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We studied the distribution of germline and somatic variants in epilepsy surgery patients with (suspected) malformations of cortical development (MCD) who underwent surgery between 2015 and 2020 at University Medical Center Utrecht (the Netherlands) and pooled our data with four previously published cohort studies. Tissue analysis yielded a pathogenic variant in 203 of 663 (31%) combined cases. In 126 of 379 (33%) focal cortical dysplasia (FCD) type II cases and 23 of 37 (62%) hemimegalencephaly cases, a pathogenic variant was identified, mostly involving the mTOR signaling pathway. Pathogenic variants in 10 focal epilepsy genes were found in 48 of 178 (27%) FCDI/mild MCD/mMCD with oligodendroglial hyperplasia and epilepsy cases; 36 of these (75%) were SLC35A2 variants. Six of 69 (9%) patients without a histopathological lesion had a pathogenic variant in SLC35A2 (n = 5) or DEPDC5 (n = 1). A germline variant in blood DNA was confirmed in all cases with a pathogenic variant in tissue, with a variant allele frequency (VAF) of ~50%. In seven of 114 patients (6%) with a somatic variant in tissue, mosaicism in blood was detected. More than half of pathogenic somatic variants had a VAF < 5%. Further analysis of the correlation between genetic variants and surgical outcomes will improve patient counseling and may guide postoperative treatment decisions., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Defined as prospective single-patient crossover studies with repeated paired cycles of active and control intervention, N-of-1 trials have gained attention as an option to obtain high-quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well-powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N-of-1 trials in individuals with epilepsy., Methods: We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within-patient, multiple-crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N-of-1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N-of-1 trials identified and discuss future recommendations., Results: Five studies met our inclusion criteria. An additional multiple-crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N-of-1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off-label medications, neurostimulation or lifestyle intervention. Three of the five N-of-1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom-specific patient-reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden., Significance: The trials identified by our search exemplify how the N-of-1 design can be applied to assess interventions in individuals with epilepsy-related disorders. Future N-of-1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non-seizure outcome measures evaluable over short periods should be considered. Tailored N-of-1 methodology could pave the way to evidence-based, treatment selection for patients with rare epilepsies., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Pathogenic variants in SCN1A can give rise to extremely variable disease severities that may be indistinguishable at their first presentation. We aim to find clinical features that can help predict the evolution of seizures into Dravet syndrome and clinical features that predict cognitive outcome in Dravet syndrome. We specifically investigate the role of contraindicated medication (CIM) as a possible modifier of cognitive decline., Methods: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated. Clinical data were collected from medical records and semistructured telephone interviews. Cognitive function was classified by a child neurologist, neuropsychologist, and clinical geneticist. Several clinical variables, including duration of CIM use in the first 5 years of disease, were evaluated in univariate and multivariate analyses., Results: A longer duration of CIM use in the first 5 years after seizure onset was significantly associated with a worse cognitive outcome at time of inclusion, and with lower interpolated intelligence quotient/developmental quotient scores after the first 5 years of disease in Dravet syndrome patients. CIM use remained a significant predictor for cognitive outcome in a multivariate regression model, as did age at the first observation of developmental delay and age at first afebrile seizure. Age at first afebrile seizure was the most accurate predictor for evolution of seizures into Dravet syndrome for the complete cohort., Significance: Our data suggest that a longer CIM use in the first 5 years of disease can have negative effects on cognitive outcome in Dravet syndrome. An early diagnosis is essential to avoid these drugs. Furthermore, we identified age at first afebrile seizure as an important predictor for evolution of seizures into Dravet syndrome and for the severity of Dravet syndrome, which can be used to counsel parents of young patients with SCN1A-related seizures., (© 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objective: Phenotypes caused by de novo SCN1A pathogenic variants are very variable, ranging from severely affected patients with Dravet syndrome to much milder genetic epilepsy febrile seizures plus cases. The most important determinant of disease severity is the type of variant, with variants that cause a complete loss of function of the SCN1A protein (α-subunit of the neuronal sodium channel Nav1.1) being detected almost exclusively in Dravet syndrome patients. However, even within Dravet syndrome disease severity ranges greatly, and consequently other disease modifiers must exist. A better prediction of disease severity is very much needed in daily practice to improve counseling, stressing the importance of identifying modifying factors in this patient group. We evaluated 128 participants with de novo, pathogenic SCN1A variants to investigate whether mosaicism, caused by postzygotic mutation, is a major modifier in SCN1A-related epilepsy., Methods: Mosaicism was investigated by reanalysis of the pathogenic SCN1A variants using single molecule molecular inversion probes and next generation sequencing with high coverage. Allelic ratios of pathogenic variants were used to determine whether mosaicism was likely. Selected mosaic variants were confirmed by droplet digital polymerase chain reaction and sequencing of different tissues. Developmental outcome was classified based on available data on intelligence quotient and school functioning/education., Results: Mosaicism was present for 7.5% of de novo pathogenic SCN1A variants in symptomatic patients. Mosaic participants were less severely affected than nonmosaic participants if only participants with truncating variants are considered (distribution of developmental outcome scores, Mann-Whitney U, P = .023)., Significance: Postzygotic mutation is a common phenomenon in SCN1A-related epilepsies. Participants with mosaicism have on average milder phenotypes, suggesting that mosaicism can be a major modifier of SCN1A-related diseases. Detection of mosaicism has important implications for genetic counseling and can be achieved by deep sequencing of unique reads., (© 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Most patients with Dravet syndrome have de novo mutations in the neuronal voltage-gated sodium channel type 1 (SCN1A) gene. We report on two unrelated fathers with severe childhood epilepsy compatible with a possible diagnosis of Dravet syndrome, who both have a child with Dravet syndrome. Analysis of the SCN1A gene revealed a pathogenic mutation in both children. One father exhibited somatic mosaicism for the mutation detected in his son. A relatively favorable cognitive outcome in patients with Dravet syndrome patients may be explained by somatic mosaicism for the SCN1A mutation in brain tissue. A mild form of Dravet syndrome in adult patients is associated with a high recurrence risk and possibly a more severe epilepsy phenotype in their offspring., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)