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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thiamine-deficient encephalopathy in the rat is characterized by ataxic gait, loss of righting reflex and curvature of the spine. Neurochemical changes include a diminished activity of cerebral pyruvate decarboxylase leading to abnormal pyruvate oxidation. The present study shows that this defective pyruvate oxidation produces a significant depletion of three important amino acid neurotransmitters, namely gamma aminobutyric acid (GABA), glutamic acid, and aspartic acid. Such changes could lead to severe neuronal dysfunction and the observed neurological symptoms of thiamine deficiency. Some implications for the pathogenesis of Friedreich's ataxia are discussed.
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PMID:Amino acid changes in thiamine-deficient encephalopathy: some implications for the pathogenesis of Friedreich's ataxia. 48 14

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.
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PMID:Leigh encephalopathy: histologic and biochemical analyses of muscle biopsies. 132 89

We report a 14-year-old boy with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) who presented repeated episodes of abdominal pain and vomiting since the age of 8 years. In addition, he developed strokelike episodes with myoclonic seizures and transient hemiplegia on three occasions. At the age of 14-1/12-years, he also developed epilepsia partialis continua persisting for 10 days, which was associated with myoclonic seizures synchronized with spike discharges at the right central area. Laboratory examination disclosed increased levels of lactate and pyruvate in serum and CSF and low density areas in the bilateral temporal regions on CT scan. Muscle biopsy showed scattered ragged-red fibers. The enzyme activities (pyruvate dehydrogenase complex, pyruvate carboxylase, phosphoenol pyruvate carboxykinase, and cytochrome c oxidase) and the rates of decarboxylation of [3-14C]pyruvate in cultured skin fibroblasts were within normal ranges.
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PMID:[A case with MELAS associated with epilepsia partialis continua]. 189 96

Defects of the pyruvate dehydrogenase complex and of mitochondrial fatty acid oxidation are important causes of disease. Defects of pyruvate dehydrogenase may present in early childhood with severe CNS changes or, as lactic acidosis or later with ataxia. Defects of fatty acid oxidation may present with hypoglycaemic coma, myopathy, liver disease with encephalopathy, cardiomyopathy or sudden infant death. The investigation of both these groups of disorders is difficult and depends upon a combination of biochemical and molecular biology techniques.
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PMID:Deficiency of the pyruvate dehydrogenase complex and of mitochondrial fatty acid oxidation. 196 58

Pyrithiamine-induced thiamine-deficiency encephalopathy in the rat shows many neuropathological and biochemical similarities to Wernicke's encephalopathy in humans. Treatment of rats with pyrithiamine resulted in moderate reductions of glutamate in thalamus and pons and in generalized severe reductions of aspartate in pons (by 89%, p less than 0.01), thalamus (by 83%, p less than 0.01), cerebellum (by 53%, p less than 0.01), and cerebral cortex (by 33%, p less than 0.05). Alanine concentrations were concomitantly increased. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were decreased in parallel with the aspartate decreases; pyruvate dehydrogenase complex activities were unchanged in all brain regions. Following thiamine administration to symptomatic pyrithiamine-treated rats, neurological symptoms were reversed and concentrations of glutamate, aspartate, and alanine, as well as alpha KGDH activities, were restored to normal in cerebral cortex and pons. Aspartate levels and alpha KGDH activities remained below normal values, however, in thalamus. Thus, pyrithiamine treatment leads to reductions of cerebral alpha KGDH and (1) decreased glucose (pyruvate) oxidation resulting in accumulation of alanine and (2) decreased brain content of glutamate and aspartate. Such changes may be of key significance in the pathophysiology of the reversible and irreversible signs of Wernicke's encephalopathy in humans.
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PMID:Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes. 256 21

