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)

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial inherited epileptic syndrome characterized by phenotypic heterogeneity from the milder febrile seizures to the severest epileptic encephalopathy such as severe myoclonic epilepsy in infancy (SMEI). GEFS+ is a disorder with a genetic heterogeneity. Molecular genetics have revealed that four genes are associated with the pathogenesis of GEFS+. These include mutations in genes encoding subunits of neuronal voltage-gated sodium channels (SCN1A, SCN1B, SCN2A) and gamma(2) subunit of the gamma amino-butyric acid (GABA)(A) receptor (GABRG2). These genes have been confirmed as having a role in autosomal dominant GEFS+ families. In addition, the phenotypes of the affected members may depend on the types and locations of these gene mutations. This review states the molecular genetic progress of GEFS+ in brief.
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PMID:[Progress in molecular genetics of generalized epilepsy with febrile seizures plus]. 1845 5

Generalized epilepsy with febrile seizures plus (GEFS+; MIM#604233) is a familial epilepsy syndrome characterized by phenotypic and genetic heterogeneity. It was associated with mutations in the neuronal voltage-gated sodium channel subunit gene (SCN1A, SCN2A, SCN1B) and ligand-gated gamma aminobutyric acid receptors genes (GABRG2, GABRD). We investigated the roles of SCN1A, SCN1B, and GABRG2 mutations in the etiology of Chinese GEFS+ families. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood lymphocytes of 23 probands and their family members. The sequences of SCN1A, SCN1B, and GABRG2 genes were analyzed by polymerase chain reaction (PCR) and direct sequencing. The major phenotypes of affected members in the 23 GEFS+ families exhibited FS and FS+, whereas rare phenotypes afebrile generalized tonic-clonic seizures (AGTCS), myoclonic-astatic epilepsy (MAE), and partial seizures were also observed. A novel SCN1A mutation, p.N935H, was identified in one family and another novel mutation in GABRG2, p.W390X, in another family. However, no SCN1B mutation was identified. The combined frequency of SCN1A, SCN1B, and GABRG2 mutations was 8.7% (2/23), extending the distribution of SCN1A and GABRG2 mutations to Chinese GEFS+ families. There were still unidentified genes contributing to the pathogenesis of GEFS+.
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PMID:SCN1A, SCN1B, and GABRG2 gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus. 1856 37

Mutations of SCN1A, encoding the voltage-gated sodium channel alpha1 subunit, represent the most frequent genetic cause of severe myoclonic epilepsy in infancy (SMEI). The purpose of this study was to determine if mutations in other seizure susceptibility genes are also present and could modify the disease severity. All coding exons of SCN1B, GABRG2, and CACNB4 genes were screened for mutations in 38 SCN1A-mutation-positive SMEI probands. We identified one proband who was heterozygous for a de novo SCN1A nonsense mutation (R568X) and another missense mutation (R468Q) of the CACNB4 gene. The latter mutation was inherited from his father who had a history of febrile seizures. An electrophysiological analysis of heterologous expression system exhibited that R468Q-CACNB4 showed greater Ba(2+) current density compared with the wild-type CACNB4. The greater Ca(v)2.1 currents caused by the R468Q-CACNB4 mutation may increase the neurotransmitter release in the excitatory neurons under the condition of insufficient inhibitory neurons caused primarily by the SCN1A mutation.
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PMID:A CACNB4 mutation shows that altered Ca(v)2.1 function may be a genetic modifier of severe myoclonic epilepsy in infancy. 1875 74

Febrile seizures (FS) represent the most common form of childhood seizures. They affect 2-5% of infants in the Caucasian population and are even more common in the Japanese population, affecting 6-9% of infants. Some familial FS are associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical FS (FS+) and afebrile seizures. A significant genetic component exists for susceptibility to FS and GEFS+: extensive genetic studies have shown that at least nine loci are responsible for FS. Furthermore, mutations in the voltage-gated sodium channel subunit genes (SCN1A, SCN2A and SCN1B) and the GABA(A) receptor subunit genes (GABRG2 and GABRD) have been identified in GEFS+. However, the causative genes have not been identified in most patients with FS or GEFS+. Common forms of FS are genetically complex disorders believed to be influenced by variations in several susceptibility genes. Recently, several association studies on FS have been reported, but the results vary among different groups and no consistent or convincing FS susceptibility gene has emerged. Herein, we review the genetic data reported in FS, including the linkage analysis, association studies, and genetic abnormalities found in the FS-related disorders such as GEFS+ and severe myoclonic epilepsy in infancy.
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PMID:Progress in searching for the febrile seizure susceptibility genes. 1920 61

Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) can both arise due to mutations of SCN1A, the gene encoding the alpha 1 pore-forming subunit of the sodium channel. GEFS+ refers to a familial epilepsy syndrome where at least two family members have phenotypes that fit within the GEFS+ spectrum. The GEFS+ spectrum comprises a range of mild to severe phenotypes varying from classical febrile seizures to Dravet syndrome. Dravet syndrome is a severe infantile onset epilepsy syndrome with multiple seizure types, developmental slowing and poor outcome. More than 70% of patients with Dravet syndrome have mutations of SCN1A; these include both truncation and missense mutations. In contrast, only 10% of GEFS+ families have SCN1A mutations and these comprise missense mutations. GEFS+ has also been associated with mutations of genes encoding the sodium channel beta 1 subunit, SCN1B, and the GABA(A) receptor gamma 2 subunit, GABRG2. The phenotypic heterogeneity that is characteristic of GEFS+ families is likely to be due to modifier genes. Interpretation of the significance of a SCN1A missense mutation requires a thorough understanding of the phenotypes in the GEFS+ spectrum whereas a de novo truncation mutation is likely to be associated with a severe phenotype. Early recognition of Dravet syndrome is important as aggressive control of seizures may improve developmental outcome.
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PMID:Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? 1920 56

SCN1A is the most clinically relevant epilepsy gene and is associated with generalized epilepsy and febrile seizure plus (GEFS+) and Dravet syndrome. We postulated that earlier onset of febrile seizures in the febrile seizure (FS) and febrile seizure plus (FS+) phenotypes may occur in the presence of a SCN1A mutation. This was because of the age-related onset of Dravet syndrome, which typically begins in the first year of life. We found that patients with FS and FS+ with SCN1A mutations had earlier median onset of febrile seizures compared to the population median. Patients with GABRG2 mutations had a similar early onset in contrast to patients with SCN1B mutations where onset was later. This study is the first to demonstrate that a specific genetic abnormality directly influences the FS and FS+ phenotype in terms of age of onset.
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PMID:Does a SCN1A gene mutation confer earlier age of onset of febrile seizures in GEFS+? 1929 58

Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na(v)1.1 alpha subunits. Sodium channels are modulated by beta1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b(-/-) versus Scn1b(+/+) mice. Scn1b(-/-) CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b(-/-) mice seize spontaneously, the seizure susceptibility of Scn1b(+/-) mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation.
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PMID:A functional null mutation of SCN1B in a patient with Dravet syndrome. 1971 Mar 27

Genetic factors play an increasingly recognized role in idiopathic epilepsies. Since 1995, positional cloning strategies in multi-generational families with autosomal dominant transmission have revealed 11 genes (KCNQ2, KCNQ3, CHRNA4, CHRNA2, CHRNB2, SCN1B, SCN1A, SCN2A, GABRG2, GABRA1, and LGI1) and numerous loci for febrile seizures and epilepsies. To date, all genes with the exception of LGI1 (leucine-rich glioma inactivated 1), encode neuronal ion channel or neurotransmitter receptor subunits. Molecular approaches have revealed great genetic heterogeneity, with the vast majority of genes remaining to be identified. One of the major challenges is now to understand phenotype-genotype correlations. This review focuses on the current knowledge on the molecular basis of these rare Mendelian autosomal dominant forms of idiopathic epilepsies.
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PMID:Advances on the genetics of mendelian idiopathic epilepsies. 1985 23

Generalized epilepsy with febrile seizure plus (GEFS+) is an autosomal dominant disorder. In the literature, 5 responsible genes were identified and 2 novel susceptibility loci for GEFS+ at 2p24 and 8p23-p21 were reported, indicating the genetic heterogeneity of this disorder. The aim of this report is to identify the responsible loci in a large affected Tunisian family by performing a 10cM density genome-wide scan. The highest multipoint logarithm of odds (LOD) score (1.04) was found for D5S407 in the absence of recombination. Two other interesting regions were found around marker D19S210 (LOD=0.799) and D7S484 (LOD=0.61) markers. To fine map these loci, additional markers in 2 regions on 5q13.3 and 7p14.2 were analyzed and positive LOD scores for both loci were obtained. Sequencing of the Sodium channel subunit beta-1 gene (SCN1B) (19q13.1) showed the absence of any causal mutation. Our findings emphasized the genetic heterogeneity of febrile seizures.
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PMID:The first genome-wide scan in a tunisian family with generalized epilepsy with febrile seizure plus (GEFS+). 2038 41

Genetic factors play an increasingly recognized role in idiopathic epilepsies. Since 1995, positional cloning strategies in multigenerational families with autosomal dominant transmission have revealed 11 genes (KCNQ2, KCNQ3, CHRNA4, CHRNA2, CHRNB2, SCN1B, SCN1A, SCN2A, GABRG2, GABRA1, and LGI1) and numerous loci for febrile seizures and epilepsies. To date, all genes with the exception of LGI1, encode neuronal ion channel or neurotransmitter receptor subunits. Molecular approaches have revealed great genetic heterogeneity, with most genes remaining to be identified. One of the major challenges is now to understand phenotype-genotype correlations. This review focuses on the current knowledge on the molecular basis of these rare mendelian autosomal dominant forms of idiopathic epilepsies.
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PMID:Advances on the genetics of Mendelian idiopathic epilepsies. 2083 59


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