Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 14-month-old female with familial dysautonomia was referred to the pediatric department with high fever (41.6 degrees C), watery diarrhea, and vomiting. A few hours later, signs of encephalopathy appeared. Laboratory tests revealed elevated levels of lactate dehydrogenase (3500 U/L), aspartate aminotransferase (640 U/L), alanine aminotransferase (320 U/L), and creatine kinase (28,420 U/L). The diagnosis was heat stroke. Impaired autonomic nervous system function may be another risk factor for the development of heat stroke in young children.
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PMID:Heat stroke in familial dysautonomia. 1458 Jun 63

Computed tomography provides a sensitive method for investigating skeletal muscle changes in neuromuscular diseases, but this method has not been applied to mitochondrial myopathies. We characterized the pattern of muscle involvement in patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), the common MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) mutation. Twenty-four patients, age 19-73 years, with 3243A>G were examined. Clinical evaluation included assessment of muscle strength and functional capacity. All the patients underwent muscle computed tomography, and muscle samples from 17 of them were examined for the presence of ragged red fibres and for the 3243A>G heteroplasmy. Venous blood lactate at rest and serum creatine kinase were determined. Clinical myopathy was found in six patients, while nine showed mild muscle weakness and nine had normal muscle function. The upper and lower limbs were equally affected, but the proximal muscles were more severely affected than the distal ones. CT revealed abnormalities in the muscles of 13 patients (54%; 95% confidence interval, 33-76%), including the six with clinical myopathy and seven without clinical myopathy. Myopathic changes were found most frequently in the pelvic muscles, with predominant involvement of the gluteus maximus. These data show that CT reveals frequent abnormal findings in the muscle of patients with the 3243A>G mtDNA mutation. Muscle CT is a useful adjunct to clinical evaluation in these patients.
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PMID:Muscle computed tomography patterns in patients with the mitochondrial DNA mutation 3243A>G. 1516 88

Mitochondrial encephalomyopathies encompass a group of disorders that have impaired oxidative metabolism in skeletal muscles and central nervous system. Many compounds have been used in clinical trials on mitochondrial diseases, but the outcomes have been variable. It remains controversial whether treatment of mitochondrial diseases with coenzyme Q 10 is effective. This paper describes a case of mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes, and exercise intolerance successfully treated with coenzyme Q 10. Efficacy of this therapy in this patient is correlated to control of lactic acidosis and serum creatine kinase levels. Disappointingly, larger studies with coenzyme Q 10 failed to demonstrate a clear beneficial effect on the entire study population with regard to clinical improvement or several parameters of the oxidative metabolism. They suggest that the use of coenzyme Q in treatment of mitochondrial diseases should be confined to protocols. There is a confounding variation in phenotype and genotype, and the natural history of the disorders in individual patients is not accurately predictable. The unpredictable a priori efficacy of therapy suggests that a long-term trial of oral coenzyme Q may be warranted.
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PMID:Coenzyme Q 10 improves lactic acidosis, strokelike episodes, and epilepsy in a patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). 1531 6

Patients affected by medium-chain acyl CoA dehydrogenase (MCAD) deficiency, a frequent inborn error of metabolism, suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. In the present study, we investigated the in vitro effect of the medium-chain fatty acids (MCFA), at concentrations varying from 0.01 to 3 mM, accumulating in MCAD deficiency on some parameters of energy metabolism in cerebral cortex of young rats. (14)CO(2) production from [U(14)] glucose, [1-(14)C] acetate and [1,5-(14)C] citrate was evaluated by incubating cerebral cortex homogenates from 30-day-old rats in the absence (controls) or presence of octanoic acid, decanoic acid or cis-4-decenoic acid. OA and DA significantly reduced (14)CO(2) production from acetate by around 30-40%, and from glucose by around 70%. DA significantly reduced (14)CO(2) production from citrate by around 40%, while OA did not affect this parameter. cDA inhibited (14)CO(2) production from all tested substrates by around 30-40%. The activities of the respiratory chain complexes and of creatine kinase were also tested in the presence of DA and cDA. Both metabolites significantly inhibited cytochrome c oxidase activity (by 30%) and complex II-III activity (DA, 25%; cDA, 80%). Furthermore, only cDA inhibited complex II activity (by 30%), while complex I-III and citrate synthase were not affected by these MCFA. On the other hand, only cDA reduced the activity of creatine kinase in total homogenates, as well as in mitochondrial and cytosolic fractions from cerebral cortex (by 50%). The data suggest that the major metabolites which accumulate in MCAD deficiency, with particular emphasis to cDA, compromise brain energy metabolism. We presume that these findings may contribute to the understanding of the pathophysiology of the neurological dysfunction of MCAD deficient patients.
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PMID:Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency. 1556 46

