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)

Febrile seizures (FSs) represent the most common form of childhood seizures, occurring in 2-5% of infants in Europe and North America and in 6-9% in Japan. It has been recognized that there is a significant genetic component for susceptibility to this type of seizure. Six susceptibility FS loci have been identified on chromosomes 8q13-q21 (FEB1), 19p (FEB2), 2q23-q24 (FEB3), 5q14-q15 (FEB4), 6q22-q24 (FEB5), and 18p11 (FEB6). Furthermore, mutations in the voltage-gated sodium channel alpha-1, alpha-2 and beta-1 subunit genes (SCN1A, SCN2A and SCN1B) and the GABA(A) receptor gamma-2 subunit gene (GABRG2) have been identified in families with a clinical subset of seizures termed "generalized epilepsy with febrile seizure plus (GEFS+)". However, the causative genes have not been identified in most patients with FSs or GEFS+. Common forms of FSs are genetically complex disorders believed to be influenced by variations in several susceptibility genes. Recently, several association studies in FSs have been reported, but the results vary among different groups and no consistent or convincing FS susceptibility genes have emerged. To find a true association, larger sample size and newer methodologic refinements are recommended.
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PMID:Molecular genetics of febrile seizures. 1688 33

Most epilepsies are characterized as "idiopathic" because of the lack of a known cause. Nevertheless, recently, there has been significant progress in the molecular genetics of idiopathic epilepsy. Mutations in gene-encoding ion channels were found to be the underlying disorder in all idiopathic epilepsies with a known molecular basis. Missense mutations in the voltage-gated sodium channel a1 subunit gene (SCN1A) were firstly identified in patients with generalized epilepsy with febrile seizures plus additional symptoms (GEFS + ). Subsequently, mutations of SCN1A were also found in patients with severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome, and in patients with borderline SMEI (SMEB), a milder form of Dravet syndrome. We describe a case of a new missense de novo mutation of SCN1A in a child with the clinical features of borderline SMEI syndrome.
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PMID:Epilepsy with a de novo missense mutation in the sodium channel a1 subunit: a case report. 1712 91

Eslicarbazepine acetate (ESL) [(S)-(--)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide], formerly known as BIA 2-093, is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It behaves as a voltage-gated sodium channel (VGSC) blocker and is currently under clinical development for the treatment of epilepsy and bipolar disorder. ESL shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11-position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11 epoxide. In pharmacokinetic studies in humans, ESL was rapidly and extensively metabolized to eslicarbazepine (S-licarbazepine), which is responsible for pharmacological activity. ESL has been tested in patients with refractory partial-onset seizures and was found to be efficacious and well tolerated. Monotherapy studies in adult epileptic patients and add-on studies in epileptic children are in the planning process. The efficacy and safety data appear to be very promising considering the refractory nature of the epileptic population enrolled in studies to date. Results of ongoing phase III studies in adult epileptic patients are expected to be available in 2007 and are required to define the position of ESL in the therapy of patients with epilepsy.
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PMID:Eslicarbazepine acetate (BIA 2-093). 1719 20

Chronic pain states and epilepsies are common therapeutic targets of voltage-gated sodium channel blockers. Inhibition of sodium channels results in central muscle relaxant activity as well. Selective serotonin reuptake inhibitors are also applied in the treatment of pain syndromes. Here, we investigate the pharmacodynamic interaction between these two types of drugs on spinal neurotransmission in vitro and in vivo. Furthermore, the ability of serotonin reuptake inhibitors to modulate the anticonvulsant and windup inhibitory actions and motor side effect of the sodium channel blocker lamotrigine was investigated. In the hemisected spinal cord model, we found that serotonin reuptake inhibitors increased the reflex inhibitory action of sodium channel blockers. The interaction was clearly more than additive. The potentiation was prevented by blocking 5-HT(2) receptors and PKC, and mimicked by activation of these targets by selective pharmacological tools, suggesting the involvement of 5-HT(2) receptors and PKC in the modulation of sodium channel function. The increase of sodium current blocking potency of lamotrigine by PKC activation was also demonstrated at cellular level, using the whole-cell patch clamp method. Similar synergism was found in vivo, in spinal reflex, windup, and maximal electroshock seizure models, but not in the rotarod test, which indicate enhanced muscle relaxant, anticonvulsant and analgesic activities with improved side effect profile. Our findings are in agreement with clinical observations suggesting that sodium channel blocking drugs, such as lamotrigine, can be advantageously combined with selective serotonin reuptake inhibitors in some therapeutic fields, and may help to understand the molecular mechanisms underlying the interaction.
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PMID:Concerted action of antiepileptic and antidepressant agents to depress spinal neurotransmission: Possible use in the therapy of spasticity and chronic pain. 1728 Jul 40