Chronic alcoholism results in thiamine deficiency as a consequence of inadequate dietary intake and of impaired absorption of the vitamin. In addition, there is evidence to suggest that alcohol reduces thiamine phosphorylation to thiamine pyrophosphate (TPP) in brain. TPP is a cofactor for the pyruvate dehydrogenase complex (PDHC), alpha-ketoglutarate dehydrogenase (alpha KGDH) and transketolase (TK), three enzymes involved in cerebral glucose and energy metabolism. Pyrithiamine-induced thiamine deficiency in the rat results in early, selective, reversible reductions of alpha KGDH in brain; PDHC activities are unaffected. Reductions of alpha KGDH are accompanied by decreased aspartate, glutamate and GABA and by concomitantly increased alanine in the brain of thiamine-deficient animals. It is suggested that decreased alpha KGDH, rather than decreased PDHC constitutes 'the biochemical lesion' in thiamine deficiency encephalopathy first enunciated by Peters in the 1930s. If sufficiently prolonged and severe, thiamine deficiency results in brain cell death. Possible mechanisms involved include compromised cerebral energy metabolism and focal accumulation of lactate, both of which could result from decreased activities of alpha KGDH. In addition, it is proposed that brain cell death in severe thiamine deficiency may result from excessive release of excitotoxic amino acids. Comparable mechanisms could be involved in the cell death and in the pathogenesis of the thiamine-unresponsive symptoms of the Wernicke-Korsakoff Syndrome in humans.
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PMID:Effects of thiamine deficiency on brain metabolism: implications for the pathogenesis of the Wernicke-Korsakoff syndrome. 267 60

Increasingly numerous studies are being devoted to mitochondrial diseases, notably those which involve the neuromuscular system. Our knowledge and understanding of these diseases is progressing rapidly. We owe to Luft et al. (1962) the first description of this type of diseases. Their patient, a woman, presented with clinical symptoms suggestive of mitochondrial dysfunction, major histological abnormalities of skeletal muscle mitochondria and defective oxidative phosphorylation coupling clearly demonstrated in mitochondria isolated from muscle. This clinical, histological and biochemical triad led to the definition of mitochondrial myopathies. Subsequently, the triad was seldom encountered, and most mitochondrial myopathies were primarily defined by the presence of morphological abnormalities of muscle mitochondria. This review deals with the morphological, clinical, biochemical and genetic aspects of mitochondrial encephalomyopathies. The various morphological abnormalities of mitochondria are described. These are not specific of any particular disease. They may be present in some non-mitochondrial diseases and may be lacking in diseases due to specific defects of mitochondrial enzymes (e.g. carnitine palmityl-transferase or pyruvate dehydrogenase). The clinical classification of mitochondrial encephalomyopathies is discussed. There are two main schools of thought: the "lumpers" do not recognize specific syndromes within the spectrum of mitochondrial "cytopathies", the "splitters" try to identify specific syndromes while recognizing the existence of borderline cases. The following syndromes are described: chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), MERRF syndrome (myoclonic epilepsy with ragged-red fibers), MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and Leigh and Alpers syndromes. The biochemical classification comprises five types of abnormalities: defects of transport through the mitochondrial membrane, of substrate utilization, of Krebs' cycle, of oxidative phosphorylation and of various complexes of the respiratory chain. The clinical pictures corresponding to these defects are briefly described. The genetic aspects of these diseases are especially interesting because mitochondria have their own genome coding for thirteen proteins, all of them belonging to the respiratory chain. Genetic mitochondrial diseases may result from alterations of the nuclear genome, which are transmitted by mendelian inheritance, but they may also be due to alterations of the mitochondrial genome and transmitted by non-mandelian "maternal" heredity. A few examples are discussed, including Leber's optic atrophy and MERRF syndrome. (ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mitochondrial encephalomyopathies. 268 27

"Energy metabolism" is deranged in a wide variety of disorders of the nervous system. This term refers rather loosely to the pathways responsible for the utilization of the major substrates of brain. Primary disorders of energy metabolism are those in which the primary insult affects the cellular machinery required for energy metabolism. A typical example would be a defect in a gene coding for a mitochondrial protein. Biochemically, defects which appear to be hereditary and which lead to disease of the central nervous system have been described in each of the pathways of energy metabolism: glycogenolysis (the break-down of glycogen to glucose); glycolysis (the break down of glucose to pyruvate and lactate); the pyruvate dehydrogenase complex (which oxidizes pyruvate to enter the Krebs tricarboxylic acid cycle); the tricarboxylic acid cycle itself (which completes the oxidation of carbohydrates and other substrates to carbon dioxide); electron transport (which carries out their oxidation to water); the pentose phosphate pathway (an alternate pathway for glucose oxidation); and several "minor" mitochondrial pathways. Clinically, the spectrum of syndromes associated with primary disorders of energy metabolism is wide. Common manifestations include psychomotor retardation, with associated lactic acidosis and/or hypoglycemia. The laboratory abnormalities may be intermittent. Syndromes which have been culled out include congenital lactic acidosis, Leigh disease, intermittent ataxia, Kearns-Sayre-Shy syndrome (KSS), myoclonus epilepsy with ragged red fibers (MERRF), and mitochondrial myopathy-encephalopathy-lactic acidosis-stroke (MELAS). As with other families of inborn errors, both clinical and biochemical heterogeneity occur. Patients with apparently similar clinical syndromes can turn out to have different inborn errors, and patients with abnormalities of the same gene product can have clinically distinguishable syndromes. Secondary disorders are those in which the derangements of energy metabolism are presumably secondary to some other insult but may still be important for the cellular pathophysiology. These include the metabolic encephalopathies and probably a number of well-known neurodegenerative disorders. In the hereditary ataxias, abnormalities of mitochondrial markers are common but do not correlate consistently with the disorders as conventionally classified; a new classification into axonal ataxias, multiple system degenerations, and ataxic encephalopathies may be easier to relate to the pathophysiology.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Energy metabolism in disorders of the nervous system. 297 43

