Biochemical studies and therapy in subacute necrotizing encephalomyelopathy (Leigh's syndrome)

ExtractProximal renal tubular acidosis has been observed in two infants who had lactic acidosis associated with subacute necrotizing encephalomyelitis. Reduced renal thresholds for bicarbonate (18-19.2 niM/liter) were found in both, in conjunction with the ability to excrete normal quantities of acid. In order to raise the level of serum bicarbonate, increasing rates of infusion of solutions containing bicarbonate were required, because of a progressive increase in serum lactate from 18 to 54 mg/dl. The infusion of sodium bicarbonate expanded the extracellular space, as measured by an increase in chloride space of 12.9%. Volume expansion was associated with a progressive fall in bicarbonate reabsorption from a maximum of 1.91 to 1.02 mM/100 ml glomerular filtration rate. In addition, the tubular reabsorption of phosphate fell from 80 to 60%, urate clearance increased from 8.7 to 20 ml/min/1.73 m 2 , lactate clearance increased from 0.23 to 22.9 ml/min/1.73 m 2 , and chloride excretion increased from 0.7 to 3.14 /iEq/min/1.73 m 2 . At autopsy, reduced activity of renal pyruvate carboxylase was demonstrated for the first time in this disease. Speculation

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“…He received thiamine and lipoic acid therapy, the details of which are reported elsewhere [19]. No major therapeutic response occurred.…”

Section: Case Reportsmentioning

confidence: 99%

Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy (Leigh's Syndrome)

et al. 1973

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“…However, if the diagnosis of Leigh's disease was confined only to those patients that have the histologic lesions described by Leigh in the brain at autopsy, correlation of a basic biochemical defect with this disease might be successful. If the more precise definition of Leigh's disease is applied to the previous reports associating Leigh's disease with pyruvate carboxylase deficiency (10,12,19,20,22,40,41), one discovers that only the patients of Hommes and associates (12) and Gruskin and associates (19,20) ' All tissues treated as described in legends of Tables 2 and 3.…”

Section: Discussionmentioning

confidence: 99%

“…The following enzymes involved in glucose or pyruvate metabolism (Fig. I) have been implicated: glucose-6-phosphatase (24,29), fructose-1,6-bisphosphatase (31,32), pyruvate carboxylase (7,10,12,13,19,20,22,37,40,41), and pyruvate dehydrogenase complex (6,15,36,39). Of these enzymes all but the last are required for gluconeogenesis.…”

Section: Speculationmentioning

confidence: 99%

“…Likewise, the function of the enzyme in brain is not well understood, although it may be to furnish oxalacetate, and cytosolic acetyl groups and reducing equivalents for various cellular func- Several patients (10,12,19,20,22,40,41) with progressive neurologic deterioration clinically resembling subacute necrotizing encephalomyelopathy (Leigh's disease) (27) have been reported to have hepatic pyruvate carboxylase deficiency. This has led some investigators to conclude that Leigh's disease may be caused by pyruvate carboxylase deficiency.…”

Section: Speculationmentioning

confidence: 99%

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Pyruvate Carboxylase Deficiency and Lactic Acidosis in a Retarded Child without Leigh's Disease

et al. 1979

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“…or type I glycogen storage disease (glucose-6-phosphatase deficiency) (26). The onset from birth, the severity of the acidosis, and the absence of a raised plasma a-ketoglutarate or citrate level made the possibility of Leigh's disease unlikely (17,36). The absence of abnormal urinary organic acids ruled out the possibility that the lactic acidosis was secondary to a block in propionate or methylmalonate metabolism.…”

Section: Robinson and Sherwood Discussion Clinical And Chemical Studimentioning

confidence: 99%

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

Robinson

Sherwood

1975

Pediatr Res

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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)...

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Biochemical studies and therapy in subacute necrotizing encephalomyelopathy (Leigh's syndrome)

Cited by 65 publications

References 15 publications

Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy (Leigh's Syndrome)

Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy (Leigh's Syndrome)

Pyruvate Carboxylase Deficiency and Lactic Acidosis in a Retarded Child without Leigh's Disease

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

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