Disorders of pyruvate metabolism and the tricarboxylic acid cycle (original) (raw)
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Systemic Deficiency of the First Component of the Pyruvate Dehydrogenase Complex
Pediatric Research, 1987
An infant with lactic acidosis and developmental delay had neuropathological changes consistent with Leigh's necrotizing encephalomyelopathy. Total pyruvate dehydrogenase complex (PDC) activity was low relative to controls in lymphocytes (0.2 versus 1.9 2 0.6 S D nmol/min/mg protein) and cultured skin fibroblasts (0.9 versus 2.7 + 1.0). Liver, muscle, heart, and kidney mitochondria oxidized several substrates normally, but did not oxidize pyruvate. PDC activity was absent in these mitochondria (0.1 versus 9.8 + 4.2 in liver and 0.7 versus 75 + 26 in muscle) and was very low in all tissue homogenates. Activity of the first component was low in liver mitochondria, whereas activities of the second and third components were normal. Western blot analysis of tissue proteins showed normal amounts of second and third component of PDC but undetectable to trace amounts of both a and B subunits of the first component of PDC in liver, brain, kidney, heart, and skin fibroblasts. Thus, profound systemic deficiency of PDC was due to lack of both subunit proteins of the first component of PDC.
Background : Pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA which ultimately generates ATP. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits, and the resulting phenotype, though very heterogeneous, mainly affects the neuro-encephalic system. The aim of this study is to describe and discuss the clinic, metabolic and genotypic profiles of thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results : The mutational spectrum revealed that seven patients (54 %) carry mutations in the PDHA1 gene , encoding the E1α subunit, five patients (38 %) carry mutations in the PDHX gene, encoding the E3 binding protein, and the remaining patient (8 %) harbors mutations in the DLD gene, encoding the E3 subunit. These data corroborate PDHA1 mutations as the predominant cause of PDC deficiency, though revealing a notable prevalence of PDHX mutations ...
Orphanet Journal of Rare Diseases
Background The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype–phenotype correlations. Results The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, m...
Pyruvate dehydrogenase deficiency: Clinical and biochemical diagnosis
Pediatric Neurology, 1993
A female neonate with pyruvate dehydrogenase (PDH) deficiency is presented with clinical, radiologic, biochemical, neuropathoiogic, and molecular genetic data. She was dysmorphic, with a high forehead, lowset ears, thin upper lip, upturned nose, and rhizomelic limbs. Cranial MRI revealed severe cortical atrophy, ventricular dilatation, and corpus caliosum agenesis. Pyruvate and lactate levels were increased in CSF and blood. Urinary organic acid profile was compatible with PDH deficiency. PDH activity was normal in fibroblasts, lymphocytes, and muscle. The PDH El-or gene was sequenced and a single base mutation was found within the regulatory phosphorylation site in exon 10. It is postulated that this mutation causes a cerebral form of PDH deficiency. Tissue-specific expression of the disease could be explained by differential X chromosome inactivation because the PDH El-ct gene is located on this chromosome. Dysmorphism with severe cerebral malformations in female patients merits a metabolic evaluation, including determination of lactate and pyruvate levels in CSF.
