Lacticacidosis, neurological deterioration and compromised cellular pyruvate oxidation due to a defect in the reoxidation of cytoplasmically generated NADH

Robinson, Brian H.; Taylor, Jennifer; Francois, B.; Beaudet, A. L.; Peterson, Dave

doi:10.1007/bf00441651

Cited by 23 publications

(13 citation statements)

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“…These conditions are accompanied to a variable degree by hyperalaninemia, hypoglycemia, neurologic impairment, and muscular hypotonia. The differential diagnosis of this group of disorders involves distinguishing among glycogen storage diseases (1,2), organic acidemias (3), carnitine deficiency (4), primary deficiencies in the enzymes of gluconeogenesis (including pyruvate carboxylase [PC]' (5,6), phosphoenolpyruvate carboxykinase [PEPCK] (7,8), and fructose 1,6-bisphosphatase [9]), defects in the pyruvate dehydrogenase complex (PDC) (10-12), pyridine nucleotide shuttle mechanisms (13), and defects in mitochondrial electron transport (14). Recently, there has been a brief report (15) of two infants in one family with congenital lactic acidosis associated with a defect in the functional activity of mitochondrial NADH-ubiquinone oxidoreductase (complex I).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis.

et al. 1984

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Abs tract. We report the case of an infant with hypoglycemia, progressive lactic acidosis, an increased serum lactate/pyruvate ratio, and elevated plasma alanine, who had a moderate to profound decrease in the ability of mitochondria from four organs to oxidize pyruvate, malate plus glutamate, citrate, and other NADW-linked respiratory substrates. The capacity to oxidize the flavin adenine dinucleotide-linked substrate, succinate, was normal. The most pronounced deficiency was in skeletal muscle, the least in kidney mitochondria. Enzymatic assays on isolated mitochondria ruled out defects in complexes II, III, and IV of the respiratory chain. Further studies showed that the defect was localized in the inner membrane mitochondrial NADHubiquinone oxidoreductase (complex I). When ferricyanide was used as an artificial electron acceptor, complex I activity was normal, indicating that electrons from NADH could reduce the flavin mononucleotide cofactor. However, electron paramagnetic resonance spectroscopy performed on liver submitochondrial particles showed an almost total loss of the iron-sulfur clusters characteristic of complex I, whereas normal signals were noted Dr. Moreadith is the recipient of a National Research Service Award from the U. S. Public Health Service. His current address is the Duke

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Section: Introductionmentioning

confidence: 99%

Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis.

et al. 1984

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“…It is not often used and then only in desperate situations. For chronic administration it is not practicable as it probably has to be given parenterally (Robinson et al, 1983). In one patient with multiple acyl-CoA dehydrogenase deficiency, glutarate excretion was almost normalized with methylene blue.…”

Section: Case Reportmentioning

confidence: 99%

Therapy of mitochondrial disorders

Przyrembel¹

1987

J of Inher Metab Disea

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Mitochondrial disorders, namely defects of fatty acid oxidation, defects of pyruvate metabolism and defects of the respiratory chain are heterogenous in clinical picture and in response to therapeutic attempts. Defects of fatty acid metabolism are amenable to therapy by dietary means, carnitine substitution and in some cases with vitamins. Defects in pyruvate metabolism do not respond to therapy except in some special cases. Therapeutic attempts include dietary measures, vitamins as coenzyme precursors. Defects in the respiratory chain appear to respond to treatment only in exceptional cases. Evaluation of treatment effects appears to be singularly difficult. General measures that can be of benefit to different defects are discussed.

