Pyruvate dehydrogenase deficiencies

Pyruvate dehydrogenase deficiency giving rise to lactic acidosis (Chapter 9). 

Pyruvate dehydrogenase deficiency is the most common biochemical cause of congeni... 

Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets studies in patients with identical mutations. Neurology 49 1655-1661,1997. 

Thiamin-Responsive Pyruvate Dehydrogenase Deficiency Genetic deficiency of pyruvate dehydrogenase Ela (which is on the X chromosome) leads to potentially fatal lactic acidosis, with psychomotor retardation, central nervous system damage, atrophy of muscle fibers and ataxia, and developmental delay. At least some cases respond to the administration of high doses (20 to 3,000 mg per day) of thiamin. In those cases where the enzyme has been studied, there is a considerable increase in the of the enzyme for thiamin diphosphate. Female carriers of this X-linked disease are affected to a variable extent, depending on the X-chromosome inactivation pattern in different tissues (Robinson et al., 1996). 

Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Ogawa Y et al. Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. Biochim Biophys Acta 2002 1588 79-84. 

The most common PDC genetic defects are in the gene forthe a subunit of Ei. The E, a-gene is X-linked. Because of its importance in central nervous system metabolism, pyruvate dehydrogenase deficiency is a problem in both males and females, even if the female is a carrier. For this reason, it is classified as an X-linked dominant disorder. 

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. 

An inherited pyruvate dehydrogenase deficiency, a thiamine deficiency, or hypoxia deprives the brain of a source of acetyl CoA for acetylcholine synthesis, as well as a source of acetyl CoA for ATP generation from the TCA cycle. 

Falk, R. E., et ak, 1976. Ketonic diet in the management of pyruvate dehydrogenase deficiency. 

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. 

Accumulation of compounds related to the mitochondrial pathway can be detected in one or more body fluids of most patients [1, 2, 15]. Special attention has to be paid to the lactate concentration. Excess of lactate and alanine will be produced after reduction or transamination of accumulated pyruvate (see Fig. 27.1). If there is a severe block in the pyruvate oxidation pathway, and the produced lactate can not adequately be removed by peripheral tissues, it accumulates in blood, urine and/or cerebrospinal fluid, dependent upon the affected tissue(s). A decreased activity of the respiratory chain will shift the equilibrium of the lactate dehydrogenase reaction to conversion of pyruvate to lactate (see also Sect. 1). Thus, patients with a respiratory chain defect should demonstrate an increased lactate/pyruvate ratio in blood, whereas pyruvate dehydrogenase deficiency should result in a normal lactate/pyruvate ratio. However, this tool for differential diagnosis is not helpful in all cases. Furthermore, some patients do not accumulate lactate in blood or urine. 

Pyruvate carboxylase deficiency Pyruvate dehydrogenase deficiencies... 

Blass, J.P. (1980), Pyruvate dehydrogenase deficiencies. In Inherited Disorders of Carbohydrate Metabolism (eds D. Burman, J.B. Holton and C.A. Pennock), MTP Press, Ltd., Lancaster, pp. 239-268. 

Borud, O. and Stromme, J.H. (1977), Metabolic studies on normal and pyruvate dehydrogenase deficient cultured human fibroblasts. Scand. J. Clin. Lab. Invest., 37, 419. 

Cederbaum, S.D., Blass, J.P., Minkoff, N., Brown, W.J., Cotton, M.E. and Harris, S.H. (1976), Sensitivity to carbohydrate in a patient with familial intermittent lactic acidosis and pyruvate dehydrogenase deficiency. Pediatr. Res., 10,713. 

Kark, R. A.P. and Rodriguez-Budelli, M. (1979), Pyruvate dehydrogenase deficiencies in six of fourteen unselected patients with spinocerebellar degenerations. Neurology, 29,126. 

---