We investigated the roles of mutations in voltage-gated sodium channel alpha 1 subunit gene (SCN1A) in epilepsies and psychiatric disorders. The SCN1A gene was screened for mutations in three unrelated Japanese families with generalized epilepsy with febrile seizure plus (GEFS+), febrile seizure with myoclonic seizures, or intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC). In the family with GEFS+, one individual was affected with panic disorder and seizures, and another individual was diagnosed with Asperger syndrome and seizures. The novel mutation V1366I was found in all probands and patients with psychiatric disorders of the three families. These results suggest that SCN1A mutations may confer susceptibility to psychiatric disorders in addition to variable epileptic seizures. Unidentified modifiers may play critical roles in determining the ultimate phenotype of patients with sodium channel mutations.
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PMID:Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation. 1750 2

The voltage-gated sodium channel gene Scn1b encodes the auxiliary subunit beta1, which is widely distributed in neurons and glia of the central and peripheral nervous systems, cardiac myocytes, skeletal muscle myocytes, and neuroendocrine cells. We showed previously that the Scn1b null mutation results in a complex and severe phenotype that includes retarded growth, seizures, ataxia, and death by postnatal day 21. We generated a floxed allele of Scn1b by inserting loxP sites surrounding the second coding exon. Ubiquitous deletion of the floxed exon by Cre recombinase using CMV-Cre-transgenic mice produced the Scn1b(del) allele. The null phenotype of Scn1b(del) homozygotes is indistinguishable from that of Scn1b nulls and confirms the invivo inactivation of Scn1b. Conditional inactivation ofthe floxed allele will make it possible to circumvent the lethality that results from complete loss of this gene, such that the physiological role of Scn1b in specific cell types and/or specific developmental time points can be investigated.
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PMID:Floxed allele for conditional inactivation of the voltage-gated sodium channel beta1 subunit Scn1b. 1786 89

The mammalian genome contains four voltage-gated sodium channel genes that are primarily expressed in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. Mutations in SCN1A and SCN2A are responsible for several dominant idiopathic epilepsy disorders, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). Mutations in SCN8A are associated with cognitive deficits and neuropsychiatric illness in humans and movement disorders in mice; however, a role for SCN8A (Na(v)1.6) in epilepsy has not been investigated. To determine the relationship between Na(v)1.6 dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8a(med) and Scn8a(med-jo), to flurothyl- and kainic acid (KA)-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Na(v)1.6 function reduces neuronal excitability. To determine whether impaired Na(v)1.6 function could ameliorate seizure severity in a mouse model of SMEI, we generated Scn1a(+/-); Scn8a(med-jo/+) double heterozygous mice. Unlike Scn1a(+/-) mice that are more susceptible to flurothyl-induced seizures, Scn1a(+/-); Scn8a(med-jo/+) mice displayed thresholds that were comparable to wild-type littermates. The Scn8a(med-jo) allele was also able to rescue the premature lethality of Scn1a(+/-) mice and extend the lifespan of Scn1a(-/-) mutants. These results demonstrate that genetic interactions can alter seizure severity and support the hypothesis that genetic modifiers contribute to the clinical variability observed in SMEI and GEFS+.
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PMID:The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. 1788 58

