Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 3-day-old infant presented with anorexia, irritability, hypotonia, and seizures. Blood ammonia was 2115 micromol/L and amino and organic acid analyses were consistent with ornithine transcarbamylase deficiency. Liver biopsy confirmed only 1% enzyme activity. The patient was treated with hemodialysis. An electroencephalogram (EEG) revealed multifocal independent spike-and-sharp-wave discharges. After initial stabilization he was placed on a low-protein diet with citrulline and phenylbutyrate. Conjugating agents (arginine, sodium benzoate, and sodium phenylacetate) have been added during periods of metabolic decompensation. Although developmentally delayed, the patient has shown signs of clinical improvement and EEG activity has likewise improved with only mild background slowing and no evidence of epileptogenic activity at 4 years of age. A second infant presented at 3 days of age with a similar history, blood ammonia of 1382 micromol/L, and metabolic studies indicative of ornithine transcarbamylase deficiency. EEG showed multifocal independent ictal and interictal discharges. Electrographic abnormalities persisted despite lowering of blood ammonia with hemodialysis and conjugating agents. The patient continued to decline clinically and died on the 7th hospital day. EEG changes parallel the clinical course of ornithine transcarbamylase deficiency and may serve as an objective marker of the effectiveness of therapeutic interventions.
 ...
PMID:Electroencephalographic findings in ornithine transcarbamylase deficiency. 1045 65

Hepatic encephalopathy (HE) and portal-systemic encephalopathy (PSE) are the terms used interchangeably to describe a complex neuropsychiatric syndrome associated with acute or chronic hepatocellular failure, increased portal systemic shunting of blood, or both. Hepatic encephalopathy complicating acute liver failure is referred to as fulminant hepatic failure (FHF). The clinical manifestations of HE or PSE range from minimal changes in personality and motor activity, to overt deterioration of intellectual function, decreased consciousness and coma, and appear to reflect primarily a variable imbalance between excitatory and inhibitory neurotransmission. Pathogenic mechanisms that may be responsible for HE have been extensively investigated using animal models of HE, or cultures of CNS cells treated with neuroactive substances that have been implicated in HE. Of the many compounds that accumulate in the circulation as a consequence of impaired liver function, ammonia is considered to play an important role in the onset of HE. Acute ammonia neurotoxicity, which may be a cause of seizures in FHF, is excitotoxic in nature, being associated with increased synaptic release of glutamate (Glu), the major excitatory neurotransmitter of the brain, and subsequent overactivation of the ionotropic Glu receptors, mainly the N-methyl-D-aspartate (NMDA) receptors. Hepatic encephalopathy complicating chronic liver failure appears to be associated with a shift in the balance between inhibitory and excitatory neurotransmission towards a net increase of inhibitory neurotransmission, as a consequence of at least two factors. The first is down-regulation of Glu receptors resulting in decreased glutamatergic tone. The down-regulation follows excessive extrasynaptic accumulation of Glu resulting from its impaired re-uptake into nerve endings and astrocytes. Liver failure inactivates the Glu transporter GLT-1 in astrocytes. The second factor is an increase in inhibitory neurotransmission by gamma-aminobutyric acid (GABA) due to (a) increased brain levels of natural benzodiazepines; (b) increased availability of GABA at GABA-A receptors, due to enhanced synaptic release of the amino acid; (c) direct interaction of modestly increased levels of ammonia with the GABA-A-benzodiazepine receptor complex; and (d) ammonia-induced up-regulation of astrocytic peripheral benzodiazepine receptors (PBZR). Brain ammonia is metabolised in astrocytes to glutamine (Gln), an osmolyte, and increased Gln accumulation in these cells may contribute to cytotoxic brain edema, which often complicates FHF. Glutamine efflux from the brain is an event that facilitates plasma-to-brain transport of aromatic amino acids. Tryptophan and tyrosine are direct precursors of the aminergic inhibitory neurotransmitters, serotonin and dopamine, respectively. Changes in serotonin and dopamine and their receptors may contribute to some of the motor manifestations of HE. Finally, oxindole, a recently discovered tryptophan metabolite with strong sedative and hypotensive properties, has been shown to accumulate in cirrhotic patients and animal models of HE.
 ...
PMID:Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. 1061 92

