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)

Febrile seizures are the most common form of childhood seizures, occurring in 2% to 5% of North American children. We report a large Utah family with 21 members affected by febrile seizures inherited as an autosomal dominant trait. All had generalized tonic-clonic seizures with onset associated with fever, consistent with the consensus febrile seizure phenotype, and none had febrile seizures beyond 6 years of age. Eighteen affected individuals had recurrent febrile seizures. Eight individuals developed afebrile seizures between ages 5 and 13 years. Afebrile seizures consisted of generalized tonic-clonic, generalized tonic, generalized atonic, simple partial, and partial complex seizure types and were associated with abnormal electroencephalographic findings in 5 individuals, all of whom were intellectually normal. We undertook linkage analysis in this family, defining the disease phenotype as febrile seizures alone. Linkage analysis in epilepsy candidate gene/loci regions failed to show evidence for linkage to febrile seizures. However, a genomewide scan and subsequent fine mapping revealed significant evidence for a new febrile seizure locus (FEB3) on chromosome 2q23-24 with linkage to the marker D2S2330 (LOD score 8.08 at theta = 0.001). Haplotype analysis defined a critical 10-cM region between markers D2S141 and D2S2345 that contains the FEB3 locus.
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PMID:A locus for febrile seizures (FEB3) maps to chromosome 2q23-24. 1085 60

Evidence that febrile seizures have a strong genetic predisposition has been well documented. In families of probands with multiple febrile convulsions, an autosomal dominant inheritance with reduced penetrance is suspected. Four candidate loci for febrile seizures have been suggested to date; FEB1 on 8q13-q21, FEB2 on 19p, FEB3 on 2q23-q24, and FEB4 on 5q14-15. A missense mutation was identified in the voltage-gated sodium (Na(+))-channel beta 1 subunit gene, SCN1B at chromosome 19p13.1 in generalized epilepsy with the febrile seizures plus type 1 (GEFS+1) family. Several missense mutations of the (Na(+))-channel alpha 1 subunit (Nav1.1) gene, SCN1A were also identified in GEFS+2 families at chromosome 2q23-q24.3. The aim of this report is precisely to describe the phenotypes of Japanese patients with novel SCN1A mutations and to reevaluate the entity of GEFS+. Four family members over three generations and one isolated (phenotypically sporadic) case with SCN1A mutations were clinically investigated. The common seizure type in these patients was febrile and afebrile generalized tonic-clonic seizures (FS+). In addition to FS+, partial epilepsy phenotypes were suspected in all affected family members and electroencephalographically confirmed in three patients of two families. GEFS+ is genetically and clinically heterogeneous, and associated with generalized epilepsy and partial epilepsy as well. The spectrum of GEFS+ should be expanded to include partial epilepsies and better to be termed autosomal dominant epilepsy with febrile seizures plus (ADEFS+).
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PMID:Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na+)-channel alpha 1 subunit gene, SCN1A. 1182 6

Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic syndrome with a marked clinical and genetic heterogeneity. Here we report the molecular characterization of a large pedigree with a severe clinical form of GEFS+. Genetic linkage analysis implied the involvement of the FEB3 in the disease phenotype of this family (parametric two-point lod-score of 2.2). Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit. The amino-acid replacement lies in the pore-forming region of domain IV of SCN1A. Our observations are consistent with the genotype-phenotype correlation studies suggesting that mutations in the pore-forming loop of SCN1A can lead to a clinically more severe epileptic syndrome.
Seizure 2005 Mar
PMID:A novel SCN1A mutation associated with severe GEFS+ in a large South American pedigree. 1569 66

Febrile seizures (FS) affect 5-12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures in approximately 7% of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomal-dominant locus has been identified on chromosome 2q23-24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Na(v)1.1 channel alpha-subunit cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy.
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PMID:Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. 1632 7

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

Febrile seizures (FS) are the most common seizure type in children. Recurrent FS are a risk factor for developing temporal lobe epilepsy later in life and are known to have a strong genetic component. Experimental FS (eFS) can be elicited in mice by warm-air induced hyperthermia. We used this model to screen the chromosome substitution strain (CSS) panel derived from C57BL/6J and A/J for FS susceptibility and identified C57BL/6J-Chr2^A /NaJ (CSS2), as the strain with the strongest FS susceptibility phenotype. The aim of this study was to map FS susceptibility loci and select candidate genes on mouse chromosome 2. We generated an F₂ population by intercrossing the hybrids (F₁ ) that were derived from CSS2 and C57BL/6J mice. All CSS2-F₂ individuals were genotyped and phenotyped for eFS susceptibility, and QTL analysis was performed. Candidate gene selection was based on bioinformatics analyses and differential brain expression between CSS2 and C57BL/6J strains determined by microarray analysis. Genetic mapping of the eFS susceptibility trait identified two significant loci: FS-QTL2a (LOD-score 3.6) and FS-QTL2b (LOD-score 6.2). FS-QTL2a contained 44 genes expressed in the brain at post natal day 14. Four of these (Arl6ip6, Cytip, Fmnl2 Ifih1) contained a non-synonymous SNP comparing CSS2 and C57BL/6J, six genes (March7, Nr4a2, Gpd2, Grb14, Scn1a, Scn3a) were differentially expressed between these strains. A region within FS-QTL2a is homologous to the human FEB3 locus. The fact that we identify mouse FS-QTL2a with high FEB3 homology is strong support for the validity of the eFS mouse model to study genetics of human FS.
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PMID:Mapping of a FEB3 homologous febrile seizure locus on mouse chromosome 2 containing candidate genes Scn1a and Scn3a. 2769 Mar 30

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