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Results for “Pyruvate Dehydrogenase Complex Deficiency Disease”

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PubMed1996

Comparative biochemical studies in fibroblasts from patients with different forms of Leigh syndrome.

We have compared respiratory chain enzyme activities, ATP synthesis, and ATP hydrolysis in cultured fibroblast mitochondria from patients with Leigh syndrome (LS) due to: (i) cytochrome oxidase (COX) deficiency (#6); (ii) pyruvate dehydrogenase complex (PDHC) deficiency (#4); and (iii) maternally inherited LS (MILS) with the T8993G mutation in the ATPase 6 gene of mtDNA (#5). Enzyme activities were normal in patients with MILS and variably decreased in those with COX and PDHC deficiency. ATP hydrolysis was normal or mildly decreased in all three groups. In contrast, ATP synthesis was decreased in all patients but more markedly in those with MILS, and especially with pyruvate/malate as substrate. These studies show that impaired ATP production is the common feature of all three forms of LS, but it is both more severe and more specific in MILS, consistent with the genetic defect.

Adenosine Triphosphatases↗
PubMed1993

E1 pyruvate dehydrogenase deficiency in a child with motor neuropathy.

We report the case of a boy who developed a motor neuropathy during infectious episodes at 18 mo and 3 y of age. When he was 7 y old, he suffered persistent weakness and areflexia; his resting lactate and pyruvate values were 3.65 mM and 398 microM, respectively (controls: 1.1 +/- 0.3 mM and 90 +/- 22 microM), and an exercise test demonstrated a lactic acidosis (13.6 mM; controls: 6.4 +/- 1.3 mM) with a high pyruvate level (537 microM; controls: 176 +/- 15 microM) and a low lactate/pyruvate ratio (24.2; controls: 35 +/- 2). The results of polarographic studies on muscle mitochondria suggested a defect in pyruvate oxidation (pyruvate 17 ng atom O/min/mg protein; controls: 115 +/- 42), whereas glutamate, palmitoylcarnitine, and succinate were good respiratory substrates. The activity of total pyruvate dehydrogenase complex (PDHC) in muscle mitochondria and in fresh mononuclear cells was markedly decreased (9.7 and 0.054 nmol 14CO2/min/mg protein, respectively; controls: 123 +/- 4.5 and 0.733 +/- 0.03, respectively). Immunochemical analysis in muscle mitochondria demonstrated an absence of the alpha and beta E1 PDHC subunits. After 2 y of treatment with 500 mg/d thiamine, the patient was clinically improved. A genetic study of the main regions of mutations (exon 10 and 11) in the X chromosome encoding for the E1 alpha subunit of PDHC did not show any mutation. These data indicate that, although genetically different, this case enters in a very rare category of patients with PDHC deficiency without cerebral dysfunction and improved by thiamine + L-carnitine therapy.

Base Sequence↗
PubMed1988

A deficiency of both subunits of pyruvate dehydrogenase which is not expressed in fibroblasts.

Pyruvate dehydrogenase complex (PDC) deficiency usually has been detected by decreased activity in cultured skin fibroblasts. We investigated two brothers in whom PDC activity was less than 10% of controls in lymphocytes but normal in skin fibroblasts. They both had abnormal neuromuscular development and lactic acidosis which was aggravated by ingestion of carbohydrate. One brother died at age 3 yr and tissues were obtained at autopsy soon after death. The brain was swollen with diffuse acute hemorrhages but without the lesions characteristic of Leigh's disease. PDC activity was virtually undetectable in mitochondria or homogenates of liver, skeletal muscle, and heart, but was about 30% of controls in kidney. The activity of the first component E1 was not detectable in mitochondria from liver, whereas the activities of the second and third components were normal; the activities of all components were normal in fibroblasts. Western immunoblot analysis showed absent to trace amounts of both the E1 alpha and E1 beta subunits in liver, skeletal muscle, and heart, with normal amounts of the second and third components. About one-fourth of control amounts of E1 alpha and E1 beta were present in kidney and normal levels were present in fibroblasts. PDC activity in lymphocytes from the mother was 35% of controls; she had normal PDC activity in her fibroblasts. PDC activity was normal in lymphocytes from the brothers' sister, father, and maternal grandparents and great-grandmother. The mode of inheritance was not established. In conclusion, PDC deficiency may not be detected in skin fibroblasts in some cases; the mechanism of variable tissue expression of E1 remains to be delineated.

Child, Preschool↗
PubMed1999

First prenatal diagnosis of defects in the HsPDX1 gene encoding protein X, an additional lipoyl-containing subunit of the human pyruvate dehydrogenase complex.

We have previously reported a genetic study of a neonatal lactic acidosis linked to a pyruvate dehydrogenase complex deficiency due to the absence of the protein X subunit. This rare autosomal recessive disorder is associated with specific deletions in this polypeptide which is encoded by the HsPDX1 gene, located on chromosome 11p1.3. The pathology of the patient was considered to arise from a large homozygous deletion (78del85) found at the 5' end of the HsPDX1 coding sequence. Her heterozygous mother underwent prenatal diagnosis during a subsequent pregnancy. Chorionic villus samples were used for three independent studies: (1) normal levels of the protein X component of the PDH complex were detected by immunoblotting; (2) RT-PCR analysis showed no deletion at the 5' end of the cDNA but the presence of a distinct heterozygous deletion (965del59) at its 3' end inherited from the father; (3) haplotype analysis revealed the presence of the father's mutated allele and the mother's normal allele. It was concluded that the fetus was heterozygous for this separate 3' deletion, so, it was likely to be not affected. This study permitted us to characterize more precisely the genetic abnormalities of the HsPDX1 cDNA occurring in each family's member.

