Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a genetic disorder characterized by unregulated insulin secretion and profound hypoglycemia. Recently, mutations of SUR1 and Kir6.2, which constitute the pancreatic beta-cell ATP-sensitive potassium (K(ATP)) channel, have been shown to be associated with familial PHHI in certain ethnic groups. In the present study, we examined clinical symptoms, therapy, and variations in the SUR1 and Kir6.2 genes in eight Japanese patients with PHHI. Four patients were being treated with pharmacological agents and the other four had required pancreatectomy to normalize glucose levels. There was no difference in timing of the onset of hypoglycemia between the groups. There also was no difference in severity between the two groups, as assessed by blood glucose levels, plasma insulin levels, and birth weight. However, all of the pancreatectomized patients and none of the medically treated group had presented with seizures. By genetic screening, we found eleven nucleotide substitutions in the SUR1 gene, three of which result in amino acid changes, and three nucleotide substitutions in the Kir6.2 gene, two of which result in amino acid changes, but all of these genetic variants had been previously reported in normal subjects. These results indicate that the mechanism of hypoglycemia in these patients is different from those previously reported in PHHI patients, giving further support to the view that PHHI is a heterogeneous disorder.
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PMID:Characterization of genes encoding the pancreatic beta-cell ATP-sensitive K+ channel in persistent hyperinsulinemic hypoglycemia of infancy in Japanese patients. 1122 46

Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata (SNr), the area with the highest expression of K(ATP) channels in the brain, plays a pivotal role in the control of seizures. Mutant mice lacking the Kir6.2 subunit of K(ATP) channels [knockout (KO) mice] were susceptible to generalized seizures after brief hypoxia. In normal mice, SNr neuron activity was inactivated during hypoxia by the opening of the postsynaptic K(ATP) channels, whereas in KO mice, the activity of these neurons was enhanced. K(ATP) channels exert a depressant effect on SNr neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures.
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PMID:Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. 1137 91

ATP-sensitive K(+) (K(ATP)) channels comprise the pore-forming subunit (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptors (SUR1 or SUR2). K(ATP) channels with different combinations of these subunits are present in various tissues and regulate cellular functions. From the analysis of mouse models with targeted deletion of the gene encoding the pore-forming subunit Kir6.1 or Kir6.2, functional roles of K(ATP) channels in various organs have been clarified. Kir6.1(-/-) mice showed sudden death associated with ST elevation and atrioventricular block in ECG, a phenotype resembling Prinzmetal angina in humans. Kir6.2(-/-) mice were more susceptible to generalized seizure during hypoxia than wild-type (WT) mice, suggesting that neuronal K(ATP) channels, probably composed of Kir6.2 and SUR1, play a crucial role for the protection of the brain against lethal damage due to seizure. In Kir6.2(-/-) mice lacking the sarcolemmal K(ATP) channel activity in cardiac cells, ischemic preconditioning failed to reduce the infarct size, suggesting that sarcolemmal K(ATP) channels play an important role in cardioprotection against ischemia/reperfusion injuries in the heart. Mitochondrial K(ATP) channels have been also proposed to play a crucial role in cardioprotection, although the molecular identity of the channel has not been established. Nicorandil and minoxidil, K(+) channel openers activating mitochondrial K(ATP) channels, decreased the mitochondrial membrane potential, thereby preventing the Ca(2+) overload in the mitochondria of guinea-pig ventricular cells. SURs are the receptors for K(+) channel openers and the activating effects on sarcolemmal K(ATP) channels in cardiovascular tissues could be modulated by the interaction of nucleotides. Due to the molecular diversity of the accessory and pore subunits of K(ATP) channels, there would be considerable differences in the tissue selectivity of K(ATP) channel-acting drugs. Studies of Kir6.1 and Kir6.2 knockout mice indicate that K(ATP) channels are involved in the mechanisms of the protection against metabolic stress. Further clarification of physiological as well as pathophysiological roles of K(ATP) channels may lead to a new therapeutic strategy to improve the quality of life.
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PMID:[Molecular and functional diversity of ATP-sensitive K+ channels: the pathophysiological roles and potential drug targets]. 1293 42

