Samuel F. Berkovic

Description:Objective: Reproduction is lower in male individuals compared with female individuals with epilepsy. The reason is unknown. We studied sex-specific reproduction in individuals with epilepsy and the role of epilepsy subtype and psychiatric comorbidity. Methods: We conducted a population-based register study in Denmark, using data from January 1, 1982, to December 31, 2021. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs) with 95% CIs for the chance of having ≥1 child. We followed all persons from 15 years of age until birth of live-born offspring, 45 years of age, emigration, death, or end of follow-up (December 31, 2021), whichever occurred first. Epilepsy status was identified from the Danish National Patient Register. The primary outcome was the occurrence of live-born children identified from the Danish Medical Birth Register among persons with and without epilepsy. Results: We included 2,593,097 individuals (49% of female individuals), including 46,243 (1.8%) with epilepsy (mean age at diagnosis of 13.1 years [SD 9.2]). Compared with individuals without epilepsy, the aHR of having ≥1 child was reduced in both sexes with epilepsy, but lower in male individuals (0.59, 95% CI 0.57-0.60) compared with female individuals with epilepsy (0.72, 95% CI 0.71-0.74). By age 45 years, the probability of being childless was 45.9% in male individuals and 30.7% in female individuals with epilepsy, compared with 22.8% in male individuals and 14.1% in female individuals without epilepsy. Compared with persons without epilepsy, the chance of having a first child was lower in female individuals with focal epilepsy (aHR 0.61, 95% CI 0.58-0.64) than in female individuals with generalized epilepsy (aHR 0.72, 95% CI 0.69-0.75), and lower in male individuals with focal epilepsy (aHR 0.51, 95% CI 0.48-0.53) than in male individuals with generalized epilepsy (aHR 0.57, 95% CI 0.54-0.60). Reproduction was particularly low in persons with epilepsy and psychiatric comorbidity (male individuals: aHR 0.30, 95% CI 0.28-0.32; female individuals: aHR 0.51, 95% CI 0.48-0.53). Conclusions: Individuals with epilepsy were less likely to become parents than individuals without epilepsy, and the association was stronger in male individuals and those with psychiatric comorbidity and varied with epilepsy subtype.

Description:Objective: Toxoplasma gondii (T. gondii) seropositivity has been reported to have up to a five-fold increased risk for epilepsy. However, substantial heterogeneity in methodology exists across these studies. Furthermore, other studies failed to replicate an association between T. gondii seropositivity and epilepsy. To address these inconsistencies, we investigated this issue in monozygotic (MZ) twin pairs discordant for epilepsy, a method that controls for age, sex and genetic factors. Methods: We analyzed 32 MZ twin pairs who are discordant for epilepsy, comparing rates of T. gondii seropositivity (IgG) between affected and unaffected twins. The odds ratio for T. gondii seropositivity in affected twins compared to their unaffected co-twins was calculated using McNemar's chi-squared paired proportion test. Factors associated with T. gondii seropositivity were assessed using Fisher's exact test and Welch's t-test, as appropriate. Results: The frequency of seropositivity in affected twins compared to their unaffected co-twins did not differ (odds ratio of 1.67 [95 % CI: 0.39-6.97], p = 0.72), indicating no significant association between T. gondii seropositivity and epilepsy in this cohort. Age at testing was associated with T. gondii seropositivity, with individuals found to be seropositive being older than those who were seronegative [mean age at testing (SD) 59.1 years (12.6) vs 47.7 years (14.3), p = 0.03]. Conclusions: In our cohort of MZ twins discordant for epilepsy, we found no evidence for an association between T. gondii seropositivity and epilepsy. Larger carefully controlled studies are warranted.

Description:By targeting the underlying etiology, precision therapies offer an exciting paradigm shift to improve the stagnant outcomes of drug-resistant epilepsies, including developmental and epileptic encephalopathies. Unlike conventional antiseizure medications (ASMs) which only treat the symptoms (seizures) but have no effect on the underlying disease, precision therapies have the potential to suppress not only the seizures but also disabling comorbidities, including cognitive and behavioral abnormalities, which share the same causative mechanisms. Monogenic epilepsies are an attractive target for precision therapies because of their well-defined molecular mechanisms which can be tested in vitro and can be counteracted by specific drugs. Unfortunately, however, for the vast majority of proposed precision therapies, the evidence for their clinical efficacy is either non-existent or limited to uncontrolled observational accounts. Everolimus is the sole precision therapy with a seizure-related indication with class I evidence of efficacy, highlighting the practical and ethical challenges in obtaining high-level evidence. Here, we review the evidence landscape for candidate precision therapies, including repurposed and innovative treatments currently in development, discuss lessons learned from their use, and highlight strategies to improve their application and evaluation in the clinical setting. PLAIN LANGUAGE SUMMARY: Precision therapies offer a new approach to treat drug-resistant monogenic epilepsies, that is, epilepsies caused by a defect in a single gene. Unlike traditional antiseizure medications, precision therapies target the cause of the disease and have the potential to improve not only seizure control but also concomitant conditions such as cognitive and behavioral disorders. To date, the evidence derived from the clinical use of most proposed precision therapies is limited. This review explores current evidence and strategies to advance their development.

Description:We describe FoundHaplo, an identity-by-descent algorithm that can be used to screen untyped disease-causing variants using single nucleotide polymorphism (SNP) array data. FoundHaplo leverages knowledge of shared disease haplotypes for inherited variants to identify those who share the disease haplotype and are, therefore, likely to carry the rare [minor allele frequency (MAF) ≤ 0.01%] variant. We performed a simulation study to evaluate the performance of FoundHaplo across 33 disease-harbouring loci. FoundHaplo was used to infer the presence of two rare (MAF ≤ 0.01%) pathogenic variants, SCN1B c.363C>G (p.Cys121Trp) and WWOX c.49G>A (p.E17K), which can cause mild dominant and severe recessive epilepsy, respectively, in the Epi25 cohort and the UK Biobank. FoundHaplo demonstrated substantially better sensitivity at inferring the presence of these rare variants than existing genome-wide imputation. FoundHaplo is a valuable screening tool for searching disease-causing variants with known founder effects using only SNP genotyping data. It is also applicable to nonhuman applications and nondisease-causing traits, including rare-variant drivers of quantitative traits. The FoundHaplo algorithm is available at https://github.com/bahlolab/FoundHaplo (DOI:10.5281/zenodo.8058286).

Description:Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes-KRIT1/CCM1, CCM2 and PDCD10/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM. In the familial cases, initial standard analyses had a low yield, we therefore searched for small copy number changes and deep intronic variants. Subsequently, pathogenic germline variants in KRIT1/CCM1 or CCM2 were identified in all 9 multiplex families. Single or multiple exon deletions or splice site variants in KRIT1/CCM1 were found in 3/9 families. Where cavernous malformation tissue was available, second hit somatic PIK3CA variants were identified in 4/7 individuals. These 4 individuals were from separate families with germline KRIT1/CCM1 variants. In 8/10 sporadic cases, we detected recurrent pathogenic somatic PIK3CA, MAP3K3 or CCM2 variants. All familial cases had multiple CCMs, whereas the sporadic cases had a single lesion only, which was in the temporal lobe in 9/10 individuals. Our comprehensive approach interrogating deep intronic variants combined with detection of small copy number variants warrants implementation in standard clinical genetic testing pipelines to increase diagnostic yield. We also build on the established second hit germline and somatic variant mechanism in some CCM lesions. Genetic diagnosis has clinical implications such as reproductive counselling and provides potential eligibility for precision medicine therapies to treat rapidly growing CCMs.