TL;DR
Overall, current evidence does not support SCN1A or ABCB1 polymorphisms as standalone predictive biomarkers for paediatric DRE, and their relevance should be interpreted cautiously and, at most, considered within broader multi-marker and clinically integrated models.
ABCB1 gene polymorphisms have been associated with drug-resistant epilepsy (DRE). This integrative review evaluates the impact of key ABCB1 single nucleotide polymorphisms (SNPs)- C3435T (rs1045642), G2677T/A (rs2032582), and C1236T (rs1128503)-on the pharmacokinetics and therapeutic response to antiseizure medications (ASMs), including carbamazepine (CBZ), lamotrigine (LTG), and topiramate (TPM). Evidence suggests that these polymorphisms significantly affect CBZ and LTG efficacy by altering drug pharmacokinetics and increasing systemic exposure. In contrast, no consistent association has been observed between these variants and TPM response. These findings support the integration of pharmacogenetic information into clinical decisionmaking to optimize ASM therapy and reduce the risk of drug resistance in epilepsy management.
In two patients with SCN2A epileptic encephalopathy, treatment with personalized allele-selective antisense oligonucleotides led to a decrease in seizure frequency with a positive safety profile, and a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders is provided.
The observed burden of DRE and polytherapy supports the potential value of integrating therapeutic profiling, neuroimaging, and genomic testing in the etiological evaluation of patients with epilepsy and additional neurological features.
Pathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. We leveraged a large, multicentre international cohort comprising 282 individuals with pathogenic KCNQ2 variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed, including time-to-event and adjusted outcome analyses. SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, time-to-event analyses showed that early SCB initiation (≤1 month) was associated with earlier seizure offset. Early SCB initiation was also associated with significantly more favourable neurodevelopmental outcomes, including higher rates of attaining major motor milestones. This association remained significant after adjustment for seizure control by 1 month and total ASM burden. Considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation, suggesting that variant severity and additional genetic or biological modifiers contribute to outcome heterogeneity.Our results support the use of SCBs, particularly CBZ and OXC, as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE. Earlier SCB initiation was associated with earlier seizure offset and more favourable developmental outcomes, underscoring the importance of early genetic diagnosis and timely SCB therapy. We however emphasise that early treatment is not universally transformative and further prospective work, including exploration of targeted therapies and standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.
Five novel HCN1 variants are reported here and trends in ASM efficacy are similar to what has been observed in Dravet syndrome, another EIEE, raising questions about potential common pathogenic mechanisms at a cellular level.
Phenytoin is an antiepileptic drug with a narrow therapeutic window that is susceptible to drug interactions and other non-genetic factors, causing significant variability in therapeutic response among epilepsy patients. This systematic review aims to examine types of drug interactions affecting pharmacokinetics and pharmacodynamics of phenytoin, analyze their impact on therapeutic effectiveness and toxicity, and present the role of non-genetic factors in response variability as a basis for individualized therapy. Literature search was conducted using PRISMA framework across PubMed, Scopus, Web of Science, Science Direct, and Cochrane Library databases from 2015-2024, yielding 10 articles meeting inclusion criteria. Review findings indicated that 66 percent of patients experienced drug interactions with pharmacokinetic predominance reaching 81.4 percent, involving omeprazole, amlodipine, and aspirin as the most frequently interacting agents. Polytherapy doubled the risk of poor seizure control, while therapy duration exceeding one year correlated with executive function impairment. Interactions with herbal products such as noni reduced plasma levels to subtherapeutic ranges. Non-genetic factors, particularly drug interactions, contribute substantially to phenytoin response variability, making individualized therapy based on therapeutic drug monitoring and comprehensive evaluation of patient medication profiles essential for optimizing therapy safety and effectiveness
