Pyruvate Dehydrogenase Deficiency Research Articles

A Case of Pyruvate Dehydrogenase Deficiency with Low Density Areas in White Matter Noticed by CT Scan

A Case of Pyruvate Dehydrogenase Deficiency with Low Density Areas in White Matter Noticed by CT Scan

Pyruvatdehydrogenase-Defizienz bei einem Kind mit persistierender Lactatacidose

Evidence is presented for defective pyruvate dehydrogenase (EC 4.1.1.1) in leukocytes and muscle tissue from a 10-year old child with persistent lactic acidosis, suffering from myasthenia and growth retardation. The defect is expressed in vitro by a depressed stimulation of pyruvate dehydrogenase catalytic activity by exogenous phosphoprotein phosphatase, and in vivo by a lack of response to muscle work, in comparison with healthy controls. Pyruvate dehydrogenase activity is in the normal range when measured without addition of phosphoprotein phosphatase in cells obtained from the resting patient. The defect reported here represents a new, hitherto undescribed form of a pyruvate dehydrogenase deficiency. The insufficient catalytic activity explains the observed accumulation of pyruvate, lactate, oxaloacetate and alanine and the decrease of citrate concentration in the blood of this patient. Electron microscope studies of the muscle tissue show an enhanced number of enlarged mitochondria with bizarre shapes and high densities of cristae.

Histological changes of muscle in a patient with pyruvate dehydrogenase deficiency

Histological changes of muscle from a 17-month-old boy with pyruvate dehydrogenase deficiency are presented. The patient had muscle hypotonia, mental retardation, seizures, lactic acidosis and hyperalaninemia. Deficient activity of the pyruvate dehydrogenase complex was found in his platelets (about 25% of normal) and of pyruvate dehydrogenase in his biopsied muscle (about 5% of normal). A muscle biopsy specimen showed an increased proportion of type IIC fibers (24%), fiber-type grouping and lipid droplet accumulation.

Determination of pyruvate dehydrogenase in cultured human fibroblasts and amniotic fluid cells

A new assay method for pyruvate dehydrogenase in platelets [1] using in situ generation of [1- 14C]pyruvate from [1- 14C]lactate has been further developed for the use in cultured human fibroblasts and amniotic fluid cells. A very low blank rate was found compared to the method using [1- 14C]pyruvate as substrate and an activity of 20 times the blank was obtained in normal fibroblasts and amniotic fluid cells. The pyruvate dehydrogenase was linear with time and protein concentration. The activity was greatly decreased by addition of non-radioactive pyruvate to the assay mixture and by preincubation with ATP. The cofactor requirement was similar to pyruvate dehydrogenase from other sources. Normal activities in cultured human fibroblasts and amniotic fluid cells were 13.9 pkat/mg protein ( n = 15) and 21.7 pkat/mg protein ( n = 10), respectively. The method was found to be very reliable and makes the diagnosis of pyruvate dehydrogenase deficiency possible in easily accessible tissue such as cultured fibroblasts. Prenatal diagnosis may also be a possibility.

Pyruvate dehydrogenase deficiency restricted to brain

We studied a child with a rapidly progressive neurologic disorder, with psychomotor retardation, hypotonia, seizures, and respiratory disturbances. Laboratory studies showed elevated levels of lactate and pyruvate in cerebrospiral fluid (CSF), without notable elevated levels in serum. In liver, muscle, leukocytes, and cultured fibroblasts we found no abnormality in pyruvate oxidation; biochemical studies of a brain biopsy showed an isolated deficiency of pyruvate dehydrogenase complex in brain tissue with the morphologic picture of progressive polio-dystrophy with hypomyelination.

The genetic heterogeneity of lactic acidosis: occurrence of recognizable inborn errors of metabolism in pediatric population with lactic acidosis.

A total of 40 skin fibroblast cultures from pediatric cases of lactic acidosis were subjected to a series of tests designed to elucidate the nature of an underlying defect in metabolism. Of these 40 cases, in 14 we were able to define the following problems. Pyruvate carboxylase deficiency was evident in five cases showing < 10% normal activity. Phosphoenolpyruvate carboxykinase deficiency was evident in one case where the whole cells showed 17% of normal activity whereas the mitochondrial activity of this enzyme was 6% of normal. Pyruvate dehydrogenase deficiency was present in six cases showing 8 to 39% of normal activity, five of them being due to deficient pyruvate decarboxylase activity and one of them being due to deficient dihydrolipoyl dehydrogenase activity. Two cases were found with normal enzymes of pyruvate metabolism in which the production of 14CO2 from [3-14C]pyruvate was deficient at 13 and 28% of normal activity, respectively, which we consider to be indicative of reduced activity of the Krebs' cycle. The grounds for the diagnosis of these 14 affected cases are documented, and the clinical presentation of these enzyme deficiencies is assessed in the light of present knowledge about lactic acidosis.

Pyruvate dehydrogenase deficiency in spinocerebellar degenerations.

To study the incidence of abnormalities of the pyruvate (PDH) or ketoglutarate (KGDH) dehydrogenase complexes in patients with spinocerebellar degenerations, we measured the activities of PDH and KGDH in platelet-enriched preparations from the blood of 14 patients. Low PDH was found in 6 of the 14 patients; low KGDH was found in 2 of the 6. PDH-normal and PDH-abnormal patients could not be distinguished by clinical criteria. These results extend previous studies, which suggested abnormalities of pyruvate oxidation in patients with hereditary ataxias. The data imply that deficient activity of the PDH complex may be associated with spinocerebellar degenerations, and that the clinical phenotypes of the inherited ataxias can be associated with several genotypes.

Pyruvate dehydrogenase deficiency in 35 patients.

