signs and symptoms described in the previous section.
In other rare cases, pyruvate dehydrogenase deficiency is caused by my mutations in other genes. For instance, mutations in the PDHB gene would result in altered E1 beta proteins. Given that two E1 beta proteins are required to combine with two E1 alpha proteins to form the E1 enzyme, mutation in the PDHB gene would result in a dysfunctional E1 enzyme. On the other hand, mutations in the DLAT gene, which contains instructions for the formation of dihydrolipoamide acetyltransferase, also known as the E2 enzyme, is another known cause of pyruvate dehydrogenase deficiency. Additionally, mutations in the PDHX gene, which contains the instructions for the formation of the E3 protein, and the PDP1 gene, which contains the instructions for the formation of pyruvate dehydrogenase phosphatase, have been found in people identified with pyruvate dehydrogenase deficiency.
However, it is not yet clear how these other mutations affect the pyruvate dehydrogenase complex. Regardless, the general trend identified has been that the alteration of one component results in the impairment of the whole complex. In other words, impairments in each of the other components work in a similar manner as a mutation in the PDHA1 gene, which reduces the activity of the pyruvate dehydrogenase complex.