The diagnosis of mitochondrial myopathy depends upon a constellation of findings, family history, type of muscle involvement, specific laboratory abnormalities, and the results of histological, pathobiochemical and genetic analysis. In the present paper, the authors describe the diagnostic approach to mitochondrial myopathies manifesting as extraocular muscle disease. The most common ocular manifestation of mitochondrial myopathy is progressive external ophthalmoplegia (PEO). To exclude myasthenia gravis, ocular myositis, thyroid associated orbitopathy, oculopharyngeal muscular dystrophy, and congenital fibrosis of the extraocular muscles in patients with an early onset or long-lasting very slowly progressive ptosis and external ophthalmoplegia, almost without any diplopia, and normal to mildly elevated serum creatine kinase and lactate, electromyography, nerve conduction studies and MRI of the orbits should be performed. A PEO phenotype forces one to look comprehensively for other multisystemic mitochondrial features (e.g., exercise induced weakness, encephalopathy, polyneuropathy, diabetes, heart disease). Thereafter, and presently even in familiar PEO, a diagnostic muscle biopsy should be taken. Histological and ultrastructural hallmarks are mitochondrial proliferations and structural abnormalities, lipid storage, ragged-red fibers, or cytochrome-C negative myofibers. In addition, Southern blotting may reveal the common deletion, or molecular analysis may verify specific mutations of distinct mitochondrial or nuclear genes.
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PMID:Extraocular mitochondrial myopathies and their differential diagnoses. 1676 Jan 17

Ethylmalonic aciduria is a common finding in patients affected by short-chain acyl-CoA dehydrogenase (SCAD) deficiency and other diseases characterized by encephalopathy, muscular symptomatology, and lactic acidemia. Considering that the pathophysiological mechanisms of these disorders are practically unknown and that lactic acidosis suggest an impairment of energy production, the objective of the present work was to investigate the in vitro effect of ethylmalonic acid (EMA), at concentrations varying from 0.25 to 5.0 mM, on important parameters of energy metabolism in human skeletal muscle, such as the activities of the respiratory chain complexes and of creatine kinase, which are responsible for most of the ATP produced and transferred inside the cell. We verified that EMA significantly inhibited the activity of complex I-III at concentrations as low as 0.25 mM, complex II-III at 1 mM and higher concentrations, and complex II at the concentration of 5 mM. In contrast, complex IV was not inhibited by the acid. Finally, we observed that the activity of creatine kinase was significantly inhibited by EMA at the concentrations of 1 and 5 mM. These results suggest that EMA compromises energy metabolism in human skeletal muscle. In case the in vitro effects detected in the present study also occur in vivo, it is tempting to speculate that they may contribute, at least in part, to explain the hypotonia/myopathy, as well as the increased concentrations of lactic acid present in the patients affected by illnesses in which EMA accumulates.
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PMID:Inhibition of the electron transport chain and creatine kinase activity by ethylmalonic acid in human skeletal muscle. 1677 66

1. Patients affected by isovaleric acidemia (IVAcidemia) suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. The objective of the present study was to investigate the in vitro effects of the metabolites that predominantly accumulate in IVAcidemia, namely isovaleric acid (IVA), 3-hydroxyisovaleric acid (3-OHIVA) and isovalerylglycine (IVG), on important parameters of energy metabolism, such as (14)CO(2) production from acetate and the activities of the respiratory chain complexes I-IV, creatine kinase and Na(+), K(+)-ATPase in synaptic plasma membranes from cerebral cortex homogenates of 30-day-old rats. 2. We observed that 3-OHIVA acid and IVG did not affect all the parameters analyzed. Similarly, (14)CO(2) production from acetate (Krebs cycle activity), the activities of creatine kinase, and of the respiratory chain complexes was not modified by IVA. In contrast, IVA exposition to cortical homogenates provoked a marked inhibition of Na(+), K(+)-ATPase activity. However, this activity was not changed when IVA was directly exposed to purified synaptic plasma membranes, suggesting an indirect effect of this organic acid on the enzyme. Furthermore, pretreatment of cortical homogenates with alpha-tocopherol and creatine totally prevented IVA-induced inhibition on Na(+), K(+)-ATPase activity from synaptic plasma membranes, whereas glutathione (GSH) and the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) did not alter this inhibition. 3. These data indicate that peroxide radicals were probably involved in this inhibitory effect. Since Na(+), K(+)-ATPase is a critical enzyme for normal brain development and functioning and necessary to maintain neuronal excitability, it is presumed that the inhibitory effect of IVA on this activity may be involved in the pathophysiology of the neurological dysfunction of isovaleric acidemic patients.
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PMID:Isovaleric acid reduces Na+, K+-ATPase activity in synaptic membranes from cerebral cortex of young rats. 1739 58

