Heterogeneity of monogenic epilepsy in loci, phenotypes, and treatment approaches

Monogenic epilepsies are a group of rare disorders that manifest in early childhood and are usually associated with neurodevelopmental abnormalities and poor drug response. The field of genetic epilepsy is continuously evolving in alignment with the vast advancements in genetic testing in the last decade. Recent studies and databases were reviewed to explore the latest updates in monogenic epilepsies. This literature review reveals the remarkable progress in understanding monogenic epilepsy classification, genetic aetiologies, and treatment over the past decade. The International League Against Epilepsy classification system continues to evolve, providing increasingly precise diagnostic frameworks that incorporate genetic and etiologic information. The genetic landscape of epilepsy has expanded dramatically, with around 2000 genes now associated with seizures and/ or epilepsy pertaining to complex and overlapping neuronal networks. Besides the locus heterogeneity, monogenic epilepsy phenotypes exhibit phenotypic variabilities due to differences in pathogenic causative variants as well as unique genetic backgrounds in affected individuals. Identification of the underlying molecular aetiology permits personalized management approaches which are currently limited approved agents. Genes encoding antiepileptic drug targets, metabolic enzymes and transporters are additionally implicated in the precision medicine. Current knowledge in Locus heterogeneity should be addressed in epilepsy phenotypes to avoid extensive diagnostic delays particularly in cases that can be rescued with available management options.