Genome scan of idiopathic generalized epilepsy: Evidence for major susceptibility gene and modifying genes influencing the seizure type

Durner, Martina; Keddache, Mehdi; Tomasini, Livia; Shinnar, Shlomo; Resor, Stanley R.; Cohen, Jeffrey Jerome; Harden, Cynthia L.; Moshé, Solomon L.; Rosenbaum, David S.; Kang, Hee-Taik; Ballaban‐Gil, Karen; Hertz, Sharon; Labar, Douglas; Luciano, Daniel; Wallace, Sibylle; Yohai, David; Klotz, Irene; Dicker, Elisa; Greenberg, David A.

doi:10.1002/ana.69

Cited by 134 publications

(52 citation statements)

References 32 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A genome scan of 91 families ascertained through IGE probands found evidence for an oligogenic model with one locus common to most IGEs, and other loci that may influence specific seizure phenotypes--such as myoclonic jerks--rather than syndromes as they are currently defined. 30 Clinical epidemiologic evidence has shown that there are distinct prognostic subgroups of certain IGEs defined by the presence or absence of GTCs. 31 A meta-analysis of 23 study cohorts including 2,303 patients identified that half of patients with ILAE-defined absence epilepsy developed GTCs; the subgroup with GTCs were less likely to go into remission.…”

Section: Discussionmentioning

confidence: 99%

Familial clustering of seizure types within the idiopathic generalized epilepsies

Winawer¹,

Marini²,

Grinton³

et al. 2005

Neurology

View full text Add to dashboard Cite

Objective: To examine the genetic relationships among epilepsies with different seizure types --myoclonic, absence, and generalized tonic-clonic --within the idiopathic generalized epilepsies (IGEs).Background: Careful phenotype definition in the epilepsies may allow division into groups that share susceptibility genes. Examination of seizure type, a phenotypic characteristic less complex than IGE syndrome, may help to define more homogeneous subgroups.

show abstract

Section: Discussionmentioning

confidence: 99%

Familial clustering of seizure types within the idiopathic generalized epilepsies

Winawer¹,

Marini²,

Grinton³

et al. 2005

Neurology

View full text Add to dashboard Cite

show abstract

“…Suggestive LOD scores were also obtained for regions of chromosomes 2 and 14. Evidence for a susceptibility gene on chromosome 18 was obtained from a genome scan of 91 families with idiopathic generalized epilepsy (24). This study concluded that genetic classification cuts across syndrome classifications and that several interacting genes influence risk for idiopathic epilepsies (24).…”

Section: Linkage Analysis Using Collections Of Small Familiesmentioning

confidence: 99%

Identification of Epilepsy Genes in Human and Mouse

et al. 2001

View full text Add to dashboard Cite

The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

show abstract

“…Although several chromosomal loci for different forms of IGEs have been identified, they have not often been replicated. Linkage studies on a large number of families with IGE have identified several susceptibility loci (18q, 2q, 3q, and 14q) [157,158]. In rare families, pathogenic mutations in single genes have been reported.…”

Section: Iges With Complex Inheritancementioning

confidence: 99%

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

2014

View full text Add to dashboard Cite

Research in genetics of epilepsy represents an area of great interest both for clinical purposes and for understanding the basic mechanisms of epilepsy. Most mutations in epilepsies without structural brain abnormalities have been identified in ion channel genes, but an increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing. Targeted molecular diagnosis is now available for different forms of epilepsy. The identification of epileptogenic mutations in patients before epilepsy onset and the possibility of developing therapeutic strategies tested in experimental models may facilitate experimental approaches that prevent epilepsy or decrease its severity. Functional analysis is essential for better understanding pathogenic mechanisms and gene interactions. In vitro experimental systems are either cells that usually do not express the protein of interest or neurons in primary cultures. In vivo/ex vivo systems are organisms or preparations obtained from them (e.g., brain slices), which should better model the complexity of brain circuits and actual pathophysiological conditions. Neurons differentiated from induced pluripotent stem cells generated from the skin fibroblasts of patients have recently allowed the study of mutations in human neurons having the genetic background of a given patient. However, there is remarkable complexity underlying epileptogenesis in the clinical dimension, as reflected by the fact that experimental models have not provided yet results having clinical translation and that, with a few exceptions concerning rare conditions, no new curative treatment has emerged from any genetic finding in epilepsy.

show abstract

Genome scan of idiopathic generalized epilepsy: Evidence for major susceptibility gene and modifying genes influencing the seizure type

Cited by 134 publications

References 32 publications

Familial clustering of seizure types within the idiopathic generalized epilepsies

Familial clustering of seizure types within the idiopathic generalized epilepsies

Identification of Epilepsy Genes in Human and Mouse

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

Contact Info

Product

Resources

About