Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

Abstract

Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

The Metabolic Role of Ketogenic Diets in Treating Epilepsy

“…Epileptic surgery is among the most successful methods to achieve a seizure-free status [ 32 , 33 ]. Approximately 50%–80% of patients became seizure-free after surgery [ 34 ].…”

Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures

“…At our institution, rapid whole-genome sequencing performed on a subset of neonates with first-time seizures led to an increase in our diag-nostic yield for what was previously termed idiopathic neonatal seizures. 5 We believe optimal practice in future studies should include whole-genome sequencing as the standard of care.…”

“…Children with neonatal-onset epilepsy should continue receiving ASM tailored to treat the underlying causative mechanism. The question of how differences in known epilepsy genes may alter the risk of epilepsy after acute seizures is one that we have explored 5 and deserves further study. The term idiopathic neonatal seizures should be discouraged.…”

“…In another autopsy series, such rare nonspe-cific inflammatory phenomena were also seen in some muscle and nerve specimens, and although they were liberally labeled myositic without myositis, they were cautiously interpreted as cytokine-released changes. 5 Without costaining MHC-I with lymphoid subsets to demonstrate T-cellmediated or macrophage-mediated myocytotoxicity, the contention that patients who were comatose with COVID-19 had myositis as an immune response against SARS-CoV-2 is unsubstantiated. The absence of complement deposits also supports the absence of ongoing muscle fiber necrosis.…”

“…Myositis is defined based on combination of muscle weakness, elevated creatine kinase, and MHC-I or CD8 or macrophage-mediated or complement-mediated cytotoxicity 4 ; none of those elements were concurrently present not only in the authors' autopsies 1 but also in the other autopsy study. 5 The few noted natural killer cells are likely not immunologically associated with muscle fiber cytotoxicity, because innate immunity is not involved in myositis.…”