Generalized epilepsy with febrile seizures plus: A common childhood-onset genetic epilepsy syndrome

Singh, Rita; Scheffer, Ingrid E.; Crossland, Kathryn M.; Berkovic, Samuel F.

doi:10.1002/1531-8249(199901)45:1<75::aid-art13>3.0.co;2-w

Cited by 268 publications

(201 citation statements)

References 21 publications

Supporting

Mentioning

180

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, it was nonpenetrant in his maternal grandmother, which is in keeping with the low penetrance observed in GEFS1 families. 35 Other unaffected SCN1B c.363C.T (p.C121W) carriers (n 5 6) have been reported, 16 and the variant is present in controls, suggesting other genetic or nongenetic factors modify the epilepsy phenotype. These observations recapitulate those seen in other patients with Dravet syndrome, where ;3-5% of cases have inherited a pathogenic SCN1A variant, typically from a more mildly affected parent with GEFS1.…”

Section: 16mentioning

confidence: 98%

GABRA1 and STXBP1 : Novel genetic causes of Dravet syndrome

et al. 2014

View full text Add to dashboard Cite

Objective: To determine the genes underlying Dravet syndrome in patients who do not have an SCN1A mutation on routine testing. Methods:We performed whole-exome sequencing in 13 SCN1A-negative patients with Dravet syndrome and targeted resequencing in 67 additional patients to identify new genes for this disorder.Results: We detected disease-causing mutations in 2 novel genes for Dravet syndrome, with mutations in GABRA1 in 4 cases and STXBP1 in 3. Furthermore, we identified 3 patients with previously undetected SCN1A mutations, suggesting that SCN1A mutations occur in even more than the currently accepted ;75% of cases. Conclusions:We show that GABRA1 and STXBP1 make a significant contribution to Dravet syndrome after SCN1A abnormalities have been excluded. Our results have important implications for diagnostic testing, clinical management, and genetic counseling of patients with this devastating disorder and their families. Neurology ® 2014;82:1245-1253 GLOSSARY cDNA 5 complementary DNA; dHPLC 5 denaturing high-performance liquid chromatography; FS 5 febrile seizures; GABA 5 g-aminobutyric acid; GEFS1 5 genetic epilepsy with febrile seizures plus; WES 5 whole-exome sequencing; WT 5 wild-type.

show abstract

Section: 16mentioning

confidence: 98%

GABRA1 and STXBP1 : Novel genetic causes of Dravet syndrome

et al. 2014

View full text Add to dashboard Cite

show abstract

“…32,33 Whereas these rare families demonstrate autosomal dominant inheritance, the marked phenotypic heterogeneity within and between families supports a more complex etiology. 33 The twin analysis confirms clear genetic influences for the GEFS1 spectrum, with very high MZ concordance estimates. However, important additional insights have been gained from the family histories of the twins, as additional affected family members were usually not found.…”

Section: 10mentioning

confidence: 99%

Genetics of epilepsy

et al. 2014

View full text Add to dashboard Cite

Objective: Analysis of twins with epilepsy to explore the genetic architecture of specific epilepsies, to evaluate the applicability of the 2010 International League Against Epilepsy (ILAE) organization of epilepsy syndromes, and to integrate molecular genetics with phenotypic analyses.Methods: A total of 558 twin pairs suspected to have epilepsy were ascertained from twin registries (69%) or referral (31%). Casewise concordance estimates were calculated for epilepsy syndromes. Epilepsies were then grouped according to the 2010 ILAE organizational scheme. Molecular genetic information was utilized where applicable.Results: Of 558 twin pairs, 418 had confirmed seizures. A total of 534 twin individuals were affected. There were higher twin concordance estimates for monozygotic (MZ) than for dizygotic (DZ) twins for idiopathic generalized epilepsies (MZ 5 0.77; DZ 5 0.35), genetic epilepsy with febrile seizures plus (MZ 5 0.85; DZ 5 0.25), and focal epilepsies (MZ 5 0.40; DZ 5 0.03). Utilizing the 2010 ILAE scheme, the twin data clearly demonstrated genetic influences in the syndromes designated as genetic. Of the 384 tested twin individuals, 10.9% had mutations of large effect in known epilepsy genes or carried validated susceptibility alleles.Conclusions: Twin studies confirm clear genetic influences for specific epilepsies. Analysis of the twin sample using the 2010 ILAE scheme strongly supported the validity of grouping the "genetic" syndromes together and shows this organizational scheme to be a more flexible and biologically meaningful system than previous classifications. Successful selected molecular testing applied to this cohort is the prelude to future large-scale next-generation sequencing of epilepsy research cohorts. Insights into genetic architecture provided by twin studies provide essential data for optimizing such approaches. Neurology ® 2014;83:1042-1048 GLOSSARY BECTS 5 benign epilepsy with centrotemporal spikes; CAE 5 childhood absence epilepsy; DS 5 Dravet syndrome; DZ 5 dizygotic; FE 5 focal epilepsies; FS 5 febrile seizures; FS1 5 febrile seizures plus; GE 5 generalized epilepsies; GEFS1 5 genetic epilepsy with febrile seizures plus; IFE 5 idiopathic focal epilepsies; IGE 5 idiopathic generalized epilepsies; ILAE 5 International League Against Epilepsy; IPOE 5 idiopathic photosensitivity occipital epilepsy; JME 5 juvenile myoclonic epilepsy; MAS 5 epilepsy with myoclonic-atonic seizures; MZ 5 monozygotic; SGE 5 symptomatic generalized epilepsies; SSCP 5 single-stranded conformation polymorphism; TLE 5 temporal lobe epilepsy.

show abstract

“…Because GEFSϩ is an autosomal dominant disease (Scheffer and Berkovic, 1997;Singh et al, 1999), neurons in patients with GEFSϩ express a heterogeneous mixture of wild-type and mutant channels. We therefore examined the effects of the R859C mutation in oocytes injected with similar amounts of wild-type and R859C RNA.…”

Section: Coexpression Of R859c Mutant With Wild-type Channels Does Nomentioning

confidence: 99%

An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

et al. 2006

View full text Add to dashboard Cite

Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABA A receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFSϩ). A novel mutation, R859C, in the Na v 1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFSϩ. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Na v 1.1 channel ␣ subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Na v 1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFSϩ sodium channel mutations, which have changes predicted to increase neuronal firing.

show abstract

Generalized epilepsy with febrile seizures plus: A common childhood-onset genetic epilepsy syndrome

Cited by 268 publications

References 21 publications

GABRA1 and STXBP1 : Novel genetic causes of Dravet syndrome

GABRA1 and STXBP1 : Novel genetic causes of Dravet syndrome

Genetics of epilepsy

An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

Contact Info

Product

Resources

About