Pyruvate is a crucial compound in the biochemistry of energy production since it can be converted into acetyl-coenzyme A, oxaloacetate, alanine, or lactate via carboxylation, decarboxylation, transamination, or reduction. Each of these metabolic processes requires catalysts and other substances with which the pyruvate reacts. If a given catalyst is not available, that process cannot occur (Berg, 2002).
Normally, the production of acetyl-coenzyme A proceeds in the citric acid or Krebs cycle to produce adenosine triphosphate (ATP), which provides energy to the cells. In pyruvate dehydrogenase complex deficiency (PDCD), the essential catalyst, pyruvate dehydrogenase complex (PDC), is not available to convert pyruvate to acetyl-coenzyme A (Ferriero et al., 2013). This stops the ATP pathway which, in normal individuals, creates 95% of the energy used by the body (Berg, 2002).
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"Pyruvate Dehydrogenase Deficiency".
Pyruvate is instead converted into alanine (via transamination) and lactate (via reduction). These compounds can also provide energy to the cell, but much less efficiently, and the cell functions with a continuous energy deficit. Also, the conversion of a large percentage of the pyruvate to lactate leads to a build-up of lactic acid, causing lactic acidosis in the tissues and fluids of the body (Berg, 2002
PDCD can be due to one of several mutations in the genes which control the mitochondria and cellular respiration. It is the most common congenital abnormality related to the mitochondria and causes degeneration of the central nervous system. In fact, damage to the developing neural system can occur as early as 10 weeks gestation – for example, malformation of the corpus callosum is common (NLM, 2013).
Sometimes the infant with PDCD is born without any obvious signs of the deficiency. However, within weeks, or months, the neurons may become demyelinated, cysts may form in the brain, and cell death may begin due to the lack of energy and the build-up of lactic acid. There is wide variation in the severity of symptoms depending on the amount of PDC produced; it is not necessarily 0% or 100%. Research suggests that infants producing less than 15% of the normal amount of PDC generally die during the first year of life, but if 25% or more is produced, the individual may experience a milder version with lethargy, motor delays and ataxia. However, since the condition is degenerative, even the milder cases may be terminal in early childhood (Ferriero et al, 2013).
The disorder is typically treated using substances called cofactors, which are essential (in small amounts) for the body to carry out metabolic processes such as the citric acid cycle. Important cofactors for PDCD include thiamine, carnitine, and lipoic acid. Other treatments are designed to enhance the action of the carboxylating enzyme complex – e.g., dichloroacetate sodium (NLM, 3013).
Phenylbutyrate is a compound that is used to treat other human diseases, and some research with animals suggests that it may be used to enhance the effectively of the amount of PDC that the individual is able to produce. Ferriero et al. (2013) found phenylbutyrate effective in zebrafish and mice, and explained its usefulness by its ability to dephosphorylate the PDC molecule, thus increasing its ability to catalyze carboxylation.
Another treatment that has improved the neuronal and muscular activity of children with PDCD is the ketogenic diet. A diet that is ketogenic contains large amounts of protein and fats and few carbohydrates; if the amount of carbohydrates is low enough, the body will begin to produce ketones. In this way, the diet provides a direct source of acetyl-coenzyme A, therefore moving past the metabolic blockage caused by PDCD and providing energy for the body. This diet has been successful in reversing developmental delays in children with mild-moderate PDCD and in reducing the frequency of seizures caused by the disorder. Certain side effects of the ketogenic diet, such as high cholesterol, may require management with other drugs (Di Pisa, 2012).
- Berg JM, Tymoczko JL, Stryer L. (2002). Biochemistry. 5th edition. New York: W.H. Freeman.
- Di Pisa V, Cecconi I, Gentile V, Di Pietro E, Marchiani V, Verrotti A, Franzoni E. (2012). Case report of pyruvate dehydrogenase deficiency with unusual increase of fats during ketogenic diet treatment. J Child Neurol. 27(12):1593-6.
- Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, et al. (2013). Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 5(175): 175ra31. National Library of Medicine. 2013. Pyruvate Dehydrogenase Deficiency. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/pyruvate-dehydrogenase-deficiency