Cytoarchitectural alterations during central nervous system (CNS) development are believed to underlie aberrations in brain morphology that lead to epilepsy. We have recently reported marked reductions in hippocampal and white matter volumes along with relative ventriculomegaly in a rat strain bred to be seizure-prone (FAST) compared to a strain bred to be seizure-resistant (SLOW) (Gilby et al., 2002, American Epilepsy Society 56th Annual Meeting). This study was designed to investigate deviations in gene expression during late-phase embryogenesis within the brains of FAST and SLOW rats. In this way, we hoped to identify molecular mechanisms operating differentially during neurodevelopment that might ultimately create the observed differences in brain morphology and/or seizure susceptibility. Using Superarray technology, we compared the expression level of 112 genes, known to play a role in neurodevelopment, within whole brains of embryonic day 21 (E21) FAST and SLOW rats. Results revealed that while most genes investigated showed near equivalent expression levels, both Apolipoprotein E (APOE) and the beta2 subunit of the voltage-gated sodium channel (SCN2beta) were significantly underexpressed in brains of the seizure-prone embryos. Currently, these transcripts have no known interactions during embryogenesis; however, they have both been independently linked to seizure disposition and/or neurodevelopmental aberrations leading to epilepsy. Thus, alterations in the timing and/or degree of expression for APOE and SCN2beta may be important to developmental cascades that ultimately give rise to the differing brain morphologies, behaviors, and/or seizure vulnerabilities that characterize these strains.
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PMID:Neurodevelopment in seizure-prone and seizure-resistant rat strains: recognizing conflicts in management. 1791 May 90

The extracellular membrane surface contains a substantial amount of negatively charged sialic acid residues. Some of the sialic acids are located close to the pore of voltage-gated channel, substantially influencing their gating properties. However, the role of sialylation of the extracellular membrane in modulation of neuronal and network activity remains primarily unknown. The level of sialylation is controlled by neuraminidase (NEU), the key enzyme that cleaves sialic acids. Here we show that NEU treatment causes a large depolarizing shift of voltage-gated sodium channel activation/inactivation and action potential (AP) threshold without any change in the resting membrane potential of hippocampal CA3 pyramidal neurons. Cleavage of sialic acids by NEU also reduced sensitivity of sodium channel gating and AP threshold to extracellular calcium. At the network level, exogenous NEU exerted powerful anticonvulsive action both in vitro and in acute and chronic in vivo models of epilepsy. In contrast, a NEU blocker (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid) dramatically reduced seizure threshold and aggravated hippocampal seizures. Thus, sialylation appears to be a powerful mechanism to control neuronal and network excitability. We propose that decreasing the amount of extracellular sialic acid residues can be a useful approach to reduce neuronal excitability and serve as a novel therapeutic approach in the treatment of seizures.
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PMID:Role of extracellular sialic acid in regulation of neuronal and network excitability in the rat hippocampus. 1848 62

The spontaneously epileptic rat (SER), a double mutant (zi/zi, tm/tm), exhibits both tonic convulsions and absence-like seizures from the age of 8 weeks. Since the first point mutation in the voltage-gated sodium channel (VGSC) beta(1) subunit in human generalized epilepsy with febrile seizures plus (GEFS+) was identified, more and more types of genetic epilepsy have been causally suggested to be related to gene changes in VGSC. However, there are no reports that can elucidate the effects of VGSC in SER. The present study was undertaken to detect sodium channel I alpha-isoform (Na(v)1.1), sodium channel III alpha-isoform (Na(v)1.3) and beta(1) subunit from both the level of mRNA and protein in SERs hippocampus compared with control Wistar rats. In this study, the mRNA expressions of Na(v)1.1, Na(v)1.3 and beta(1) subunit in SERs hippocampus were significantly higher than those in control rats hippocampus by real-time RT-PCR; The protein distributions and expressions of Na(v)1.1, Na(v)1.3 and beta(1) subunit in SERs hippocampus were detected by immunofluorescence, immunohistochemistry and western blot, and the protein expressions of Na(v)1.1, Na(v)1.3 and beta(1) subunit were significantly increased. In conclusion, our study suggested for the first time that sodium channel Na(v)1.1, Na(v)1.3 and beta(1) subunit up-regulation at the mRNA and protein levels of SER hippocampus might contribute to the generation of epileptiform activity and underlie the observed seizure phenotype in SER. The results of this study may be of value in revealing components of the molecular mechanisms of hippocampal excitation that are related to genetic epilepsy.
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PMID:Voltage-gated sodium channel Nav1.1, Nav1.3 and beta1 subunit were up-regulated in the hippocampus of spontaneously epileptic rat. 1815 13


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