Genetic Landscape of Common Epilepsies: Advancing towards Precision in Treatment

Abstract

Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types: common and rare epilepsies. Common epilepsies affecting nearly 95% people with epilepsy, comprise generalized epilepsy which encompass idiopathic generalized epilepsy like childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy and epilepsy with generalized tonic-clonic seizure on awakening and focal epilepsy like temporal lobe epilepsy and cryptogenic focal epilepsy. In 70% of the epilepsy cases, genetic factors are responsible either as single genetic variant in rare epilepsies or multiple genetic variants acting along with different environmental factors as in common epilepsies. Genetic testing and precision treatment have been developed for a few rare epilepsies and is lacking for common epilepsies due to their complex nature of inheritance. Precision medicine for common epilepsies require a panoramic approach that incorporates polygenic background and other non-genetic factors like microbiome, diet, age at disease onset, optimal time for treatment and other lifestyle factors which influence seizure threshold. This review aims to comprehensively present a state-of-art review of all the genes and their genetic variants that are associated with all common epilepsy subtypes. It also encompasses the basis of these genes in the epileptogenesis. Here, we discussed the current status of the common epilepsy genetics and address the clinical application so far on evidence-based markers in prognosis, diagnosis, and treatment management. In addition, we assessed the diagnostic predictability of a few genetic markers used for disease risk prediction in individuals. A combination of deeper endo-phenotyping including pharmaco-response data, electro-clinical imaging, and other clinical measurements along with genetics may be used to diagnose common epilepsies and this marks a step ahead in precision medicine in common epilepsies management.

The newest TRP channelopathy: Gain of function TRPM3 mutations cause epilepsy and intellectual disability

“…In epilepsy, normal electrical activity in the brain is disrupted by sudden, synchronized bursts, resulting in recurrent seizures. Mutations in ion channels can cause epilepsy [66]. Generally, either a loss of function of K + channels, or a gain of function of Na + or nonselective cation channels increases excitability of neurons and thus can lead to epilepsy.…”

Regulation of microRNA Expression in Sleep Disorders in Patients with Epilepsy

“…Less documented for the pathogenesis of this epilepsy syndrome are mutations within KCNJ10 and CACNA1A. Seizures are sometimes provoked by fatigue, sleep deprivation, emotions, and alcohol abuse [ 40 , 41 ] ( Table 1 ).…”

Anormalidades da formação cerebral e os transtornos de desenvolvimento neural

“…Em casos de epilepsias raras, o fator genético geralmente é uma característica que afeta um único gene (mutação única, ou causa monogênica). Já em casos de epilepsias comuns, diversas características genéticas podem atuar simultaneamente para a manifestação da epilepsia (causa poligênica) e em conjunto com fatores ambientais (não genéticos) (THAKRAN et al, 2020). Neste artigo, o tipo de epilepsia que interessa é a epilepsia que acompanha transtornos do desenvolvimento neural, ou seja, um tipo de epilepsia que faz parte de um quadro clínico que engloba outras manifestações (por isso chamado de síndrome), de causa genética ou não.…”