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 with 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 with dizygotic pairs (17/47 concordant monozygotic versus 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 versus 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 versus 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.

Figure 1

Genetic contributions to TLE subtypes based on casewise concordances for TLE. PcMZ– casewise concordance for TLE in MZ twins. This was calculated as P_c = 2n_c/(2n_c + n_d), where n_c is the number of twin pairs concordant for TLE and n_d is the number of twin pairs discordant for TLE. None of the DZ twin pairs were concordant for TLE. The difference in the number of concordant pairs between MZ and DZ twin pairs for TLE and each TLE subtype was analysed using a two-sided Fisher's exact test. *Adjusted P < 0.05 (adjustment for multiple comparisons) was considered statistically significant. DZ = dizygotic; HS = hippocampal sclerosis; MZ = monozygotic; MTLE = mesial temporal lobe epilepsy; TLE = temporal lobe epilepsy.

Figure 2

Probability of co-twin being diagnosed with TLE at various time points after the TLE diagnosis made in the index twin, stratified according to zygosity n = 80. The shaded colour regions define the 95% confidence intervals. Coloured vertical dashes along each survival curve denote the most recent age of co-twin known without a diagnosis of TLE (censored observations). The probability of TLE diagnosis in co-twin 10 years after the index twin's diagnosis for each group is indicated by black dashed lines. DZ = dizygotic; MZ = monozygotic; TLE = temporal lobe epilepsy.

Figure 3

MRI coronal T2-weighted images for two monozygotic twin pairs with neurofibromatosis type 1 who were concordant for hippocampal sclerosis. (A and B) Pair 1. (C and D) Pair 2. In each case, both hippocampi were abnormal; however, there was a lateralized emphasis. The hippocampus ipsilateral to the TLE in each twin met the diagnostic criteria for hippocampal sclerosis (HS), while the contralateral hippocampus displayed a high T2 signal. Pair 1: (A) left HS (arrow). This twin also had an increased T2 signal in the posterior body of the right hippocampus (not shown). (B) Left HS (arrow) and high T2 signal in the right hippocampus. Pair 2: (C) right HS (arrow) and high T2 signal in the left hippocampus. (D) Right HS (arrow) and increased T2 signal in the left hippocampus. TLE = temporal lobe epilepsy.

Figure 4

MRIs of a monozygotic twin pair concordant for MTLE and antecedent febrile seizure but discordant for hippocampal sclerosis. Right hippocampal sclerosis (HS) was demonstrated only in twin (A) with a history of prolonged febrile seizures. (B) Similarly positioned image from co-twin with no evidence of HS but with generalized parenchymal loss of undetermined cause. The MRI in Fig. 4A was taken at age 41 years before her epilepsy surgery, while her co-twin's MRI in Fig. 4B was taken at age 54 years. This twin pair was not included in our previous study of monozygotic twins with HS. MTLE = mesial temporal lobe epilepsy.

Figure 5

Genetic contributions to hippocampal sclerosis (HS) and the interaction between acquired and genetic factors in HS. The genetic contributions to HS can be categorized into two main types: germline variants, which can be either rare or common, and somatic mutations affecting the Ras/Raf/Mitogen-activated protein kinase (MAPK) pathway within the hippocampus. The mechanisms underlying HS are likely influenced by one or more of these genetic factors, as well as interactions with acquired insults (indicated by the shaded green area) that also contribute to the development of HS. *Genetic factors, e.g. variants in SCN1A and SCN1B predispose to febrile seizures and very rarely prolonged febrile seizures.^{,  #}Hippocampal abnormalities have been observed in families with HS, suggesting a potential association between these abnormalities and HS. SNP = single nucleotide polymorphisms. Created in BioRender. Dang, Y. (2025) https://BioRender.com/k71a861.