The effect of chronic perfusion of ammonia on the seizure threshold against pentylenetetrazol was studied. Ammonia plus sodium bicarbonate and saline (0.9%) was continuously administered to two groups of rats respectively. All animals were tested three times for seizure threshold, and were then decapitated and the brains removed for analysis of the amino acids. The results showed that the infusion of ammonia increased the seizure threshold, and this protective effect was accompanied by selective changes in brain glutamate and glutamine. Thus, continuous infusion of ammonia may cause an imbalance between excitatory and inhibitory systems in favor of inhibitory systems. These findings may provide insights into the basic mechanisms of seizures observed in hepatic failure, in other hyperammonemic states, and in epilepsy.
 ...
PMID:Effects of ammonia on pentylenetetrazole-induced seizure threshold. 1085 May 49

Seizures in human temporal lobe epilepsy are characterized by paroxysmal activity in the limbic system. The primary olfactory or piriform cortex is a central part of the limbic system. Since a relationship between olfactory sensation and limbic seizures has been described, we were interested in the effect of strong olfactory stimulation on the seizure susceptibility of amygdala-kindled rats, a model of human temporal lobe epilepsy. Olfactory stimulation with toluene was able to suppress seizures in most kindled rats after stimulation at 20% above the threshold for eliciting epileptic afterdischarges. Olfactory stimulation with toluene or ammonia increased the threshold by 27 and 25% compared to control conditions. Our data substantiate that olfactory brain regions, such as the piriform cortex, are involved in amygdala-kindled seizures and suggest that strong physiological stimulation of this nucleus interferes with on-going seizure activity in the limbic system. Thus, olfactory stimulation could contribute to anticonvulsant therapy.
 ...
PMID:Strong olfactory stimulation reduces seizure susceptibility in amygdala-kindled rats. 1086 29

Neonatal seizures are frequently manifested by subtle movements that are referable to brain stem structure, ie, nystagmus, conjugate eye movements, posturing, sucking movements, and so forth. Electroencephalogram (EEG) confirmation of abnormal movements is essential in diagnosing seizures in the neonate. Clinical seizure signs are often a clue to etiology. Metabolic abnormalities must always be considered, and blood gases, calcium, magnesium, glucose, and ammonia obtained. Neonatal seizures are an indication for cerebrospinal fluid examination. Specific metabolic abnormalities are treated with metabolic approaches, not conventional anticonvulsant drugs. Hypertensive encephalopathy is treated by controlling blood pressure, and not through anticonvulsant drugs. Critically ill infants bind anticonvulsants in an unpredictable fashion, and unbound or free anticonvulsant drug concentrations should be used to guide therapy. Phenobarbital is the most commonly used drug in treating nonmetabolic seizures. Doses to achieve free concentrations of at least 35 mg/L should be used. Use in vitro binding determinations with this formula to calculate loading doses. Dose is 25 mg/kg multiplied by volume and distribution (1 L/kg) divided by % free. Phenytoin is the second most commonly used agent, and doses should be calculated to achieve, but not exceed, 3 mg/L. Dose is 3 mg/kg multiplied by volume and distribution (1 L/kg) divided by % free. Benzodiazepines, notably lorazepam and diazepam are used at doses of 0.15 mg/kg and 0.3 mg/kg, respectively.
 ...
PMID:Neonatal Seizures. 1128 39

Hyperammonemia associated with inherited disorders of amino acid and organic acid metabolism is usually manifested by irritability, somnolence, vomiting, seizures, and coma. Although the majority of these patients present in the newborn period, they may also present in childhood, adolescence, and adulthood with failure to thrive, persistent vomiting, developmental delay, or behavioral changes. Persistent hyperammonemia, if not treated rapidly, may cause irreversible neuronal damage. After the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle defects and other causes of hyperammonemic encephalopathy. In a patient with a presumed inherited metabolic disorder, the aim of therapy should be to normalize blood ammonia levels. Recent experience has provided treatment guidelines that include minimizing endogenous ammonia production and protein catabolism, restricting nitrogen intake, administering substrates of the urea cycle, administering compounds that facilitate the removal of ammonia through alternative pathways, and, in severe cases, dialysis therapy. Initiation of dialysis in the encephalopathic patient with hyperammonemia is indicated if the ammonia blood level is greater than three to four times the upper limit of normal. Hemodialysis is the most effective treatment for rapidly reducing blood ammonia levels. Continuous hemofiltration and peritoneal dialysis are also effective modalities for reducing blood ammonia levels. An improved understanding of the metabolism of ammonia and neurological consequences of hyperammonemia will assist the nephrologist in providing optimal care for this high-risk patient population.
 ...
PMID:Hyperammonemia in urea cycle disorders: role of the nephrologist. 1132 92