Blotting, Western↗
PubMed1987

Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease).

Leigh disease is a disorder with great clinical variability and for which diverse biochemical causes have been proposed. Clarification requires rigorous correlation of biochemical abnormalities with strict morphologic diagnosis; such an unambiguous association is the subject of this report. A patient with well-documented clinical and biochemical pyruvate dehydrogenase complex deficiency is shown on postmortem examination to have the specific CNS pathology of Leigh disease. These findings, considered together with the aggregate data in the literature, suggest strongly that pyruvate dehydrogenase complex deficiency is the basic defect in a subgroup of patients with Leigh disease.

Acidosis, Lactic↗
PubMed1993

Neurodevelopmental abnormalities and lactic acidosis in a girl with a 20-bp deletion in the X-linked pyruvate dehydrogenase E1 alpha subunit gene.

We describe a girl with developmental abnormalities of the CNS and a lactic acidosis whose cultured fibroblasts showed a profound deficiency of pyruvate dehydrogenase complex (PDHC) activity (patient = 0.14 nmol/mg protein per minute, controls = 0.7 to 1.1 nmol/mg protein per minute). Immunocytochemistry demonstrated the fibroblast culture to be mosaic, with 14% of cells expressing the PDHC E1 alpha subunit protein in normal amounts and the remaining 86% having no detectable immunoreactive activity. Direct sequencing of cDNA for the X-linked PDHC E1 alpha subunit established that the patient was heterozygous for a 20-bp deletion beginning in the codon for Ser300 of the derived amino acid sequence. The pattern of methylation at the DXS255 locus suggested predominant expression of the X chromosome carrying the mutant allele in the fibroblast culture. There was a good correlation between the residual PDHC activity, the proportion of cells with immunoreactive E1 alpha protein, and the X chromosome inactivation ratio, demonstrating the importance of X-inactivation for expression of this X-linked neurometabolic disease in females.

Acidosis, Lactic↗
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↗
PubMed1998

[Vitamin B1 dependency].

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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1995

[Adult Leigh syndrome. A rare differential diagnosis of central respiratory insufficiency].

Subacute necrotizing encephalomyelopathy (Leigh's syndrome) is a rare neurodegenerative disease in the adult. The precise metabolic defect is unknown, but abnormalities of a mitochondrial enzyme system related to cytochrome-c oxidase or pyruvate dehydrogenase are described. The clinical picture usually consists of an altered breathing pattern, oculomotor paralysis, other signs of cranial nerve dysfunction, ataxia, myoclonic jerks, nystagmus, generalized seizures, optic atrophy and demyelinating peripheral neuropathy. Hypopnea leads to CO2-retention with consecutive loss of consciousness demanding mechanical ventilation. Respiratory failure is the most frequent cause of death. Here we describe two patients with adult onset Leigh's syndrome and we discuss the longterm treatment strategies including vitamin B1 and CPAP mask.

Adult↗
PubMed2003

Immunocapture and microplate-based activity measurement of mammalian pyruvate dehydrogenase complex.

Altered pyruvate dehydrogenase (PDH) functioning occurs in primary PDH deficiencies and in diabetes, starvation, sepsis, and possibly Alzheimer's disease. Currently, the activity of the enzyme complex is difficult to measure in a rapid high-throughput format. Here we describe the use of a monoclonal antibody raised against the E2 subunit to immunocapture the intact PDH complex still active when bound to 96-well plates. Enzyme turnover was measured by following NADH production spectrophotometrically or by a fluorescence assay on mitochondrial protein preparations in the range of 0.4 to 5.0 micro g per well. Activity is sensitive to known PDH inhibitors and remains regulated by phosphorylation and dephosphorylation after immunopurification because of the presence of bound PDH kinase(s) and phosphatase(s). It is shown that the immunocapture assay can be used to detect PDH deficiency in cell extracts of cultured fibroblasts from patients, making it useful in patient screens, as well as in the high-throughput format for discovery of new modulators of PDH functioning.

Adenosine Triphosphate↗
PubMed1999

Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain.

An infant with a neurodegenerative disorder accompanied by lactic acidemia is described. In muscle homogenate, the activity of lipoamide dehydrogenase (LAD), the third catalytic subunit of pyruvate dehydrogenase complex (PDHc), alpha-ketoglutarate dehydrogenase complex (KGDHc), and branched-chain keto acid dehydrogenase complex was reduced to 15% of the control. The activity of PDHc was undetectable and the activity of KGDHc was 2% of the control mean. The immunoreactive LAD protein was reduced to about 10% of the control. Direct sequencing of LAD cDNA revealed only one mutation, substituting Asp for Val at position 479 of the precursor form. The mutation resides within the interface domain and likely perturbs stable dimerization. The phenotypic heterogeneity in LAD deficiency is not directly correlated with the residual LAD activity but rather with its impact on the multienzymatic complex activity.

Amino Acid Sequence↗