ATP-sensitive K+ (KATP) channels couple the intracellular metabolic state to electrical activity, which is important in the control of neuronal excitability and seizure propagation. In this study, we investigated the changes in the gene and protein expression of KATP channel subunits in the brain of picrotoxin (PTX)-kindled rats, which were daily administered with a subconvulsant dose of PTX for 20 days. At 14 days after the last administration of PTX, kindled rats were retreated with PTX and killed by decapitation at 12 h, 1 and 3 days, as well as retreated with vehicle and killed at 0 h after starting the retreatment. The abundance of Kir6.1, Kir6.2, SUR1 and SUR2A/B mRNAs was evaluated by reverse transcription polymerase chain reaction (RT-PCR) using endogenous gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal control, and the level of Kir6.2 and SUR1 proteins was measured by Western blot. At 0 h, the brain showed decreasing expression of various subunit mRNAs, with the exception of the SUR2A mRNA. In contrast, from 12 h to 3 days, the amount of various subunit mRNAs was up-regulated dynamically, but SUR2A of which was not changed significantly both from cortical and hippocampal samples. Furthermore, we demonstrated that the levels of Kir6.1, Kir6.2, SUR1 and SUR2B mRNAs at 12 h and 3 days (excepting SUR1 at 3 days) from hippocampal samples, as well as Kir6.1 at 1 day and SUR1 at 3 days from cortical samples, were significantly higher than that detected at 0 h. In addition, low levels of Kir6.2 and SUR1 proteins were observed both from cortical and hippocampal samples at 0 h and also, from 12 h to 3 days, a marked up-modulation of Kir6.2 and SUR1 protein expressions especially from hippocampal samples was found. These results suggest that the PTX-induced changes in the KATP channels may play a key role in the induction and maintenance of kindling and the PTX-induced seizures might be important for the acute changes of KATP channels observed in kindled rat brain.
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PMID:Changes in the gene and protein expression of K(ATP) channel subunits in the hippocampus of rats subjected to picrotoxin-induced kindling. 1533 20

Physiological and pathophysiological roles of K(ATP) channels have been clarified recently in genetically engineered mice. The Kir6.2-containing K(ATP) channels in pancreatic ss-cells and the hypothalamus are essential in the regulation of glucose-induced insulin secretion and hypoglycemia-induced glucagon secretion, respectively, and are involved in glucose uptake in skeletal muscles, thus playing a key role in the maintenance of glucose homeostasis. Disruption of Kir6.1-containing K(ATP) channels in mice leads to spontaneous vascular spasm mimicking vasospastic (Prinzmetal) angina in humans, indicating that the Kir6.1-containing K(ATP) channels in vascular smooth muscles participate in the regulation of vascular tonus, especially in coronary arteries. Together with protective roles of K(ATP) channels against cardiac ischemia and hypoxia-induced seizure propagation, it is now clear that K(ATP) channels, as metabolic sensors, are critical in the maintenance of homeostasis against acute metabolic changes.
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PMID:Roles of KATP channels as metabolic sensors in acute metabolic changes. 1591 Aug 76

The substantia nigra pars reticulata, the area with the highest expression of ATP-sensitive potassium channels in the brain, plays a pivotal role in suppressing the propagation of generalized seizures by its silence. Mice lacking the Kir6.2 subunit of the channels were extremely susceptible to generalized seizures after brief hypoxia. The nigral neuron activity, which is among highest in the brain, was rapidly inactivated during hypoxia by the opening of the post-synaptic ATP-sensitive potassium channels in normal mice, while the neuron activity was enhanced in the mutant mice. During seizure, the cerebral metabolic rate of oxygen increases more than under any other circumstance, leading ultimately to irreversible cell damage. Thus, rapid minimization of energy consumption during metabolic stresses such as hypoxia may be effective protection from the seizure-induced lethal effects. The ATP-sensitive potassium channels in the reticulata neurons may be involved in the protection mechanism against energy-consuming generalized seizure by earlier response to hypoxia than those in other, less active neuron types.
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PMID:Neuroprotection by KATP channels. 1591 Aug 79

