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)

A mutation in the voltage-gated sodium-channel Scn2a results in moderate epilepsy in transgenic Scn2a(Q54) mice maintained on a C57BL/6J strain background. The onset of progressive epilepsy begins in adults with short-duration partial seizures that originate in the hippocampus. The underlying abnormality is an increase in persistent sodium current in hippocampal neurons. The voltage-gated potassium channel Kcnq2 is responsible for generating M current (I(KM)) that is thought to control excitability and limit repetitive firing of hippocampal neurons. To determine whether impaired M current would exacerbate the seizure phenotype of Scn2a(Q54) mice, we carried out genetic crosses with two mutant alleles of Kcnq2. Szt1 mice carry a spontaneous deletion that removes the C-terminal domain of Kcnq2. A novel Kcnq2 missense mutation V182M was identified by screening the offspring of ENU-treated males for reduced threshold to electrically evoked minimal clonic seizures. Double mutant mice carrying the Scn2a(Q54) transgene together with either of the Kcnq2 mutations exhibited severe epilepsy with early onset, generalized tonic-clonic seizures and juvenile lethality by 3 weeks of age. This dramatic exacerbation of the sodium-channel mutant phenotype indicates that M current plays a critical role in preventing seizure initiation and spreading in this animal model. The genetic interaction between Scn2a and Kcnq2 demonstrates that combinations of mild alleles of monogenic epilepsy genes can result in severe disease and provides a model for complex inheritance of human epilepsy. The data suggest that interaction between these genes might contribute to the variable expressivity observed in human families with sodium-channel mutations. In a screen of 23 SMEI patients with missense mutations of SCN1A, no second-site mutations in KCNQ2 were identified.
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PMID:Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. 1646 83

The M-type K+ current [IK(M)] activates in response to membrane depolarization and regulates neuronal excitability. Mutations in two subunits (KCNQ2 and KCNQ3; Kv7.2 and Kv7.3) that underlie the M-channel cause the human seizure disorder benign familial neonatal convulsions (BFNC), presumably by reducing IK(M) function. In mice, the Szt1 mutation, which deletes the genomic DNA encoding the KCNQ2 C terminus and all of CHRNA4 (nicotinic acetylcholine receptor alpha4 subunit) and ARFGAP-1 (GTPase-activating protein that inactivates ADP-ribosylation factor 1), reduces seizure threshold, and alters M-channel pharmacosensitivity. Genomic deletions affecting the C terminus of KCNQ2 have been identified in human families with BFNC, and truncation of the C terminus prevents proper KCNQ2/KCNQ3 channel assembly in Xenopus oocytes. We showed previously that Szt1 mice have a reduced baseline seizure threshold and altered sensitivity to drugs that act at the M-channel. Specifically, the proconvulsant M-channel blocker linopirdine and anticonvulsant enhancer retigabine display increased and decreased potency, respectively, in Szt1 mice. To investigate the effects of the Szt1 mutation on IK(M) function explicitly, perforated-patch electrophysiology was performed in CA1 pyramidal neurons of the hippocampus in brain slices prepared from C57BL/6J-Szt1/+ and control C57BL/6J+/+ mice. Our results show that Szt1 reduces both IK(M) amplitude and current density, inhibits spike frequency adaptation, and alters many aspects of M-channel pharmacology. This is the first evidence that a naturally occurring Kcnq2 mutation diminishes the amplitude and function of the native neuronal IK(M), resulting in significantly increased neuronal excitability. Finally, the changes in single-cell biophysical properties likely underlie the altered seizure threshold and pharmacosensitivity reported previously in Szt1 mice.
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PMID:A spontaneous mutation involving Kcnq2 (Kv7.2) reduces M-current density and spike frequency adaptation in mouse CA1 neurons. 1648 38

The syndrome of benign familial neonatal convulsions (BFNC) is characterized by seizures starting within the first days of life and disappearing within weeks to months. BFNC is caused by loss-of-function mutations in the potassium channels KCNQ2 and KCNQ3 which can well explain the resulting neuronal hyperexcitability. However, it is not understood why seizures predominantly occur in the neonatal period. A potential explanation might be a change in the expression pattern of these channels during development. We therefore performed an immunohistochemical analysis of mouse brain slices at different stages of postnatal development using an antibody recognizing the C-terminus of the KCNQ2 channel. A widespread immunohistochemical staining was observed, particularly in the hippocampus, caudoputamen, globus pallidus, cortex, thalamus, hypothalamus and midbrain. In the adult mouse brain, a predominantly axonal staining pattern was found, most observed in the caudoputamen, the alveus and the mossy fiber pathway of the hippocampus. The hippocampal staining pattern of adult mice was not observed before P8 and gradually developed between P11 and P21. Differences in the distribution of KCNQ2 channels within neurons between the neonatal period and adult stages might contribute to the increased seizure susceptibility in BFNC in humans.
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PMID:Immunohistochemical analysis of KCNQ2 potassium channels in adult and developing mouse brain. 1650 Jun 30

