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At least 19 recordsLinked to original sources
PubMed1976

[Enzymopathic congenital hyperlactacidemia].

Congenital enzymopathic hyperlactacidemia results from a defect of utilisation of pyruvate either at the level of the pyruvate junction (pyruvate-carboxylase, pyruvate-dehydrogenase and Kreb's cycle), or at the level of the unidirectional enzymes on neo-glucogenesis and of neo-glycogenogenesis, e.g. glucose-6-phosphatase, phosphoenol-pyruvate-carboxykinase and glycogen synthetase. The enzymopathies which affect neoglucogenesis associate hyper-lactacidemia and fasting hypoglycemia and more or less marked hepatomegaly. Type I glycogenesis (von Gierke's disease) is the best known example. Enzymopathies which affect the pyruvate junction and the Krebs cycle, may be manifested in addition by: --either chronic neuropathies, e.g. Leigh's disease, recurrent ataxia, and moderate hyperalactacidemia,--or, as in congenital lactic acidoses, which have a rapid and severe prognosis with major hyperlactacidemia. Functional investigation, in particular, loading tests are of great value in orientation and justify the practice of tissue biopsy which permits the enzyme diagnosis. Recent, still unconfirmed knowledge of the pathogenesis of these diseases emphasizes the considerable importance of estimation of blood lactic acid in the investigation of metabolic acidoses of hereditary origin.

Acidosis↗
PubMed1976

Ketonic diet in the management of pyruvate dehydrogenase deficiency.

Two brothers, aged 11 years 6 months and 2 years 3 months, with psychomotor and growth retardation, episodes of weakness, ataxia, ophthalmoplegia, and elevated levels of blood pyruvate were shown to have a deficiency in the pyruvate dehydrogenase complex (PDH). When they ate a diet high enough in fats to cause ketonemia but not acidosis, there was a fall in blood pyruvate levels, a decrease in the frequency and severity of the episodes of neurological deterioration, an increased rate of growth and development in the younger brother, and increased strength and endurance in the older one. The possibility of dietary treatment makes the early diagnosis of PDH deficiency more important. Determination of blood pyruvate and lactate levels following a standard glucose meal (glucose-pyruvate test) appears to be the most reliable screening test for this condition.

Alanine↗
PubMedDate not supplied

Leigh encephalopathy: histologic and biochemical analyses of muscle biopsies.

To elucidate the pathogenesis of Leigh encephalopathy, histologic, biochemical, and mitochondrial DNA analyses were performed on biopsied muscles from 33 patients with the clinical characteristics of this disorder. On muscle histochemistry, cytochrome c oxidase activity was decreased or absent in 7 patients (21%), although none had ragged-red fibers. In 2 patients with cytochrome c oxidase deficiency, staining for this enzyme was poor in the muscle fibers and fibroblasts but was normal in the arterial wall, indicating tissue-specific involvement. Ten patients (30%) had biochemical defects, including 2 with pyruvate dehydrogenase complex, 4 with cytochrome c oxidase, 1 with NADH-cytochrome c reductase (complex I), and 3 with multiple complex deficiencies. None of the 28 patients in whom muscle mitochondrial (mt)DNA was analyzed had DNA deletions or point mutation at nucleotide positions 3,243 or 8,344. These results indicate that the underlying defect in Leigh encephalopathy is heterogeneous because only 30% of patients had enzyme defects demonstrable in muscle biopsy material.

Child↗
PubMed1976

[Congenital enzyme deficiency in carbohydrate metabolism. Its significance for clinical pediatrics and human biochemical genetics (author's transl)].

A review of the enzyme deficiencies of carbohydrate metabolism known at the present time is given. Through prominent clinical symptoms and consideration of food as a pathological agent, it is possible to suspect the various diseases before the results of the biochemical determinations are available. On account of the sometimes striking course, therapy can consequently be started at the earliest possible moment.

Carbohydrate Metabolism, Inborn Errors↗
PubMed1976

Fatal lactic acidosis in a newborn attributable to a congenital defect of pyruvate dehydrogenase.

An infant suffering from metabolic acidosis attributable to hyperlactatemai (6.1 mmol/liter) accompanied by hyperalaninemia (1 mmol/liter) and hyperserinemia (0.6 mmol/liter) is described. The urinary excretion of lactate and pyruvate was greatly elevated; the lactate to pyruvate ratio was normal. The urine showed low levels of citrate, isocitrate, and cis-aconitate, and low or normal levels of alpha-oxoglutarate, succinate, malate, and methylmalonate. Aspartate was slightly elevated in serum and urine, indicating a corresponding increase if its alpha-ketoacid oxaloacetatae. These patterns of organic acids and amino acids suggested an in vivo defect in the oxidation of pyruvate. Fibroblasts cultured from skin biopsy from the patient metabolized radioactive pyruvate (final concentration 0.04-2 mmol/liter) to CO2 at rates from 5 to 17% of that of fibroblasts from normal control subjects. Enzyme studies with fibroblast sonicates revealed a severe deficiency of the pyruvate dehydrogenase complex (about 8% of normal), and this error was localized to the first unit of the complex, i.e., the pyruvate dehydrogenase (about 4% of normal). Fibroblasts from both parents metabolized pyruvate to CO2 at a slightly reduced rate, suggesting parental heterozygosity.