Immunochemical evidence of pyruvate dehydrogenase (E1) deficiency
Journal of Inherited Metabolic Disease, 1988
Mammalian pyruvate dehydrogenase complex (PDHC) is a multienzyme complex with a total Mr of approximately 7 × 106. It consists of five components: pyruvate dehydrogenase (El; EC 1.2.4.1), dihydrolipoyl transacetylase (E2; EC 2.3.1.12), lipoamide dehydrogenase (E3; EC 1.6.4.3) and two specific regulatory enzymes. E1 consists of two different peptides, EI~ and EI~. An additional component of PDHC, protein X, has been elucidated immunochemically. PDHC deficiency is a rare disease and is a cause of primary lactic acidosis. While there are many reports of this disease, there are few analyses of its molecular basis in the literature. We report here our immunochemical analyses of PDHC in skin fibroblasts and/or Epstein-Barr transformed lymphoid cells obtained from three patients with this disease. MATERIALS AND METHODS Case 1: The proband was a 1-year-old girl delivered by cesarian section at a full term. Ventricular dilatation in the fetus was detected by ultrasound. At birth, there was a slight cyanosis, her cry and muscle tonus were weak and her fingers were contracted. Brain CT scan showed ventricular dilatation and agenesis of the corpus callosum. Serum lactate and pyruvate were greatly elevated, the values being lactate 112.9mg/dl and pyruvate 8.6mg/dl. Case 2: This patient was a 9-year-old girl born after a full-term pregnancy and spontaneous delivery. Tube feeding was required because of a poor sucking ability from birth on. Delay in development was prominent at the age of 3 months when she had no visual response or head control. At 6 months, she was prescribed anticonvulsant drug therapy for infantile myoclonic seizures which had become difficult to control. Brain CT scan showed a diffuse brain atrophy. The levels of lactate (41.2mg/dl) and pyruvate (3.9mg/dl) were elevated.
Heterogeneous Expression of Protein and mRNA in Pyruvate Dehydrogenase Deficiency
Proceedings of the National Academy of Sciences of the United States of America, 1988
Deficiency of pyruvate dehydrogenase [pyruvate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-acetylating), EC 1.2.4.1], the first component of the pyruvate dehydrogenase complex, is associated with lactic acidosis and central nervous system dysfunction. Using both specific antibodies to pyruvate dehydrogenase and cDNAs coding for its two alpha and beta subunits, we characterized pyruvate dehydrogenase deficiency in 11 patients. Three different patterns were found on immunologic and RNA blot analyses. (i) Seven patients had immunologically detectable crossreactive material for the alpha and beta proteins of pyruvate dehydrogenase. (ii) Two patients had no detectable crossreactive protein for either the alpha or beta subunit but had normal amounts of mRNA for both alpha and beta subunits. (iii) The remaining two patients also had no detectable crossreactive protein but had diminished amounts of mRNA for the alpha subunit of pyruvate dehydrogenase only. These results indicate that loss of pyruvate dehydrogenase activity may be associated with either absent or catalytically inactive proteins, and in those cases in which this enzyme is absent, mRNA for one of the subunits may also be missing. When mRNA for one of the subunits is lacking, both protein subunits are absent, suggesting that a mutation affecting the expression of one of the subunit proteins causes the remaining uncomplexed subunit to be unstable. The results show that several different mutations account for the molecular heterogeneity of pyruvate dehydrogenase deficiency.
Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis
Developmental Medicine & Child Neurology, 2009
METHOD Twenty-two participants with enzymologically and genetically confirmed PDHc deficiency were analysed for clinical and imaging features over a 15-year period. RESULTS Four groups were identified: (1) those with neonatal encephalopathy with lactic acidosis (one male, four females; diagnosis at birth); (2) those with non-progressive infantile encephalopathy (three males, three females; age at diagnosis 2-9mo); (3) those with Leigh syndrome (eight males; age at diagnosis 1-13mo); and (4) those with relapsing ataxia (three males; 18-30mo). Seventeen mutations involved PDHA1 (a hotspot was identified in exons 6, 7, and 8 in seven males with Leigh syndrome or recurrent ataxia). Mutations in the PDHX gene (five cases) were correlated with non-progressive encephalopathy and long-term survival in four cases. INTERPRETATION Two types of neurological involvement were identified. Abnormal prenatal brain development resulted in severe non-progressive encephalopathy with callosal agenesis, gyration anomalies, microcephaly with intrauterine growth retardation, or dysmorphia in both males and females (12 cases). Acute energy failure in infant life produced basal ganglia lesions with paroxysmal dystonia, neuropathic ataxia due to axonal transport dysfunction, or epilepsy only in males (11 cases). The ketogenic diet improved only paroxysmal dysfunction, providing an additional argument in favour of paroxysmal energy failure.