Pyruvate dehydrogenase complex deficiency

Lissens, W., De Meirleir, L., Seneca, S. et al. Mutations in the X-linked pyruvate dehydrogenase (El) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum. Mut. 15 209-219, 2000. 

Table 7-3. Reported Clinical, Metabolic, and Anatomical Manifestations of Pyruvate Dehydrogenase Complex Deficiency... 

Okajima K, Mewhort LZ, Lusk MM, et al. Relationships of clinical and biochemical manifestations to genotype analysis in patients with pyruvate dehydrogenase complex deficiency. Molecular Genetics and Metabolism 84 232-33, 2005. 

Weber TA, Antognetti MR, Stacpoole PW Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. / Pediatr 138 390-395, 2001. 

The second section of the book is Fuel Metabolism and Energetics. Important pathways and enzymes involved in fuel utilization are discussed in the chapters Pyruvate Dehydrogenase Complex Deficiency Mitochondrial En-cephalomyopathy, and Systemic Carnitine Deficiency. The role of gluconeogenesis in glucose homeostasis is illustrated by a discussion in the chapter Neonatal Hypoglycemia. 

X gene in a case of pyruvate dehydrogenase complex deficiency. 26. Hum. Mol. Genet. 1998 7 501-505. 

Nervous system abnormalities may be attributed in part to diminished synthesis of neurotransmitters rather than to inadequate synthesis of ATP. In pyruvate dehydrogenase complex deficiency, diminished levels of acetyl-CoA cause decreased production of acetylcholine in pyruvate carboxylase deficiency, decreased production of... 

Holatko, J., Bartek, T., Oldiges, M., and Eikmanns, B.J. (2007) L-valine production with pyruvate dehydrogenase complex-deficient Corynebacterium glutamicum. Appl. Environ. Microbiol, 73 (7), 2079-2084. 

Bartek, T., Blombach, B., Lang, S., Eikmanns, B.J., Wiechert, W, Oldiges, M., Noh, K., and Noack, S. (2011) Comparative C metabolic flux analysis of pyruvate dehydrogenase complex-deficient, L-valine-producing Corynebacterium glutamicum. 

Pyruvate dehydrogenase complex deficiency Hereditary fructose Aldolase B intolerance... 

At present prenatal diagnosis in mitochondrial disorders can be performed in families in which the proband is suffering (suffered) from a complex I, complex IV or pyruvate dehydrogenase complex deficiency, at least in our centre. A prerequisite for prenatal diagnosis at the enzyme level is the establishment of the defect in fibroblasts from the proband. Prenatal diagnosis is preferably performed in native chorionic villi because they can be obtained earlier in pregnancy as compared with amniocytes. Moreover, it is not necessary to cultivate chorionic villi in contrast with amniocytes, thus... 

X component of pyruvate dehydrogenase complex deficiency Xanthine dehydrogenase deficiency Xanthine oxidase deficiency X-linked adrenoleukodystrophy... 

Defects of substrate utilization. Pyruvate dehydrogenase (PDH) deficiency can cause alterations of pyruvate metabolism, as can defects of pyruvate carboxylase, as discussed earlier. Over 200 patients have been described with a disturbance of the PDH complex (PDHC) [15,16]. The clinical picture includes several phenotypes ranging from a severe, devastating metabolic disease in the neonatal period to a benign, recurrent syndrome in older children. There is considerable overlap clinically and biochemically with other disorders (see below). 

Coenzymes The pyruvate dehydrogenase complex contains five coenzymes that act as carriers or oxidants for the intermediates of the reactions shown in Figure 9.3. Ei requires thiamine pyrophosphate, Ep requires lipoic acid and coenzyme A, and E3 requires FAD and NAD+. [Note Deficiencies of thiamine or niacin can cause serious central nervous system problems. This is because brain cells are unable to produce sufficient ATP (via the TCA cycle) for proper function if pyruvate dehydrogenase is inactive.]... 

Table 7-4. Naturally Occurring Compounds of Unproven Efficacy Administered Singly or in Combination to Patients with Pyruvate Dehydrogenase Complex (PDC) Deficiency ...

Why does TPP deficiency lead primarily to neurological disorders The nervous system relies essentially on glucose as its only fuel. In contrast, most other tissues can use fats as a source of fuel for the citric acid cycle. The product of aerobic glycolysis, pyruvate, can enter the citric acid cycle only through the pyruvate dehydrogenase complex. 

Lactic acidosis. Patients in shock will often suffer from lactic acidosis due to a deficiency of O2. Why does a lack of O2 lead to lactic acid accumulation One treatment for shock is to administer dichloroacetate, which inhibits the kinase associated with the pyruvate dehydrogenase complex. What is the biochemical rationale for this treatment ... 

Thiamine deficiency causes decreased pyruvate oxidation, leading to accumulation of pyruvate and lactate, particularly in the blood and brain, and is accompanied by impairment of the cardiovascular, nervous, and gastrointestinal systems (Chapter 38). Inherited deficiency of pyruvate dehydrogenase complex is accompanied by lactic acidemia and abnormalities of the nervous system (e.g., ataxia and psychomotor retardation). Pyruvate carboxylase deficiency causes similar abnormalities (Chapter 15). Both inherited disorders of pyruvate utilization are autosomal recessive. 

Under aerobic conditions pyruvate is converted to acetyl CoA. The coenzymes NAD+, FAD, thiamine pyrophosphate, and coenzyme A are required by the pyruvate dehydrogenase complex for the conversion of pyruvate to acetyl CoA. These coenzymes are synthesized from the vitamins niacin, riboflavin, thiamine, and pantothenic acid, respectively. If the vitamins are not available, the coenzymes will not be available and pyruvate cannot be converted to acetyl CoA. Because the complete oxidation of the acetyl group of acetyl CoA produces the vast majority of the ATP for the body, ATP production would be severely inhibited by a deficiency of any of these vitamins. 

Pyruvate dehydrogenase complex (PDHC) deficiency and electron transport chain disorders are examples of mitochondrial energy disorders. The primary goal of treatment is to minimize acidosis. In prevention of lactic acidosis (especially in PDHC deficiency) glucose supply has to be limited. 

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