Mutations that reduce the function of KCNQ2 channels cause neuronal hyperexcitability, manifested as epileptic seizures and myokymia. These channels are present in nodes of Ranvier in rat brain and nerve and have been proposed to mediate the slow nodal potassium current I(Ks). We have used immunocytochemistry, electrophysiology and pharmacology to test this hypothesis and to determine the contribution of KCNQ channels to nerve excitability in the rat. When myelinated nerve fibres of the sciatic nerve were examined by immunofluorescence microscopy using antibodies against KCNQ2 and KCNQ3, all nodes showed strong immunoreactivity for KCNQ2. The nodes of about half the small and intermediate sized fibres showed labelling for both KCNQ2 and KCNQ3, but nodes of large fibres were labelled by KCNQ2 antibodies only. In voltage-clamp experiments using large myelinated fibres, the selective KCNQ channel blockers XE991 (IC50 = 2.2 microm) and linopirdine (IC50 = 5.5 microm) completely inhibited I(Ks), as did TEA (IC50 = 0.22 mm). The KCNQ channel opener retigabine (10 microm) shifted the activation curve to more negative membrane potentials by -24 mV, thereby increasing I(Ks). In isotonic KCl 50% of I(Ks) was activated at -62 mV. The activation curve shifted to more positive potentials as [K+]o was reduced, so that the pharmacological and biophysical properties of I(Ks) were consistent with those of heterologously expressed homomeric KCNQ2 channels. The ability of XE991 to selectively block I(Ks) was further exploited to study I(Ks) function in vivo. In anaesthetized rats, the excitability of tail motor axons was indicated by the stimulus current required to elicit a 40% of maximal compound muscle action potential. XE991 (2.5 mg kg(-1) i.p.) eliminated all nerve excitability functions previously attributed to I(Ks): accommodation to 100 ms subthreshold depolarizing currents, the post-depolarization undershoot in excitability, and the late subexcitability after a single impulse or short trains of impulses. Due to reduced spike-frequency adaptation after XE991 treatment, 100 ms suprathreshold current injections generated long trains of action potentials. We conclude that the nodal I(Ks) current is mediated by KCNQ channels, which in large fibres of rat sciatic nerve appear to be KCNQ2 homomers.
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PMID:KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. 1652 53

Retigabine has anticonvulsant properties that appear to be primarily mediated by opening neuronal voltage-gated potassium channels. This action has been shown in neuronal KCNQ2/3 and KCNQ3/5 potassium channels. In addition to this unique action, retigabine also potentiates GABA-evoked currents in cortical neurons at high concentrations. When used as adjunctive therapy in patients with partial seizures, retigabine 600-1200 mg/day (200-400 mg three times daily) was associated with significant linear dose-dependent reductions in monthly seizure frequency compared with placebo in a large 16-week randomised phase II trial. Median monthly seizure frequency decreased from baseline by up to 35% among patients in the retigabine treatment arms compared with 13% in the placebo group. Retigabine 1200 mg/day was also significantly more effective than retigabine 600 mg/day. Responder rates, defined as the proportion of patients with > or = 50% reduction in seizure frequency, were significantly higher among patients in the retigabine 900 and 1200 mg/day groups than in those who received placebo. CNS-related adverse events were the most commonly reported treatment-emergent adverse events associated with retigabine in clinical trials. Across all three retigabine groups in the large phase II trial, somnolence (20.3%), dizziness (14.6%), confusion (12.3%) and speech disorder (11.3%) were the most frequent CNS-related adverse events.
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PMID:Retigabine: in partial seizures. 1680 Jul 18

Ring chromosome 20 is a rare chromosome disorder characterized by a typical seizure phenotype consisting of complex partial seizures, frequent progression to generalized tonic or tonic-clonic seizures, and nocturnal frontal lobe seizures with frequent episodes of non-convulsive status epilepticus. Development may be normal or mildly delayed, followed by cognitive and behavioral decline after seizure onset. Here, we describe a patient with a typical severe seizure phenotype and a mosaic ring chromosome 20 without loss of p or q subtelomere regions or telomeric sequences. The ring had a longer telomere length than either of the telomere ends of its homologous chromosome 20 by quantitative fluorescence in situ hybridization analysis, suggesting that it might be derived from telomere-telomere fusion. The phenotypic comparison of this patient and other chromosome 20 cases that had terminal deletions of 20qter (n = 1) and 20pter (n = 7), shows that the epilepsy phenotype and electroencephalographic abnormalities are characteristic in patients with ring chromosome 20. Several hypotheses have been proposed to address the elusive mechanisms underlying the seizure disorder in ring chromosome 20. These possibilities include haploinsufficiency of two epilepsy genes CHRNA4 and KCNQ2 located at 20qter, silencing of these genes by a telomere position effect, or microdeletions or rearrangements of genetic material during the ring formation.
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PMID:Mosaic ring 20 with no detectable deletion by FISH analysis: Characteristic seizure disorder and literature review. 1683 34

