Twins with temporal lobe epilepsy: genetic contributions to hippocampal sclerosis and other subtypes

Abstract

Temporal lobe epilepsy is the most common focal epilepsy in adults. While temporal lobe epilepsy was historically perceived to have a largely acquired aetiology, growing evidence points to important genetic contributions. There are several temporal lobe epilepsy subtypes, including mesial temporal lobe epilepsy with or without hippocampal sclerosis, but the relative genetic contributions to each of these subtypes have not been directly studied. In this study, we use the classical twin model in 80 twin pairs where at least one twin had temporal lobe epilepsy. We assessed the genetic contribution to various subtypes [lesional temporal lobe epilepsy, non-lesional temporal lobe epilepsy, mesial temporal lobe epilepsy (with or without hippocampal sclerosis), lateral temporal lobe epilepsy, and non-localized temporal lobe epilepsy], by analysing the concordance for temporal lobe epilepsy in monozygotic twins compared to dizygotic twins. In the 10 monozygotic pairs where at least one twin had hippocampal sclerosis, we searched for within-pair acquired differences between affected and unaffected individuals. There was an excess of monozygotic pairs concordant for temporal lobe epilepsy compared to dizygotic pairs (17/47 concordant monozygotic vs 0/33 concordant dizygotic, p<0.05). This supports a genetic contribution to temporal lobe epilepsy, but notably this concordance was driven by non-lesional temporal lobe epilepsy cases, particularly mesial temporal lobe epilepsy without hippocampal sclerosis (14/22 concordant monozygotic vs 0/11 concordant dizygotic, p<0.05). No concordant monozygotic or dizygotic pairs were observed in the lesional temporal lobe epilepsy (n=8) and non-localized temporal lobe epilepsy (n=15) groups. The concordance for temporal lobe epilepsy in monozygotic twins with mesial temporal lobe epilepsy with hippocampal sclerosis was much lower (2/10 concordant monozygotic vs 0/9 concordant dizygotic, p=1), suggesting a lesser contribution from germline genetic causes to mesial temporal lobe epilepsy with hippocampal sclerosis. Eight monozygotic twin pairs were discordant for hippocampal sclerosis. In four of these pairs, both twins had febrile seizures, but hippocampal sclerosis was only present in the twin who had prolonged seizures. The two monozygotic twin pairs concordant for hippocampal sclerosis had clinical neurofibromatosis type 1 with pathogenic germline NF1 variants. Our findings confirm a germline genetic component in temporal lobe epilepsy, strongest in mesial temporal lobe epilepsy without hippocampal sclerosis and present in lateral temporal lobe epilepsy but absent in lesional and non-localized temporal lobe epilepsy. In our mesial temporal lobe epilepsy with hippocampal sclerosis twins, we found both genetic factors (NF1) and prolonged febrile seizures contributed to the aetiology of hippocampal sclerosis.

Keywords: genetics; hippocampal sclerosis; neurofibromatosis; temporal lobe epilepsy; twin study.