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.

• Authors: Dalia Kasperaviciute, Claudia B Catarino, Mar Matarin, Costin Leu, Jan Novy, Anna Tostevin, Bárbara Leal, Ellen V S Hessel, Kerstin Hallmann, Michael S Hildebrand, Hans-Henrik M Dahl, Mina Ryten, Daniah Trabzuni, Adaikalavan Ramasamy, Saud Alhusaini, Colin P Doherty, Thomas Dorn, Jörg Hansen, Günter Krämer, Bernhard J Steinhoff, Dominik Zumsteg, Susan Duncan, Reetta K Kälviäinen, Kai J Eriksson, Anne-Mari Kantanen, Massimo Pandolfo, Ursula Gruber-Sedlmayr, Kurt Schlachter, Eva M Reinthaler, Elisabeth Stogmann, Fritz Zimprich, Emilie Théâtre, Colin Smith, Terence J O'Brien, K Meng Tan, Slave Petrovski, Angela Robbiano, Roberta Paravidino, Federico Zara, Pasquale Striano, Michael R Sperling, Russell J Buono, Hakon Hakonarson, João Chaves, Paulo P Costa, Berta M Silva, António M da Silva, Pierre N E de Graan, Bobby P C Koeleman, Albert Becker, Susanne Schoch, Marec von Lehe, Philipp S Reif, Felix Rosenow, Felicitas Becker, Yvonne Weber, Holger Lerche, Karl Rössler, Michael Buchfelder, Hajo M Hamer, Katja Kobow, Roland Coras, Ingmar Blumcke, Ingrid E Scheffer, Samuel F Berkovic, Michael E Weale, UK Brain Expression Consortium, Norman Delanty, Chantal Depondt, Gianpiero L Cavalleri, Wolfram S Kunz, Sanjay M Sisodiya
• Journal: Brain : a journal of neurology (Brain) Vol. 136 Issue Pt 10 Pg. 3140-50 (Oct 2013) ISSN: 1460-2156 [Electronic] England
• PMID: 24014518 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NAV1.1 Voltage-Gated Sodium Channel
• SCN1A protein, human

Topics

• Epilepsy, Temporal Lobe (etiology, genetics)
• Genome-Wide Association Study (methods)
• Hippocampus (pathology)
• Humans
• Mutation (genetics)
• NAV1.1 Voltage-Gated Sodium Channel (genetics)
• Prospective Studies
• Sclerosis (genetics)
• Seizures, Febrile (diagnosis, genetics)
• Temporal Lobe (pathology)