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)

Hepatic encephalopathy can arise from portal-systemic shunting in the absence of intrinsic liver disease. However, there are few descriptions of this form of encephalopathy. Portal vein thrombosis is an infrequent disease that causes portal-systemic shunting. Episodic hepatic encephalopathy has been described in patients with portal vein thrombosis, but it is not known if these patients develop minimal hepatic encephalopathy. We designed a study to investigate the neurological consequences of portal vein thrombosis in patients without cirrhosis and no clinical signs of encephalopathy. For this purpose, 10 patients underwent neuropsychological tests, an oral glutamine challenge test, and brain magnetic resonance (MR) imaging. The results were compared with those obtained in 10 healthy controls. Patients with portal vein thrombosis exhibited abnormalities in the results of neuropsychological tests, oral glutamine challenge test, and MR similar to those described in hepatic encephalopathy associated with cirrhosis. MR spectroscopy revealed a decrease in myo-inositol and an increase in glutamine. The increase in glutamine correlated with an increase in ammonia following the oral glutamine challenge test, signs of increased brain water (decrease in magnetization transfer ratio), and impairment of attention tests. In conclusion, patients with noncirrhotic portal vein thrombosis develop subclinical neurological abnormalities compatible with minimal hepatic encephalopathy. These disturbances, which include signs of increase in brain water and a compensatory osmotic response (decrease in brain myo-inositol), appear to be secondary to brain exposure to ammonia induced by portal-systemic shunting.
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PMID:Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy. 1655 41

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy. We have thoroughly reviewed the predisposing factors and their screening, the biochemical and physiopathological mechanisms involved, the different treatments described, and those that are being investigated. Etiopathogenesis is not completely understood, although hyperammonemia has been postulated as the main cause of the clinical syndrome. The increase in serum ammonium level is due to several mechanisms, the most important one appearing to be the inhibition of carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Polytherapy with several drugs, such as phenobarbital and topiramate, seems to contribute to hyperammonemia. Hyperammonemia leads to an increase in the glutamine level in the brain, which produces astrocyte swelling and cerebral edema. There are several studies that suggest that treatment with supplements of carnitine can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. Development of the progressive confusional syndrome, associated with an increase in seizure frequency after VPA treatment onset, obliges us to rule out VHE by screening for blood ammonium levels and the existence of urea cycle enzyme deficiency, such as ornithine carbamoyltransferase deficiency. Electroencephalography (EEG) is characterized by signs of severe encephalopathy with continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal intermittent rhythmic delta activity, and triphasic waves. These EEG findings, as well as clinical manifestations and hyperammonemia, tend to normalize after VPA withdrawal.
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PMID:Valproate-induced hyperammonemic encephalopathy. 1677 19

The ND1 subunit gene of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) is a hot spot for mutations causing Leber hereditary optic neuropathy and several mutations causing the mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). We have used Escherichia coli and Paracoccus denitrificans as model systems to study the effect of mutations 3946 and 3949, which change conserved residues in ND1 and cause MELAS. The vicinity of these mutations was also explored with a series of mutations in charged residues. The 3946 mutation results in E214K substitution in human ND1. Replacement of the equivalent residue in E. coli with lysine or glutamine detracted from enzyme assembly and the assembled enzyme was inactive. However, the equivalent E234Q mutant enzyme in P. denitrificans failed to assemble completely (or was rapidly degraded). Also the corresponding substitution with aspartate decreased the enzyme activity in P. denitrificans and E. coli. The 3949-equivalent substitution, Y229H in E. coli, lowered the catalytic activity by 30%. In addition, an activation of the enzyme during catalytic turnover was seen in this bacterial NDH-1, something that was even more pronounced in another mutant in the same loop, D213E. Several other mutations in this region decreased the enzyme activity. The studied MELAS mutations are situated in a matrix-side loop, which appears to be highly sensitive to structural perturbations. The results provide new information on the function of the region affected by the MELAS mutations 3946 and 3949 that is not obtainable from patient samples or current eukaryote models.
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PMID:The MELAS mutations 3946 and 3949 perturb the critical structure in a conserved loop of the ND1 subunit of mitochondrial complex I. 1684 71

