NADH dehydrogenase deficiency

Deficiencies of enzymes involved in glycolysis, the hexose monophosphate pathway, the closely related glutathione metabolism and synthesis, and nucleotide metabolism have emerged as causes of hereditary nonspherocytic hemolytic anemias (Table 1) (F10, Fll, M27). Some enzyme deficiencies, such as diphospho-glycerate mutase deficiency, lactate dehydrogenase deficiency, and NADH cy-... 

Hypoxia and inherited deficiencies of subunits in the electron transport chain impair NADH oxidation, resulting in a higher NADH/NAD ratio in the cell, and, therefore, a higher lactate/pyru-vate ratio in blood. In contrast, conditions that cause lactic acidemia as a result of defects in the enzymes of pyruvate metabolism (thiamine deficiency or pyruvate dehydrogenase deficiency) would increase both pyruvate and lactate in the blood and have little effect on the ratio. 

The 2-ketoglutarate dehydrogenase (2-KGD) complex is composed of three separate enzymes 2-ketoglutarate decarboxylase, or El lipoate succi-nyltransferase, or E2 and lipoamide dehydrogenase, or E3. The complex catalyses the oxidation of 2-ketoglutarate to yield succinyl-CoA and NADH. 2-KGD deficiency together with pyruvate dehydrogenase deficiency and branched chain ketoacid decarboxylase deficiency has been ascribed to E3 deficiency because the three enzyme complexes have the E3 component in common. E3 deficiency will not be discussed. 

The most important factor in the regulation of the cycle is the NADH/NAD ratio. In addition to pyruvate dehydrogenase (PDH) and oxoglu-tarate dehydrogenase (ODH see p. 134), citrate synthase and isodtrate dehydrogenase are also inhibited by NAD deficiency or an excess of NADH+HT With the exception of isocitrate dehydrogenase, these enzymes are also subject to product inhibition by acetyl-CoA, suc-cinyl-CoA, or citrate. 

In Al Martini s heart failure, which is caused by a dietary deficiency of the vitamin thiamine, pyruvate dehydrogenase, a-ketoglutarate dehydrogenase, and the branched chain a-keto acid dehydrogenase complexes are less functional than normal. Because heart muscle, skeletal muscle, and nervous tissue have a high rate of ATP production from the NADH produced by the oxidation of pyruvate to acetyl CoA and of acetyl CoA to COj in the TCA cycle, these tissues present with the most obvious signs of thiamine deficiency. 

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