Dang Yew Li, Esnault Kate, Fitt Gregory, O'Brien Terence J, Jackson Graeme D, Perucca Piero, Berkovic Samuel F
Epilepsy Research Centre, Department of Medicine (Austin Health), the University of Melbourne, 3084 VIC, Australia.
Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Melbourne, 3084 VIC, Australia.
Brain. 2025 Jun 18. doi: 10.1093/brain/awaf209.
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.
颞叶癫痫是成人中最常见的局灶性癫痫。虽然颞叶癫痫在历史上被认为主要是后天病因，但越来越多的证据表明遗传因素起着重要作用。颞叶癫痫有几种亚型，包括伴或不伴海马硬化的内侧颞叶癫痫，但尚未直接研究每种亚型的相对遗传贡献。在本研究中，我们对80对双胞胎进行了经典双胞胎模型研究，其中至少有一名双胞胎患有颞叶癫痫。我们通过分析同卵双胞胎与异卵双胞胎中颞叶癫痫的一致性，评估了遗传因素对各种亚型[病灶性颞叶癫痫、非病灶性颞叶癫痫、内侧颞叶癫痫（伴或不伴海马硬化）、外侧颞叶癫痫和非定位性颞叶癫痫]的贡献。在10对至少有一名双胞胎患有海马硬化的同卵双胞胎中，我们寻找了患病个体与未患病个体之间的同对内后天差异。与异卵双胞胎相比，同卵双胞胎中颞叶癫痫一致性更高（同卵双胞胎17/47一致，而异卵双胞胎0/33一致，p<0.05）。这支持了遗传因素对颞叶癫痫的作用，但值得注意的是，这种一致性是由非病灶性颞叶癫痫病例驱动的，特别是无海马硬化的内侧颞叶癫痫（同卵双胞胎14/22一致，而异卵双胞胎0/11一致，p<0.05）。在病灶性颞叶癫痫组（n=8）和非定位性颞叶癫痫组（n=15）中未观察到同卵或异卵双胞胎一致的情况。伴有海马硬化的内侧颞叶癫痫的同卵双胞胎中颞叶癫痫的一致性要低得多（同卵双胞胎2/10一致，而异卵双胞胎0/9一致，p=1），这表明种系遗传因素对伴有海马硬化的内侧颞叶癫痫的作用较小。八对同卵双胞胎在海马硬化方面不一致。在其中四对中，双胞胎都有热性惊厥，但海马硬化仅出现在发作时间延长的双胞胎中。两对同卵双胞胎在海马硬化方面一致，他们患有临床1型神经纤维瘤病，带有致病的种系NF1变异。我们的研究结果证实了颞叶癫痫中的种系遗传成分，在无海马硬化的内侧颞叶癫痫中最为明显，在外侧颞叶癫痫中也存在，但在病灶性和非定位性颞叶癫痫中不存在。在我们伴有海马硬化的内侧颞叶癫痫双胞胎中，我们发现遗传因素（NF）和长时间热性惊厥都对海马硬化的病因有影响。