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“…(12) administered DCA (1 50 mg/kg/day and 15 mg/kg every 2nd day) to an 18-month-old baby and 12-year-old child, respectively, with chronic congenital lactic acidosis due to a defect of PDH and Krebs cycle dysfunction (BH Robinson, personal communication). More recently, Robinson et al (14) used DCA (50 mg/kg three times per day) to treat congenital lactic acidosis due to a defect in the reoxidation of cytoplasmically generated NAD in a 2-month-old girl (14). In all these patients, DCA reduced the blood lactate level, while the blood glucose level was only slightly reduced in two patients (4,12).…”

Section: Dlscusslonmentioning

confidence: 99%

“…Moreover, administration of DCA to man and animals reduces the blood levels of lactate, pyruvate, and alanine by its action on PDH (6,15,17). Therefore, this drug has been used in attempts to treat chronic congenital lactic acidosis in humans (4,12,14). At the doses of DCA used, no neurologic improvement was observed during DCA therapy, although the blood lactate level…”

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Effects of Dichloroacetate on Pyruvate Metabolism in Rat Brain in Vivo

et al. 1984

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Summarywas lowered. However, the effect of DCA on the lactate level in the cerebrospinal fluid'in the patients has not been reported. The effects of dichloroacetate On the activity of the Therefore, we investigated the in vivo effects of small and large pyruvate deh~drogenase (PDH) and associated changes doses of DCA on the activity of the PDH complex in the brain in the lactate and glucose levels in rat brain were investigated in and consequent changes in the lactate and glucose levels in rats. vivo. The average activities of the active form of the PDH complex in the brain, liver and muscle of starved rats were respectively 0.40 f 0.04, 0.07 f 0.04, and 0.17 + 0.11 pmol/ min/g tissue, and amounted to 21, 11, and 16% of the total activity of the complex. Intraperitoneal injection of DCA (125 mg/kg) increased the percentage of the active form of the PDH complex in the brain, liver, and muscle to 107, 40, and 84%, respectively. DCA significantly lowered the lactate and glucose concentrations of the brain and blood. A lower dose of DCA (1 2.5 mg/kg) also caused significant increase in activity of the PDH complex in the brain, but did not significantly change the lactate or glucose concentration of the brain. These results suggest that DCA crosses the blood-brain barrier reasonably well. Abbreviations PDH, pyruvate dehydrogenase DCA, dichloroacetate Chronic congenital lactic acidosis of childhood is characterized by persistently high levels of blood pyruvate and lactate. Dietary control and other rational biochemical manipulations have been tried in attempts to lower the blood lactate level in patients with this disease, but with only limited success (2). In two patients with chronic lactic acidosis due to defects of pyruvate carboxylase (EC 6.4.1.1) and PDH (EC 1.2.4. I), the blood lactate and pyruvate were reduced to nearly normal levels by lipoic acid and dietary therapy, but despite this therapy the levels of lactate and pyruvate in the cerebrospinal fluid remained high, and neurologic deterioration continued ( I I, 16). Usually, the lactate and pyruvate levels in the cerebrospinal fluid are also elevated in patients with chronic congenital lactic acidosis. Therefore, it may be important to maintain the lactate level within a normal range not only in the blood but also in the cerebrospinal fluid in therapy of chronic congenital lactic acidosis.DCA is known to activate the PDH complex in various tissues in vitro by inhibiting PDH kinase (EC 2.7.1.99) (1,5,13). Moreover, administration of DCA to man and animals reduces the blood levels of lactate, pyruvate, and alanine by its action on PDH (6,15,17). Therefore, this drug has been used in attempts to treat chronic congenital lactic acidosis in humans (4,12,14). At the doses of DCA used, no neurologic improvement was observed during DCA therapy, although the blood lactate level MATERIALS AND METHODS Animals.Male Wistar rats weighing 1 70-195 g were given free access to water and laboratory chow.Chemicals. Sodium DCA was obtained from Tokyo Kasei Kogyo Co., (Tokyo,...

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Lacticacidosis, neurological deterioration and compromised cellular pyruvate oxidation due to a defect in the reoxidation of cytoplasmically generated NADH

Cited by 23 publications

References 17 publications

Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis.

Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis.

Therapy of mitochondrial disorders

Effects of Dichloroacetate on Pyruvate Metabolism in Rat Brain in Vivo

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