Presentations

Abstract

Introduction: Sudden Unexpected Death in Epilepsy (SUDEP) is a complication of epilepsy where otherwise healthy patients die suddenly, most often at night while the patient sleeps. Previous studies have found that 1/1000 patients with epilepsy die from SUDEP every year. Multiple tonic-clonic seizures are one of the main risk factors for SUDEP. Although the mechanism behind SUDEP is not yet fully understood, there are many hypothesized mechanisms of SUDEP. Some of the most promising include the idea that respiratory distress, cardiac failure, or tonic-clonic seizures during sleep lead to SUDEP in patients. Thus, this review aims to establish a genetic link between generalized seizures and SUDEP.

Main Body: This review obtained data from several articles and a database. Published in 2023, a genome-wide association study (GWAS) was conducted to analyze 29,944 patients with epilepsy. This study found that 29 genes are associated with epilepsy and other complications, 23 of which are associated with genetic generalized epilepsy (GGE). This review identifies the relationship between mutations in these 23 genes and SUDEP. In a 2016 study, mutations in the DEPDC5, SCN2A, SCN1A, GAGRB3, SCN1B, KCNQ2, or PAFAH1B1 genes were found in 25% of SUDEP patients analyzed, and 15% had mutations in the KCNH2, RYR2, SCN5A, AKAP9, HCN4, or TRPM4 genes. Both SCN1A and RYR2 were categorized into the 'GGE' phenotype in the previously mentioned 2023 GWAS. Additionally, a study published in 2022 states that mutations in SCN1A are found in 80% of patients with Dravet Syndrome, for which there is a markedly increased risk of SUDEP. Another gene found to be associated with SUDEP is SCN8A, as mentioned in a different study published in 2023. Like the aforementioned 2016 study, this 2023 study also found that patients who suffered from SUDEP had mutations in SCN2A or SCN1A, along with STXBP1. Another of the 23 genes from the GWAS study that was found to be associated with SUDEP is GRIK1. This was discovered by a research team analyzing data from 8 SUDEP patients. This study was published in 2018. Thus, this review found that 4/23 (17%) of the genes found by the GWAS to be associated with GGE are also related to SUDEP, including mutations in RYR2, SCN1A, SCN8A, and GRIK1. This also means that 19/23 (83%) of the genes found to be associated with GGE are not related to SUDEP. These genes are CHRM3, BCL11A, POU3F3, GLS, STAC, CACNA2D2, PCDH7, KCNN2, SPOCK1, PTPRK, SUGCT, RMI1, KCNIP2, RBFOX1, ARHGEF15, CDK5RAP3, AP3D1, TMPRSS15, and FAM19A5. In addition, the previously mentioned study published in 2016 discovered a possible relationship between mutations in genes associated with cardiac arrhythmias and patients who suffered from SUDEP. This study performed exome sequencing and analysis on 61 SUDEP patients. These researchers looked for specific gene mutations that are already known to be associated with Long QT Syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and other cardiac arrhythmias. 7% of SUDEP patients analyzed in this study were found to have a mutation in either the KCNH2, KCNQ1, or SCN5A genes, all of which are highly associated with LQTS (70% of instances). 15% of SUDEP patients were found to have mutations in the KCNH2, RYR2, SCN5A, AKAP9, HCN4, or TRPM4 genes, all of which are associated with cardiac arrhythmias. RYR2 is also associated with CPVT. In addition, the researchers also analyzed genes that are already known to be associated with epilepsy for both new and previously discovered mutations. 25% of SUDEP patients had mutations in the DEPDC5, SCN2A, SCN1A, GAGRB3, SCN1B, KCNQ2, or PAFAH1B1 genes. Finally, 10% of SUDEP patients had mutations in DEPDC5, the most prevalent out of all the genes.

Conclusion: Despite its fatality and prevalence within the population of epilepsy patients, SUDEP remains understudied. Though there are several theories postulated surrounding its mechanism, there is little case-based data supporting many of these theories. This review suggests that there may be a genetic component that places patients with epilepsy at risk. Mutations in 4 genes, RYR2, SCN1A, SCN8A, and GRIK1, are associated with both genetic generalized epilepsy and SUDEP. Additionally, several genes known to be associated with malignant cardiac arrhythmias were found in patients who suffered from SUDEP. Thus, additional research needs to be done to investigate these relationships and determine if there may be a genetic mechanism behind SUDEP. Identifying the mechanism behind SUDEP will bring us one step closer to developing a preventative measure for this seemingly silent complication of epilepsy.