Acidosis↗
PubMed1978

[Pyruvate-dehydrogenase deficiency. Lethal course of the disease during infancy (author's transl)].

The course of pyruvate dehydrogenase deficiency in an infant is described. During pregnancy fetal movements were reduced, and since birth severe neurologic involvement was noticed. Permanent metabolic acidosis due to lactic acidemia as well as hyperpyruvic acidemia and hyperalaninemia were present. Alanine accumulated in CSF and urine, urinary excretion of lactate and pyruvate was highly elevated. Pyruvate dehydrogenase activity in a liver biopsy was only 5% of that for normal controls, and pyruvate decarboxylation by cultured fibroblasts was equally decreased. Therapy required permanent administration of bicarbonate. The administration of thiamine had no effect. The infant died within three months. Recently prenatal diagnosis during a subsequent pregnancy of the mother revealed normal results when pyruvate degradation with cultured amniotic fluid cells was investigated, and a healthy child was born.

Acidosis↗
PubMed1992

Investigation of enzyme defects in children with lactic acidosis.

Screening for enzyme deficiencies was carried out in cultured skin fibroblasts and leukocytes of 19 patients with lactic acidosis and neurological problems. Pyruvate carboxylase deficiency was demonstrated in three cases. Reduced pyruvate oxidation was found in seven cultures; six showed no significant stimulation of the oxidation rate by methylene blue and in three a decreased pyruvate dehydrogenase complex activity was confirmed. Methylene blue restored a near normal oxidation rate in the seventh culture which had decreased cytochrome c oxidase activity.

Acidosis, Lactic↗
PubMed1975

Absence of pyruvate decarboxylase activity in man: a cause of congenital lactic acidosis.

A complete deficiency in the pyruvate dehydrogenase system activity contributed to the death of a 6-month-old infant with congenital lactic acidosis. The enzymatic block could be isolated to the first component, pyruvate decarboxylase (E1) of the pyruvate dehydrogenase complex. This enzymatic deficiency allowed a demonstration of an "intercomplex" exchange of the components of the mammalian pyruvate dehydrogenase system and indicated that the first component is normally present in an apparent excess.

Acidosis↗
PubMed1976

Sensitivity to carbohydrate in a patient with familial intermittent lactic acidosis and pyruvate dehydrogenase deficiency.

A 9-year old boy with severe mental and growth retardation and diffuse neurologic damage had minimal elevation of blood pyruvate (0.21 mM) and lactate (2.1 mM) on a normal diet but developed life-threatening lactic acidosis (pH 7.14; lactate 21.0 MM) on a diet containing 65% carbohydrate and 15% fat. Subsequently, blood pyruvate levels rose significantly higher than in 16 control subjects during a glucose tolerance test whereas the glucose levels were normal. Two sisters died with spontaneous lactic acidosis and an otherwise similar clinical course...

Acidosis↗
PubMed1976

Lactic acidosis in three sibs due to defects in both pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes.

A Canadian Indian family is described in which three of the children were mentally retarded, and had seizures and other neurological abnormalities. They had chronic metabolic acidosis associated with elevated blood levels of lactate, pyruvate, and alanine. Two of the children excreted large amounts of pyruvic and alpha-ketoglutaric acids in the urine and had elevated plasma levels of glutamic acid and proline. Hypoglycemia occurred with fasting in two of the children. Treatment with pharmacological doses of thiamine, lipoic acid, biotin, riboflavin, and various dietary regimes was without effect. One child died at 3 1/2 months and another at 4 1/2 months; the third is still alive at 23 months of age. Enzyme assays revealed a low level of activity of both the pyruvate and alpha-ketoglutarate dehydrogenase complexes in cultured fibroblasts of one of the sibs. These patients appeared to have partial defects in the oxidation of pyruvate, as well as of alpha-ketoglutarate within the tricarboxylic acid cycle.

Acidosis↗
PubMed1978

Evidence for a primary defect of lipoamide dehydrogenase in Friedreich's ataxia.