Pyruvate dehydrogenase deficiency in 35 patients.

Thiamine dependency in a patient with congenital lacticacidaemia due to pyruvate dehydrogenase deficiency

A patient with congenital lactic acidosis, muscular hypotonia and severe ataxia is reported. The aetiology of his disease was found to be a deficiency of pyruvate dehydrogenase (E.C. 4.1.1.1.). Thiamine treatment (1.8 g/day) was successful in correcting biochemical and clinical symptoms. The mechanism of its action is probably based on activation of pyruvate dehydrogenase through interference in the physiologic regulation.

Rapid diagnosis of pyruvate and ketoglutarate dehydrogenase deficiencies in platelet-enriched preparations from blood

Radiochemical methods are described in detail to measure the activities of the pyruvate dehydrogenase complex and of the ketoglutarate dehydrogenase complex in platelet-enriched fractions. Determinations can be completed in one day with as little as 5 ml of venous blood. Activities are proportional to the length of the incubation and the amount of tissue protein added, show appropriate dependence on added cofactors, are stable for up to 2 days at −20°C, and do not appear to be affected by diet. The pyruvate dehydrogenase complex appears to be fully activated (dephosphorylated) in these preparations. Activities were comparable in platelet-enriched fractions from 25 normal subjects and 25 patients with a variety of neurological and psychiatric diagnoses. Mean values (± S.E.M.) for these 50 individuals were 169 ± 9 pmol/min per mg protein for the pyruvate dehydrogenase complex and 535 ± 27 pmol/ min per mg protein for the ketoglutarate dehydrogenase complex. These values are comparable to those found in cultured skin fibroblasts with similar techniques. Deficient pyruvate dehydrogenase activity (19 ± 6 and 11 ± 4 pmol/min per mg protein) was demonstrated in platelet-enriched preparations from two brothers whose fibroblasts had previously been shown to be deficient in pyruvate dehydrogenase and who responded to a ketogenic diet. Experimental details critical to obtaining reproducible results with these methods are stressed (notably the crucial importance of maintaining the purity of the radioactive substrates). These techniques allow identification of patients with pyruvate dehydrogenase deficiencies within one day without requiring liver or muscle biopsy.

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.

Sensitivity to Carbohydrate in a Patient with Familial Intermittent Lactic Acidosis and Pyruvate Dehydrogenase Deficiency

Extract: 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% carbohydrates 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. Their brains at autopsy were severely deficient in myelin but showed no evidence for active demyelination.Cultured skin fibroblasts from the patient oxidized [1-14C]pyruvate (0.16 ± 0.07 cpm/mg protein/min) and [2-14C]pyruvate (0.10 ± 0.03) to 14CO2 at a significantly slower rate than control cells (0.93 ± 0.03 and 0.30 ± 0.02; P < 0.001), but oxidized [1-14C] palmitate, [1,5-14C]citrate, [U-14C]glutamate, and [1-14C]valine normally. The activity of the pyruvate dehydrogenase complex in cell-free extracts (59 ± 16 pmol/min/mg protein) was significantly less than that for control subjects (389 ± 35; P < 0.001), but the activities of pyruvate decarboxylase and of the 2-oxoglutarate dehydrogenase complex were within the normal range. Pyruvate dehydrogenase levels in extracts of the parents' cells were midway between those of the patients and the control subjects. Mixing experiments, addition of excess cofactor, and studies of activation failed to implicate a soluble inhibitor, abnormal binding of cofactors, or defective activation as causes of the reduced enzyme activity.The data are consistent with an inherited defect in the seconed enzyme of the pyruvate dehydrogenase complex, lipoate acetyl-transferase (EC. 2.3.1.12). The defect appears to be inherited in an autosomal recessive manner.Speculation: Diets low in carbohydrate and enriched in fats may benefit patients with pyruvate dehydrogenase deficiency.

A possible mechanism for selective cerebellar damage in partial pyruvate dehydrogenase deficiency

In patients with partial deficiencies of pyruvate dehydrogenase, cerebellar ataxia has been the most prominent and sometimes the only neurologic abnormality. It is not clear how this generalized enzyme deficiency (with activity 15 to 30 percent of normal in several tissues) might lead to clinical signs referable to a limited part of the nervous system. We therefore compared the normal activity of pyruvate dehydrogenase with the normal rate of pyruvate oxidation in different parts of animal brains and then calculated the effect on pyruvate oxidation of partial deficiencies of the enzyme. The data indicate that pyruvate oxidation could be impaired in an area of anterior cerebellar vermis by deficiencies of pyruvate dehydrogenase too mild to affect pyruvate oxidation in the other areas of the brain we examined.

Urinary lactate excretion in normal children and in children with enzyme defects of carbohydrate metabolism

Urinary lactate was analyzed in 53 normal children, 7 children with glucose-6-phosphatase-deficient glycogenosis, 1 child with fructose-1,6-diphosphatase deficiency and 1 child with pyruvate dehydrogenase deficiency. Lactate in 24-h urine was expressed as concentration, total excretion, excretion per kg body weight and per 1.73 m 2 body surface, and as lactate/creatinine quotient. Of these parameters, the lactate concentration in 24-h urine showed the smallest variation in normal children (0.155 ± 0.053 mM), whereas in patients with one of the above mentioned enzymopathies 10 — 300-fold elevations were found. The lactate/creatinine quotient, normal range 0.010 to 0.058 (mM/mM) was also used to correct for unnoticed losses of urine. Both parameters, used in conjunction with blood lactate analysis, are suitable for a first screening of patients with enzymopathies of carbohydrate metabolism, and for the follow-up study of the steady or unsteady state of the patient with an enzyme defect of carbohydrate metabolism.