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INTRODUCTION

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Disorders of pyruvate metabolism and the tricarboxylic acid (TCA) cycle represent a major subset of other recognized disorders of energy metabolism, including a large number of defects of the mitochondrial electron transport chain (ETC) and oxidative phosphorylation (see Chapter 11) along with defects of fatty acid β-oxidation and gluconeogenesis. Many of these defects of energy metabolism are associated clinically with lactic acidemia. Inherited disorders of pyruvate metabolism, gluconeogenesis, the TCA cycle, ETC, and oxidative phosphorylation are commonly referred to as primary genetic lactic acidemias. Other groups of genetic disorders can also lead to lactic acidemia, especially during states of severe metabolic decompensation, and are commonly referred to as secondary genetic lactic acidemias, including defects of fatty acid β-oxidation and organic acid catabolism. In addition, lactic acidemia is commonly caused by a range of acute or chronic acquired conditions that produce impaired peripheral oxygenation. Clinical differentiation among the primary genetic lactic acidemias, secondary lactic acidemias, and acquired conditions associated with ischemia or hypoxemia is not simple and ultimately may require detailed metabolic, enzymatic, and/or genetic testing.

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PYRUVATE DEHYDROGENASE COMPLEX DEFICIENCY

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Etiology/Pathophysiology
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In the normal fed state, in the presence of oxygen and increased insulin, glucose is converted to pyruvate via the glycolytic pathway in the cytosol, transported into mitochondria, and irreversibly decarboxylated to acetyl-coenzyme A (CoA) by the activated pyruvate dehydrogenase complex (PDC). PDC thereby serves as the gateway for pyruvate into the TCA cycle, permitting complete oxidation of pyruvate to carbon dioxide and maximum energy production via oxidative phosphorylation (Figures 8-1, 8-2, and 8-3). Alternatively, excess acetyl-CoA generated under these conditions can be exported (via citrate) from the mitochondria to the cytosol, where it is used as a substrate for fatty acid synthesis, providing storage of energy. In the fasting state with diminished insulin, PDC is inactivated by phosphorylation of the pyruvate dehydrogenase component E1 by pyruvate dehydrogenase kinase, thus conserving pyruvate for gluconeogenesis and replenishment of the TCA cycle.

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FIGURE 8-1.

Overview of energy metabolism, showing relationships between carbohydrate, fatty acid, and amino acid oxidation, acetyl-CoA formation, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, gluconeogenesis, and fatty acid synthesis. The relative locations of cytosolic and mitochondrial reactions are indicated in this simplified metabolic diagram. G6P, glucose-6-phosphate; PEP, phosphoenolpyruvate; OAA, oxaloacetate; 2KG, 2-ketoglutarate; BOHB, β-hydroxybutyrate; AcAc, acetoacetate; NADH, reduced nicotinamide adenine dinucleotide; FADH2, reduced dihydro-flavin adenine dinucleotide; ADP, adenosine diphosphate; and ATP, adenosine triphosphate. Specific anaplerotic and gluconeogenic amino acids that are potential sources of TCA cycle intermediates, including glutamate (converted to 2-ketoglutarate), aspartate (transaminated to oxaloacetate), and isoleucine, valine, methionine, and threonine (catabolized to succinyl-CoA via propionyl-CoA) are not shown.

Graphic Jump Location
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FIGURE 8-2.

Detailed view of relationships of pyruvate metabolism, acetyl-CoA, and the TCA cycle. PDC, pyruvate dehydrogenase complex; PEP, phosphoenolpyruvate; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate ...

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