Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Abstract

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

No association between ApoE polymorphism and febrile seizures

“…Since hundreds of genes have the potential to influence these cellular pathways, this hypothesis could be further tested with a genome-wide approach to identify possible genetic markers of febrile seizures. Using this approach, recent studies found that variants of the sodium channel gene SCN1A are associated with general and MMR vaccine-related febrile seizures [4], but also with mesial temporal lobe epilepsy with hippocampal sclerosis, with and without a history of febrile seizures [5]. If such markers can be found, the development and use of cost-effective sequencing technologies available to clinicians should be combined with the development and use of functional analysis tools that can comprehend multiple gene pathways for routine diagnostic.…”

“…Adequate diagnosis is, therefore, key to adequate treatment and patient education that can alleviate parents' anxiety and allow the family return to normal life. To achieve this goal, a number of researchers and practitioners have called for an increased effort to determine the genetic factors predisposing to febrile seizures and understand the relation between febrile seizures and specific epilepsy syndromes [2][3][4][5][6][7][8].…”

“…The importance of genetic factors in the incidence of febrile seizures has long been recognized [9,10], but specific genes that affect febrile seizure cases, and which are not part of a broader phenotypic spectrum that includes afebrile seizures, have yet to be conclusively identified [5,11]. For example, interleukin 1-beta has been linked to the generation of febrile seizures [3], but increased frequency of the interleukin-1-beta-511T allele has also been reported in patients with temporal lobe epilepsy [12].…”

Hippocampal sclerosis: pathogenesis, clinical features, diagnosis, and treatment

“…Изучение полногеномных ассоциаций показало, что фе-брильные приступы со склерозом гиппокампа могут быть генетическим синдромом, так как они связаны с наличи-ем специфического аллеля однонуклеотидной последо-вательности, расположенной рядом с геном натриевого канала SCN1а. Такой ассоциации не было выявлено для случаев эпилепсии с СГ без фебрильных приступов [13]. Консенсусным мнением эпилептологов является идея, что существует некая исходная генетическая предраспо-рис.…”

Genetic Biomarkers in Epilepsy

“…One study suggested association of a polymorphism in SCN1A with the dosage of sodium channel blockers used in treated patients [49], but others could not confirm these results [50]. A more robust genetic association of polymorphisms in SCN1A with epilepsy has been reported in 2 recent genome-wide association studies [51,52]; however, an association with pharmacoresponse has not been explored in these studies. Thus, the role of common polymorphisms in SCN1A or other genes encoding potential AED targets for pharmacoresponse needs to be elucidated in the future.…”