Pyruvate Dehydrogenase Phosphatase Deficiency: A Cause of Congenital Chronic Lactic Acidosis in Infancy

Abstract

ExtractA male child presented on the first day of life with metabolic acidosis with elerated blood lactate 115 mM), pyruvate (0.4 mM I, and free fatty acid (1.3 m V ) levels and a blood pH of 7.16. The reverity of the acidosis was diminished by intravenous administration of glucose in large doses and by bicarbonate. On two occasions, when the acidosis was particularly se\ere. peritoneal dialvsis using an acetate buffer was required. Restriction of the dietar! intake of saturated fatty acids or treatment with nicotinic acid also appeared to diminish the se~erity of acidosis. Uo improvement was achieted by the administration of thiamine or biotin. Tissues taken at postmortem showed normal activity of gluconeogenic enzymes and pyruvate dehydrogenase. The activity of pvrutate dehydrogenase in tissue homogenates preincubated with ATP was reduced by 6&7S% both in liver of the patient and of the controls because of the inactitation of the enzyme by pyruvate dehydrogenase kinase. Addition of C a + + and M g + + to the inactivated enzyme caused a prompt return of the activity to normal in controls but not in the patient. This defect, which was apparent in muscle and liter but not in brain, we attribute to a markedly reduced acthity of pyrurate dehydrogenase phosphatase in the patient. SpeculationCertain cases of chronic congenital lactic acidosis in infancy may be due to pvruvate dehydrogenase phosphatase deficiency.Chronic congenital lactic acidosis of infancy is a disease characterized hy a persistent elevation of blood pyruvate and lactate (9,15,16, 21). In three patients with chronic congenital lactic acidosis, markedly reduced activity of pyruvate dehydrogenase (EC. 1.2.4.1) was reported. In two of these, the defect was localized in the py ruvate decarboxylase (EC. 4. I. I . I) component of the enzyme complex (8,14) and in the third patient in the dehydrolipoyl transacetylase (EC. 2.3.1.12) or the dihydrolipoyl dehydrogenase (EC. 1.6.4.3) component (9).In this communication, we report a patient with chronic congenital lactic acidosis in whom biochemical investigations on tissue obtained at postmortem revealed a defect in the phosphorylation-dephosphorylation mechanisms controling the overall activity of the pyruvate dehydrogenase complex in the liver and muscle. The postulated defect is correlated with the clinical manifestations of the disease during the life of the patient.noted from the first day of life. At birth in our patient the Apgar score was 8 at 1 min, hut acidosis developed during the first day of life and the patient was transrerred to The Hospital for Sick Children.He was 3 well developed newborn with severe tachypnoea of the Kussmaul type. poor peripheral perfusion, hypotonicity, ond diminished consciousness. He did not have evidence of cardiopulmonary disease nor hepatomegaly. His biochemical data on admission are shown in Table 1 and indicated a metabolic acidosis associated with elevated levels of blood lactate (15 m M N < 2 mM), pyruvate (0.4 m M N < 0.2 mM), @-hydroxybutyrate (1.8 m M N < 0.5 mM)...

Partial pyruvate decarboxylase deficiency with profound lactic acidosis and hyperammonemia: Responses to dichloroacetate and benzoate

“…Plasma ammonia levels are not mentioned in previous reports of pyruvate dehydrogenase deficiency [Blass et al, 1970;Farmer et al, 1973;Goodman and Markey, 1981;Robinson and Sherwood, 1975;Robinson et al, 1977Robinson et al, , 1981Stromme et al, 19761. Elevations in ammonia have been reported for many of the organic acidemias, presumably owing to inhibition of several steps of ureagenesis by the accumulated organic acids or their CoA esters [Mahoney, 19761. Furthermore, synthesis of N-acetylglutamate, a required compound for activation of carbamyl phosphate synthetase, may be decreased owing to intramitochondrial depletion of acetyl CoA or competitive inhibition by propionyl and methylmalonyl CoA of N-acetylglutamate synthetase [Brusilow et al, 19821.…”

Yeast Pyruvate Dehydrogenase Complex Is Regulated by a Concerted Activity of Two Kinases and Two Phosphatases

“…These regulatory enzymes themselves are regulated by a variety of conditions, including the intramitochondrial concentrations of cofactors and substrates or products of PDC reaction (1,3,7,11,(47)(48)(49), indicating a complex multilayer regulatory network. Failure of the human PDC (50) or of one of its regulatory enzymes (51,52) results in serious disorders. In yeast, however, the conversion of pyruvate to acetyl-CoA can be bypassed by two additional mitochondrial and cytoplasmic pathways (53,54).…”

Pyruvate Carboxylase and Phosphoenolpyruvate Carboxykinase Activity in Leukocytes and Fibroblasts from a Patient with Pyruvate Carboxylase Deficiency

“…3.1.3.9) (19,23), fructose 1,6-bisphosphatase (E.C. 3.1.3.1 1) (27,28), pyruvate carboxylase (1, 8, 11, 15, 16, 18, 33, 37), pyruvate dehydrogenase complex (PDC) (7,13,32,35), and PEPCK (14,17,40). With the exception of PDC which catalyzes the first step in the Krebs cycle, the enzymes are necessary for gluconeogenesis in mammalian renal cortex and liver.…”