There is now a great deal of evidence to link genetic defects of pyruvate metabolism to brain disease. Experimental evidence is reviewed in Chapter 12, and clinical evidence has been reviewed above. Severe lesions of components of the pyruvate dehydrogenase complex are associated with severe generalized brain disease, and milder defects with inherited ataxias. Nearly half of one series of our ataxic patients had deficient activity of pyruvate dehydrogenase, and 40% of another series have deficient activity of the lipoamide dehydrogenase component. This last group corresponds to 60% of the patients with Friedreich's ataxia and its clinical variants at UCLA. There is an association between defective activity of lipoamide dehydrogenase and disease, and the data suggest there is a structural mutation of the gene for the enzyme. Preliminary studies suggest that obligate heterozygotes as a group have enzyme activities between those for controls and those for patients. Moreover, the obligate heterozygotes from families in which there are kinetic defects of lipoamide dehydrogenase also appear to have kinetic abnormalities of the enzyme. The ataxic patients with reduced lipoamide dehydrogenase activity currently fall into two clinical groups. One is ragged-red ataxia, and the other is a disorder that is a subgroup of the classic Friedreich's ataxia syndrome. Studies need to be undertaken on a larger group of patients, with more diverse inherited ataxias, to test the present clinical associations of the enzyme defect. A dietary treatment derived from a knowledge of the presumed defect has modified the ataxia that is associated with defects of pyruvate decarboxylase, but the diet has not yet been tested with defects of lipoamide dehydrogenase.

Ataxia↗
PubMedDate not supplied

Evoked potentials in children with oxidative metabolic defects leading to Leigh syndrome.

We studied evoked potentials in 15 children (age range: 2 wks to 4 yrs; mean: 10 mos) with metabolic disturbances that led to Leigh syndrome. These disturbances included deficiencies of pyruvate dehydrogenase (N = 5), complex 1 (N = 7), complex 4 or cytochrome oxidase (N = 2), and complex 5 (N = 1) deficiencies. Subsequent studies were performed in 11 children. All of the children with pyruvate dehydrogenase deficiency had abnormal brainstem auditory evoked potentials (BAEPs) due to poor morphology and reproducibility of the waveforms; central conduction time was normal in 4 of 5 initial studies. The patients with complex 4 or cytochrome oxidase deficiency had abnormal BAEPs, due to increased interpeak latencies and low amplitude or absent waves IV/V. Six of 7 of the children with complex 1 deficiency had normal BAEPs. The remaining patient (the youngest, age 6 wks) had only waves I and II bilaterally and suffered from the rapidly progressive form of complex 1 deficiency; the other 6 with complex 1 deficiency had the slowly progressive form. The one patient with complex 5 deficiency had normal BAEPs when first tested at 4 mos; abnormal BAEPs with loss of later waves were observed 10 weeks later. The visual evoked potentials and somatosensory evoked potentials usually were abnormal in these patients, but the findings were not specific to the patient subgroups. In all but one patient, subsequent studies disclosed a lack of normal maturational changes and/or deterioration across all 3 modalities. The BAEPs appeared to covary with the specific metabolic findings in these patients and with the patient's clinical course, but no BAEP could be considered characteristic of Leigh syndrome.

Acidosis, Lactic↗
PubMed1979

Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease.

A child with lactic acidosis, severe mental and developmental retardation, and proximal renal tubular acidosis is presented. Biopsy and autopsy studies show severe hepatic, renal cortical, and cerebral deficiencies in pyruvate carboxylase (EC 6.4.1.1) activity. The patient had 1.81 +/- 0.20 units/g fresh weight at biopsy and 0.75 +/- 0.07 units/g fresh weight hepatic pyruvate carboxylase activity at autopsy compared with 10.9, 11.3, and 9.5 units/g fresh weight in two autopsy and one biopsy controls, respectively. The patient's renal cortical pyruvate carboxylase activity at autopsy was 0.008 +/- 0.004 units/g fresh weight compared with 5.05 units/g in the autopsy control. The patient had no detectable (less than 0.018 units/g fresh weight) cerebral pyruvate carboxylase activity at autopsy compared with 0.44, 0.53, and 0.695 units/g in the autopsy cerebrum of one human and two rhesus monkeys, respectively. Pyruvate dehydrogenase complex, phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32), and fructose-1,6-bisphosphatase (EC 3.1.3.11) activities were in the normal range. The patient's urine pH was above 7.9 when the total serum CO2 was greater than 7.8 mM. However, the patient was able to acidify the urine to pH 5.1 when the total serum CO2 was 1.6 mM. The neuropathologic examination of the brain at autopsy revealed no sign of Leigh's disease, although developmental and degenerative lesions were observed. This is the first reported patient with a primary deficiency in hepatic, renal, and cerebral pyruvate carboxylase deficiency in whom the neuropathologic lesions, distinct from those of Leigh's disease, and proximal renal tubular acidosis have both been documented.

Acidosis↗