Abstract
Epilepsy, Hippocampal Sclerosis and Febrile Seizures Linked by Common Genetic Variation around SCN1A
Kasperavičiūte D, Catarino CB, Matarin M, Leu C, Novy J, Tostevin A, Leal B, Ellen Hessel EVS, Hallmann K, Hildebrand MS, Dahl H-HM, Ryten M, Trabzuni D, Ramasamy A, Alhusaini S, Doherty CP, Dorn T, Hansen J, Krämer G, Steinhoff BJ, Zumsteg D, Duncan S, Kälviäinen RK, Eriksson KJ, Kantanen A-M, Pandolfo M, Gruber-Sedlmayr U, Schlachter K, Reinthaler EM, Stogmann E, Zimprich F, Thé a∘tre E, Smith C, O'Brien TJ, Tan KM, Petrovski S, Robbiano A, Paravidino R, Zara F, Striano P, Sperling MR, Buono RJ, Hakonarson H, Chaves J, Costa PP, Silva BM, da Silva AM, de Graan PNE, Koeleman BPC, Becker A, Schoch S, von Lehe M, Reif PS, Rosenow F, Becker F, Weber Y, Lerche H, Ro¨ssler K, Buchfelder M, Hamer HM, Kobow K, Coras R, Blumcke I, Scheffer IE, Berkovic SF, Weale ME, UK Brain Expression Consortium Delanty N, Depondt C, Cavalleri GL, Kunz WS, Sisodiya SM. Brain 2013:36;3140–3150
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.
Commentary
Although uncommon, the progression of febrile seizures (FS) early in life to mesial temporal lobe epilepsy with MTS is well-described; however, underlying mechanisms and predictors are poorly understood. Proposed mechanisms include prolonged FS at an early age damaging the hippocampus, initial hippocampal injury peri- or prenatally, or a hippocampal formation genetically predisposed to MTS triggered or activated by remote FS. This latter proposed mechanism is associated with the largest number of epilepsies demonstrating a history of FS and an association with variants within the alpha 1 subunit of voltage dependent sodium channels (SCN1A) (8). The SCN1A-related epilepsies compose a continuum of disorders with incomplete penetrance and variable expressivity. The febrile-associated epilepsies range from self-limited simple FS and generalized epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, also known as severe myoclonic epilepsy in infancy (SMEI). SCN1A phenotypes also include myoclonic-astatic epilepsy, or Doose syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures (7). The overall prevalence of SCN1A-related epilepsies is not known. MTS is a relatively uncommon finding in these epilepsies (1,6). In fact, Dravet syndrome is not associated with hippocampal sclerosis (7).
SCN1A-associated epilepsies can be inherited in an autosomal dominant manner, or as a de novo mutation. SCN1A is part of a cluster of sodium channel genes encoded on chromosome 2q24 that includes SCN2A and SCN3A (5). SCN1A encodes a voltage-gated sodium channel alpha subunit. The alpha subunit of sodium channels forms the membrane pore. Each alpha subunit protein has four domains with six transmembrane segments connected by loops. The majority of SCN1A mutations cluster in the C-terminus and the pore loops in the first three domains of the protein (5,10). The pathophysiology of SCN1A mutations is a decrease in the activity of GABAergic inhibitory neurons. For example, most of the mutations that cause Dravet syndrome (SMEI) result in loss of function, whereas mutations that cause GEFS+ are missense, likely altering channel activity (3). However, about 5% of individuals with mutation-positive SMEI have a familial missense SCN1A mutation associated with a milder phenotype (i.e., GEFS+) in other family members (5).
The study by Kasperaviciute et al., is a multicenter, multinational genetic association study involving a large cohort of subjects with MTS with and without a history of FS. The aim of this study was to identify an association, if not a mechanism, of the most common focal-onset epilepsy when associated with early FS. A detailed meta-analysis demonstrated a target at the sodium channel gene cluster on chromosome 2q24.3 (rs7587026, within an intron of the SCN1A gene). Those subjects with early FS followed to nearly age 15 without developing hippocampal sclerosis HS did not possess the mutation. Although this study does not explain whether FS cause MTS, or whether pre-existing hippocampal abnormalities predispose to FS (2), it suggests that patients with MTS, with or without a history of FS possess different underlying pathogenetic mechanisms.
The study controls for the specificity of the association for MTS + FS rather than FS alone, since developing epilepsy following a history of FS is most often apparent by age 15 (4). No association of the rs7587026 with FS where patients did not develop epilepsy was found in comparison with controls from the same cohort. The authors reported observing a signal in MTS + FS not due to a history of FS alone. In addition, a dissociation was demonstrated where no significant relationship was detected in a group of patients with other partial epilepsies and a history of FS. The authors reported that their genetic association strategy did not differentiate between cell types (interneurons as proposed in Dravet syndrome vs principal neurons). Additionally, the authors did not address possible mechanisms underlying the specificity of hippocampal pathophysiology, or insight as to the critical age range of onset. Translational implications of this study include developing potential pharmacogenetic testing as a tool for individualized therapy. For example, mutations in the alpha-unit of the SCN1A gene have been associated with decreased efficacy of sodium channel blocking anti-epileptic medications. A single nucleotide polymorphism in SCN1A is associated with carbamazepine-resistant epilepsy. As a result, such individuals require higher maintenance dose of carbamazepine (9). Of note, children with SCN1A-related epilepsy may be at high risk of sudden unexpected death in epilepsy (SUDEP).
SCN1A has been closely connected with a number of other voltage-gated sodium channel genes (i.e., SCN1B, SCN2A, SCN3A). These genes may contribute both pathophysiologically and phenotypically to a number of the genetic epilepsies. Moreover, phenotypic expression of these other genes can overlap with those of SCN1A. This information suggests a heterogeneous group of genetic epilepsies. Nevertheless, this important well-organized multinational study contributes a better understanding of SCN1A-related mesial temporal lobe epilepsy with hippocampal sclerosis. Moreover, it provides a systematic approach that could inevitably lead to both prognosis and potential therapies in a subgroup of children with MTLE and a history of FS.