An infant aged 3 days presented with hyperammonaemic coma and seizures, which were found to be a result of a urea-cycle defect. Haemofiltration, alternative pathway metabolites, and glucose and insulin failed to lower the plasma ammonia concentration below 2000 micromol/L. The infant was then cooled to a rectal temperature of 34 degrees C for 48 h and put on haemofiltration for 12 h. Plasma ammonia fell to around 100 micromol/L and remained at this concentration after haemofiltration. He roused from his coma, breathed spontaneously, and resumed bottle feeding. Hypothermia may be therapeutic in such instances of metabolic coma because it lowers the enzymatic rate of production of the toxin while non-enzymatic methods remove the toxin.
 ...
PMID:Emergency treatment of neonatal hyperammonaemic coma with mild systemic hypothermia. 1172 74

The clinical syndrome of encephalopathy is most often encountered in the context of decompensated liver disease and the diagnosis is usually clear cut. Non-hepatic causes of encephalopathy are rarer and tend to present to a wide range of medical specialties with variable and episodic symptoms. Delay can result in the development of potentially life threatening complications, such as seizures and coma. Early recognition is vital. A history of similar episodes or clinical risk factors and early assessment of blood ammonia levels help establish the diagnosis. In addition to adequate supportive care, investigation of the underlying cause of the hyperammonaemia is essential and its reversal, where possible, will often result in complete recovery. Detection of an unborn error of metabolism should lead to the initiation of appropriate maintenance therapy and genetic counselling.
 ...
PMID:Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy. 1215 92

The significant role the amino acid glutamate assumes in a number of fundamental metabolic pathways is becoming better understood. As a central junction for interchange of amino nitrogen, glutamate facilitates both amino acid synthesis and degradation. In the liver, glutamate is the terminus for release of ammonia from amino acids, and the intrahepatic concentration of glutamate modulates the rate of ammonia detoxification into urea. In pancreatic beta-cells, oxidation of glutamate mediates amino acid-stimulated insulin secretion. In the central nervous system, glutamate serves as an excitatory neurotransmittor. Glutamate is also the precursor of the inhibitory neurotransmittor GABA, as well as glutamine, a potential mediator of hyperammonemic neurotoxicity. The recent identification of a novel form of congenital hyperinsulinism associated with asymptomatic hyperammonemia assigns glutamate oxidation by glutamate dehydrogenase a more important role than previously recognized in beta-cell insulin secretion and hepatic and CNS ammonia detoxification. Disruptions of glutamate metabolism have been implicated in other clinical disorders, such as pyridoxine-dependent seizures, confirming the importance of intact glutamate metabolism. This article will review glutamate metabolism and clinical disorders associated with disrupted glutamate metabolism.
 ...
PMID:Disorders of glutamate metabolism. 1175 24

Acute hyperammonemia resulting from congenital urea cycle disorders, Reye syndrome or acute liver failure results in severe neuronal dysfunction, seizures and death. Increasing evidence suggests that acute hyperammonemia results in alterations of mitochondrial and cellular energy function resulting from ammonia-induced inhibition of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase and by activation of the NMDA receptor. Antagonists of this receptor and NOS inhibitors prevent acute ammonia-induced seizures and mortality and prevent acute ammonia-induced changes in mitochondrial calcium homeostasis and cellular energy metabolism. Acute hyperammonemia also results in decreased activities of free radical scavenging enzymes and again, free radical formation due to ammonia exposure is prevented by either NMDA receptor antagonists or NOS inhibitors. Acute hyperammonemia also results in activation of "peripheral-type" benzodiazepine receptors and monoamine oxidase-B, enzymes which are localized on the mitochondrial membranes of astrocytes in the CNS. Activation of these receptors results in mitochondrial swelling and in increased degradation of monoamines, respectively. Alterations of mitochondrial function could contribute to the neuronal dysfunction characteristic of acute hyperammonemic syndromes.
 ...
PMID:Mitochondrial dysfunction in acute hyperammonemia. 1185 Jan 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>