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HomePediatrics: Genetics and Metabolic DiseasePyruvate Dehydrogenase Deficiency (PDCD)

Pyruvate Dehydrogenase Deficiency (PDCD)

Background

Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. PDC metabolically converts pyruvate into acetyl-coenzyme A (ACoA), one of the first steps in the citric acid cycle (CAC). The CAC is a major biochemical process in the mitochondrial matrix that derives energy from several metabolic substrates, including carbohydrates, fatty acids, and amino acids. Malfunction of this cycle deprives the body of energy. In PDCD, pyruvate, which is derived from the breakdown of carbohydrates, is not converted into ACoA. This decreases the major substrate necessary for the CAC to function and results in an abnormal buildup of lactate and alanine, which are alternative metabolic products of pyruvate. Without function of the CAC, the mitochondria cannot produce energy for the cells to function. Lack of energy product and the buildup of unusable metabolites results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.

In PDCD, progressive neurological symptoms usually start in infancy but may be evident at birth or in later childhood and very rarely in adulthood. Symptoms may include developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, or seizures. Childhood- and adult-onset forms of this disorder are often associated with intermittent periods of decompensation but normal or mildly delayed neurological development. Therapies are suboptimal for most forms of pyruvate dehydrogenase complex deficiency; although resolution of the lactic acidosis may occur, cessation of the underlying progressive neurological damage is rare.

The key feature of this condition is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem in many but not all patients. The group of disorders that result in this pathology are termed Leigh syndrome. Defects in one of many of the mitochondrial enzymes involved in energy metabolism may demonstrate similar brain pathology. Leigh syndrome may be caused by mitochondrial defects other than PDCD.

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