ATP-sensitive K(+) (K(ATP)) channel's function is a key determinant of both excitability and viability of neurons. In the present report, in situ hybridization histochemistry and Western blot were used to examine whether picrotoxin (PTX)-kindling convulsions involved the changes in distribution of K(ATP) channels. The data demonstrated that the formation of kindling state was associated with a decreased amount of Kir6.2 mRNAs and proteins both in cerebral cortex and dentate gyrus (DG) as well as with a decreased amount of (regulatory subunit) SUR 1 mRNAs in DG. In contrast, resulting from a PTX re-induced seizure insult, both subunits were transiently up-modulated but not exactly paralleled between them and among different regions. In DG, Kir6.2 mRNAs increased toward normal levels at 12 h, followed a gradual decrease from 1 day to 3 days, being distinct from that detected in CA1-3 regions in which no significant change was shown. Further, SUR1 mRNAs markedly increased at 12 h, decreased significantly at 1 day, and even went down to a faint level at 3 days which was similar to that of CA1-3 regions, and there was no significant change in CA1-3 regions of SUR1 mRNAs. Also, at 7 days after a PTX re-treatment, Kir6.2 proteins increased significantly in the cortex, CA1, CA3 and DG (increasing 49.52%, 39.36%, 33.41%, and 54.79%, respectively) as well, SUR1 proteins increased significantly in DG (increasing 3.42 times), as compared with kindling rats without PTX retreatments (P < 0.05). These results indicated that K(ATP) channels in brain particularly in DG are likely related to enhanced seizure susceptibility and dynamic controls of seizure propagation of chronic epilepsy induced by PTX in rats.
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PMID:The pattern of ATP-sensitive K+ channel subunits, Kir6.2 and SUR1 mRNA expressions in DG region is different from those in CA1-3 regions of chronic epilepsy induced by picrotoxin in rats. 1802 73

We describe 3 years follow-up of glyburide therapy in a child with permanent neonatal diabetes mellitus (PND) born to a 19 year-old mother with congenital diabetes mellitus. Genetic analysis identified a KCNJ11 mutation (R201H) in both the child and her mother. After 2 years of insulin therapy, the patient was switched to oral glyburide. After initial stabilization, glyburide therapy resulted in a marked decrease in glucose excursions in comparison to insulin. The patient had 3-10 episodes of hypoglycemia per week, including a total of eight episodes resulting in seizures, while on insulin. In contrast, no severe hypoglycemia was reported on glyburide. The patient's basal C-peptide was undetectable on insulin therapy (< 166 pmol/l) but was easily detectable on glyburide (189-761 pmol/l). The range of HbA1c improved significantly from 8-12% on insulin to 4.7-6% on glyburide. The frequency of glucose monitoring was gradually decreased from 4-8 times to 2-3 times a day on oral glyburide. This report confirms the superiority of sulfonylurea therapy in the treatment of PND with Kir6.2 mutations and shows sustained improved glycemic control over a 3-year follow-up period. Genetic exploration in other family members with diabetes might provide further insight into the nature of familial neonatal diabetes.
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PMID:Familial permanent neonatal diabetes with KCNJ11 mutation and the response to glyburide therapy--a three-year follow-up. 1892 82

Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders. Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on beta-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma beta-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy. The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.
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PMID:[Hyperinsulinism in infancy and childhood: when an insulin level is not always enough]. 1815 85

Congenital hyperinsulinism of infancy (CHI) is the most common cause of hypoglycemia in newborns and infants. Several molecular mechanisms are involved in the development of CHI, but the most common genetic defects are inactivating mutations of the ABCC8 or KCNJ11 genes. The classical treatment for CHI has been pancreatectomy that eventually leads to diabetes. More recently, conservative treatment has been attempted in some cases, with encouraging results. Whether or not the patients with heterozygous ABCC8 mutations submitted to conservative treatment may spontaneously develop type 2 diabetes in the long run, is a controversial issue. Here, we report a family carrying the dominant heterozygous germ line E1506K mutation in ABCC8 associated with persistent hypoglycemia in the newborn period and diabetes in adulthood. The mutation occurred as a de novo germ line mutation in the mother of the index patient. Her hypoglycemic symptoms as a child occurred after the fourth year of life and were very mild, but she developed glucose metabolism impairment in adulthood. On the other hand, in her daughter, the clinical manifestations of the disease occurred in the neonatal period and were more severe, leading to episodes of tonic-clonic seizures that were well controlled with octreotide or diazoxide. Our data corroborate the hypothesis that the dominant E1506K ABCC8 mutation, responsible for CHI, predisposes to the development of glucose intolerance and diabetes later in life.
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PMID:Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation. 2004 13


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