Inherited or de novo mutations in at least a dozen genes encoding ion channels may present as paroxysmal disorders during the neonatal period or first year of life. These channelopathies include genes encoding voltage-gated channels specific for sodium (SCN1A, SCN2A, SCN1B, SCN9A) and potassium (KCNQ2, KCNQ3) which account for a variety of epilepsy phenotypes ranging from mild, such as Benign familial neonatal seizures (BFNS) to severe, such as Dravet syndrome (severe myoclonic epilepsy of infancy, SMEI) and the rare and unusual syndrome paroxysmal extreme pain disorder (PEPD). Ligand-gated channels involved include the GABA(A) receptor in a variety of epilepsy phenotypes and the human glycine receptor. Mutations in five genes encoding subunits of this receptor and accessory molecules underlie hyperekplexia or stiff-baby syndrome. All these conditions are rare but correct diagnosis is of value not only for genetic counselling but to allow the specific treatment which is available.
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PMID:Molecular genetics of infantile nervous system channelopathies. 1704 61

Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, delayed muscle relaxation after contraction (pseudomyotonia), and hyperhidrosis, associated with well described spontaneous electromyographic features. It is usually an acquired disorder associated with autoantibodies against neuronal voltage-gated potassium channels. However, mutations of KCNA1, encoding the K(+) channel subunit hKv1.1, have been reported in rare families with neuromyotonia, and mutations in KCNQ2, encoding voltage-gated potassium M channel subunit, in families with benign neonatal seizures and myokymia. We report a three-generation family with inherited neuromyotonia without evidence of immunological involvement. Genetic study excluded mutations in KCNA1, KCNA2, KCNA6 and KCNQ2 genes. Our study does not completely exclude the involvement of other genes encoding ion channels subunits in the pathogenesis of this disorder. Further studies of familial cases will shed light on the molecular basis of inherited neuromyotonia.
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PMID:Inherited neuromyotonia: a clinical and genetic study of a family. 1714 Jul 92

Epilepsy is a heterogeneous group of multifactorial diseases, the vast majority determined by interactions between many genes and environmental factors; however, there are rare epilepsy syndromes that can be caused by a single gene mutation and are inherited according to classical mendelian genetic principles. Finding disease-causing genetic mutations in epilepsy has provided new opportunities for aiding diagnosis and developing therapies. Thus, the discovery of KCNQ2 mutations in benign familial neonatal convulsions, SCN1A mutations in severe myoclonic epilepsy of infancy and in generalized epilepsy with febrile seizures plus, and CHRA4 and CHRB2 mutations in autosomal-dominant nocturnal frontal lobe epilepsy, has led to the establishment of epilepsy as a disorder of ion channel function and, furthermore, has led to the introduction of genetic tests that are available clinically to aid in diagnosis and treatment. At the present time, clinical use of genetic testing in epilepsy is greatest in suspected cases of severe myoclonic epilepsy of infancy, generalized epilepsy with febrile seizures plus, atypical cases of benign familial neonatal convulsions and 'occult' cases of autosomal-dominant nocturnal frontal lobe epilepsy without a family history. Overall, clinical use is limited by the low number of documented disease-associated mutations and the uncertain clinical significance of many test results. Further elucidation of the relationship between gene mutations and channel function will add value to genetic testing in the future, as will better characterization of the association between gene mutations and clinical phenotypes.
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PMID:Role of genetics in the diagnosis and treatment of epilepsy. 1718 26

In recent years, progress in understanding the genetic basis of idiopathic generalized epilepsies has proven challenging because of their complex inheritance patterns and genetic heterogeneity. Genetic polymorphisms offer a convenient avenue for a better understanding of the genetic basis of idiopathic generalized epilepsy by providing evidence for the involvement of a given gene in these disorders, and by clarifying its pathogenetic mechanisms. Many of these genes encode for some important central nervous system ion channels (KCNJ10, KCNJ3, KCNQ2/KCNQ3, CLCN2, GABRG2, GABRA1, SCN1B, and SCN1A), while many others encode for ubiquitary enzymes that play crucial roles in various metabolic pathways (HP, ACP1, ME2, LGI4, OPRM1, GRIK1, BRD2, EFHC1, and EFHC2). We review the main genetic polymorphisms reported in idiopathic generalized epilepsy, and discusses their possible functional significance in the pathogenesis of seizures.
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PMID:Genetic polymorphisms and idiopathic generalized epilepsies. 1776 2


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