Encephalopathy may accompany acute or chronic renal failure, and the mechanisms responsible for neurological complications in patients with renal failure are poorly known. Considering that creatine kinase (CK) is important for brain energy homeostasis and is inhibited by free radicals, and that oxidative stress is probably involved in the pathogenesis of uremic encephalopathy, we measured CK activity (hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex) in brain if rats submitted to renal ischemia and the effect of administration of antioxidants (N-acetylcysteine, NAC and deferoxamine, DFX) on this enzyme. We verified that CK activity was not altered in cerebellum and striatum of rats. CK activity was inhibited in prefrontal cortex and hippocampus of rats 12h after renal ischemia. The treatment with antioxidants prevented such effect. Cerebral cortex was also affected, but in this area CK activity was inhibited 6 and 12h after renal ischemia. Moreover, only NAC or NAC plus DFX were able to prevent the inhibition on the enzyme. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity after renal failure may be associated to neuronal loss and may be involved in the pathogenesis of uremic encephalopathy.
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PMID:Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration. 1830 34

3-Hydroxyisobutyric aciduria is an inherited metabolic disease caused by 3-hydroxyisobutyryl-CoA dehydrogenase deficiency. Tissue accumulation and high urinary excretion of 3-hydroxyisobutyric acid is the biochemical hallmark of this disorder. Clinical phenotype is heterogeneous and generally includes dysmorphic features, delayed motor development, profound mental impairment, and acute encephalopathy. Lactic acidemia is also found in the affected patients, indicating that mitochondrial dysfunction may be involved in the pathophysiology of this disorder. Therefore, the aim of the present work was to investigate the in vitro effect of 3-hydroxyisobutyric acid (0.1, 0.5 and 1mM) on essential enzymes of energy metabolism, namely the activities of the respiratory chain complexes I-V, total, cytosolic and mitochondrial creatine kinase and Na(+), K(+)-ATPase in cerebral cortex homogenates of 30-day-old rats. We also measured the rate of oxygen consumption in brain mitochondrial preparations in the presence of 3-hydroxyisobutyric acid. 3-Hydroxyisobutyric acid significantly reduced complex I-III (20%), without affecting the other activities of the electron transport chain. Furthermore, 3-hydroxyisobutyric acid did not change state III, state IV and the respiratory control ratio in the presence of glutamate/malate or succinate, suggesting that its effect on cellular respiration was weak. On the other hand, the activities of total and mitochondrial creatine kinase, but not cytosolic creatine kinase, were inhibited (30%) by 3-hydroxyisobutyric acid. We also observed that 3-hydroxyisobutyric acid-induced inhibition of mitochondrial creatine kinase activity was fully prevented by pre-incubation of the homogenates with reduced glutathione, alpha-tocopherol or the combination of superoxide dismutase plus catalase, suggesting that this inhibition was mediated by oxidation of essential thiol groups of the enzyme probably by superoxide, hydrogen peroxide and/or peroxyl radicals. It was also demonstrated that Na(+), K(+)-ATPase activity from synaptic plasma membranes was markedly suppressed (37%) by 3-hydroxyisobutyric acid and that this effect was prevented by alpha-tocopherol co-incubation implying that peroxyl radicals were probably involved in this action. Considering the importance of the affected enzyme activities for brain metabolism homeostasis and neurotransmision, it is suggested that increased tissue levels of 3-hydroxyisobutyric acid may contribute to the neurodegeneration of patients affected by 3-hydroxyisobutyric aciduria and possibly explain previous reports describing elevated production and excretion of lactate.
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PMID:Evidence that 3-hydroxyisobutyric acid inhibits key enzymes of energy metabolism in cerebral cortex of young rats. 1832 19

High concentrations of ethylmalonic acid (EMA) are found in tissues and biological fluids of patients affected by ethylmalonic encephalopathy (EE), as well as by deficiency of short-chain acyl-CoA dehydrogenase (SCAD) activity and other illnesses characterized by developmental delay and other neurological and muscular symptoms. The pathophysiological mechanisms responsible for the brain damage in these patients are virtually unknown. However, they may be due to the neurotoxic actions of EMA. Therefore, in the present work we investigated whether chronic exposure of EMA during early development (from 5th to 28th day of life) could alter the behavioral performance of adult rats in the Morris water maze (MWM) and elevated plus maze tasks. Control rats were treated with saline in the same volumes. We observed that adult rats pretreated with EMA presented impairment in the learning and memory in water maze task spending significantly less time in the training quadrant. However, chronic EMA administration did not affect rat performance in the elevated plus maze tasks, suggesting that anxiety-like behavior was not changed by EMA. We also evaluated the in vitro effect of EMA on lipoperoxidation and on creatine kinase (CK) activity in rat hippocampus and observed that this metabolite induced lipid peroxidation and diminished creatine kinase activity. The results provide evidence that early chronic EMA treatment induces long-lasting spatial behavioral deficit that may be possibly related to a secondary bioenergetics dysfunction and/or increase of free radical production caused by this organic acid.
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PMID:Chronic early postnatal administration of ethylmalonic acid to rats causes behavioral deficit. 1895 Jun 61


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