The authors report a 3-year 8-month-old girl presenting with episodic hyperammonemic encephalopathy probably due to a proximal urea cycle disorder. The magnetic resonance imaging (MRI) of the brain performed during the third episode revealed extensive and diffuse cerebral cortical signal changes with sparing of occipital cortex. It is believed that intracerebral accumulation of glutamine mainly in astrocytes is the major cause of the encephalopathy. This results in astrocyte swelling, brain edema, intracranial hypertension, and cerebral hypoperfusion.
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PMID:Extensive cortical magnetic resonance signal change in proximal urea cycle disorder. 1762 92

Hypoxic-ischaemic (HI) encephalopathy is a severe complication of perinatal asphyxia and remains a frequent cause of a variety of brain disorders with long-term effects on the patients' life. The associated brain damage is strongly related to the toxic action of excitatory amino acids, especially glutamate and aspartate. Lamotrigine is an anti-epileptic drug that blocks the voltage-gated sodium channels of the presynaptic neuron and inhibits the release of glutamate. In the present study a well-established model of perinatal asphyxia in 7-d-old rats was used to investigate the effect of lamotrigine on HI-induced damage to different hippocampal brain structures, since disruption of this brain area is thought to play a key role in schizophrenia and epilepsy. Therefore, a combination of ischaemia, induced by unilateral occlusion of the left common carotid artery, followed by exposure to a 1-h period of hypoxia, was carried out in neonatal 7-d-old rats. Immediately after the insult, lamotrigine was given i.p. The histological outcome in the hippocampus was conducted and the tissue levels of glutamate, aspartate, GABA, and glutamine in the same area were determined. A remarkable reduction of HI-evoked damaged neurons in most of the investigated hippocampal regions was noted after lamotrigine administration. Furthermore, lamotrigine decreased the asphyxia-induced hippocampal tissue levels of glutamate and aspartate. Immediately after perinatal asphyxia GABA levels were enhanced, while levels of glutamine were decreased. Lamotrigine administration did not affect either GABA or glutamine levels. These results suggest a neuroprotective effect of lamotrigine in this particular animal model of neonatal HI encephalopathy.
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PMID:Neuroprotection by lamotrigine in a rat model of neonatal hypoxic-ischaemic encephalopathy. 1789 82

Ornithine transcarbamylase deficiency is the commonest urea cycle disorder which is transmitted in X-linked inheritance. It is mainly characterized in males by acute encephalopathy and hyperammonaemia with fatal outcomes in both classical neonatal and late-onset types. We report a 3-year-old healthy Hong Kong Chinese boy who presented with acute encephalopathy and coma after three days of gastroenteritis. He had no focal neurological deficit and brain CT imaging was normal. His plasma ammonia (54 micromol/L) and glutamine (747 micromol/L) concentrations were normal. The only biochemical abnormalities detected were marked orotic aciduria (700 micromol/mmol creatinine) and elevated urinary uracil. He regained consciousness spontaneously after three days under intensive care with parenteral fluid therapy. He recovered completely without any neurological deficits. Five months after discharge, urinary uracil concentration remained elevated despite normalized orotic acid concentration. Finally, ornithine transcarbamylase deficiency was diagnosed by DNA analysis. A missense mutation of arginine-to-glutamine substitution on amino acid 277 (p.R277Q) was revealed to be a late-onset mutant. Our case strengthens the argument that in any child with coma or acute encephalopathy of undetermined cause, genetic analysis of the OTC gene and the measurement of urinary uracil concentration remain the most reliable indicators of late-onset OTCD during acute and even quiescent phases. Existing neonatal screening programmes for inheritable metabolic disorders fail to detect late-onset variants. Therefore, a high clinical suspicion is a key to correct and timely diagnosis, especially in those patients with atypical presentations.
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PMID:Complete recovery from acute encephalopathy of late-onset ornithine transcarbamylase deficiency in a 3-year-old boy. 1792 16

Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) and lactate in ALF and associate the results with other liver function parameters. Five pediatric patients with ALF-related encephalopathy and five controls, examined after successful liver transplantation, were examined by brain MRI/MRS. ALF patients had higher Glx and lactate concentrations in brain white matter than controls (Glx + 125%: P < 0.01; lactate + 33%, P < 0.05) and higher Glx in grey matter (Glx + 125%: P < 0.01). Within the group of ALF patients positive correlations were found between grey or white matter lactate concentration and serum ammonia (P < 0.05), and negative correlations between grey or white matter Glx and venous pH (P < 0.001). This is the first study presenting evidence of high Glx levels in both white and grey matter brain tissue in ALF-related encephalopathy. The elevations in CNS Glx and lactate concentrations appear to relate to hepatic detoxification (ammonia, venous pH), rather than to liver parenchymal integrity (aspartate aminotransferase, alanine aminotransferase) or biliary cholestasis (bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase).
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PMID:Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure. 1849 80

Acute hyperammonaemia (HA) causes cerebral oedema and severe brain damage in patients with urea cycle disorders (UCDs) or acute liver failure (ALF). Chronic HA is associated with developmental delay and intellectual disability in patients with UCDs and with neuropsychiatric symptoms in patients with chronic liver failure. Treatment often cannot prevent severe brain injury and neurological sequelae. The causes of the brain oedema in hyperammonaemic encephalopathy (HAE) have been subject of intense controversy among physicians and scientists working in this field. Currently favoured hypotheses are astrocyte swelling due to increased intracellular glutamine content and neuronal cell death due to excitotoxicity caused by elevated extracellular glutamate levels. While many researchers focus on these mechanisms of cytotoxicity, others emphasize vascular causes of brain oedema. New data gleaned from expression profiling of astrocytes acutely isolated from hyperammonaemic mouse brains point to disturbed water and potassium homeostasis as regulated by astrocytes at the brain microvasculature and in the perisynaptic space as a potential mechanism of brain oedema development in hyperammonaemia.
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PMID:Profiling of astrocyte properties in the hyperammonaemic brain: shedding new light on the pathophysiology of the brain damage in hyperammonaemia. 1868 79

In two children with near drowning hypoxic encephalopathy and normal-appearing structural MRI, acute proton magnetic resonance spectroscopy ((1)H MRS) showed biochemical alterations that correctly indicated prognosis and helped to guide management decisions. Elevation of the lipid-lactate and glutamine-glutamate peaks, on the early (72 hour) (1)H MRS, predicts a poor prognosis. Absence of lipid-lactate and glutamine-glutamate peaks on the early (1)H MRS and reversibility of early mild metabolite abnormalities on follow up examination relates with good outcome.
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PMID:Prognostic value of proton magnetic resonance spectroscopy findings in near drowning patients: reversibility of the early metabolite abnormalities relates with a good outcome. 1933 Feb 12

This review addresses recent and not so recent works that emphasize on the mechanisms by which liver damage can induce encephalopathy. Hepatic encephalopathy constitutes an intriguing complication in severe liver acute and chronic disease, whose pathophysiology is still not completely understood. In this pathology, alterations in normal brain function are associated with morphological and functional impairments of astrocytes and neurons. A wide spectrum of psychoneurological symptoms has been described and the anatomical substratum is usually associated with brain edema and intracranial hypertension, as well as with changes in the function of brain cells. An increase in blood ammonia, toxic to the brain, depends on the activity of the enzyme glutamine synthetase, the glutamine/glutamate cycle and the brain capacity to eliminate toxic substances. When the concentration of the excitotoxic neurotransmitter glutamate is increased, it acts as a toxic agent, especially when its specific transporters are altered and its uptake is decreased. Glutamine has also been recently considered a toxic substance when its concentration is high, and consequently contributes to brain edema. Finally, the formation of reactive oxygen species, basically produced by mitochondria, influence with their toxic action on membrane lipids, proteins and DNA. In conclusion we suggest that at least these four elements are involved directly in the mechanism of hepatic encephalopathy.
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PMID:Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress. 1950 50


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