Thiamine-deficient encephalopathy is characterized by morphologic lesions in the brainstem and less extensively in the cerebellum, but the early neurologic signs reverse rapidly and fully with thiamine, indicating a metabolic disorder. The suggested causal mechanisms of the encephalopathy involve two thiamine-dependent enzymes: (a) impairment of pyruvate decarboxylase activity with decreased cerebral energy (ATP) synthesis, and (b) reduction of transketolase activity with possible impairment of the hexose monophosphate shunt and subsequent decrease in NADPH formation. The latter may be important in maintaining glutathione in a reduced form (GSH), which apparently functions by keeping enzymes in a reduced (active) conformation. To examine some of these postulated mechanisms, in this study we measured pyruvate decarboxylase and transketolase activity, lactate, ATP and GSH levels in the cerebral cortex, cerebellum, and brainstem, and thiamine concentration in whole brain of rats with diet-induced low thiamine encephalopathy. Pair-fed and normally fed asymptomatic control animals were similarly investigated. To assess the functional importance of some of our results, we repeated the studies in rats, immediately (16-36 hr) after reversal of the neurological signs with thiamine administration. THE DATA OBTAINED LED TO THE FOLLOWING CONCLUSIONS: (a) Brain contains a substantial reserve of thiamine in that thiamine level has to fall to below 20% of normal before the onset of overt encephalopathy and an increase in brain thiamine to only 26% of normal results in rapid reversal of neurologic signs. (b) Both cerebral transketolase and pyruvate decarboxylase activities are impaired in low thiamine encephalopathy and the abnormality in the pyruvate decarboxylase is reflected in a rise in brain lactate. These biochemical abnormalities occur primarily in the brainstem and cerebellum, the sites of the morphologic changes. (c) Although the fall in cerebral transketolase is about twofold greater than that of pyruvate decarboxylase activity during encephalopathy, both enzymes rise on reversal of neurologic signs and the degree of the transketolase rise is slight. Accordingly, this study cannot ascertain the relative functional importance of these two pathways in the induction of the encephalopathy. The data suggest, however, that the depression of transketolase is not functionally important per se, but may only be an index of some other critical aspect of the hexose monophosphate shunt. (d) The normal cerebral ATP concentration and small GSH fall during encephalopathy, with little GSH rise on reversal of neurologic signs, suggest that a depletion of neither substance is instrumental in inducing thiamine-deficient encephalopathy.
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PMID:Encephalopathy of thiamine deficieny: studies of intracerebral mechanisms. 567 22

Changes in the rates of glycolysis, glycogenolysis, activities of pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, serum glutamic pyruvic and oxaloacetic transaminases in the brain hemispheres and stem of rats exposed to 5-7 hypoglycemic comas were studied. No noticeable changes were detected in glycolysis intensity or activities of Krebs' cycle enzymes in the large hemispheres. The intensity of glycogenolysis and activities of transaminases in the brain stem reduce on day 2 of repair period after the last hypoglycemic coma. The detected changes result from multiple exposures of the brain to hypoglycemia and may be important in the development of posthypoglycemic encephalopathy.
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PMID:[Intensity of glycolysis and activity of energy metabolism enzymes in rat brain after multiple exposures to hypoglycemic doses of insulin]. 789 47


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