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Rational Small Molecule Treatment for Genetic Epilepsies.

ABSTRACT: Genetic testing has yielded major advances in our understanding of the causes of epilepsy. Seizures remain resistant to treatment in a significant proportion of cases, particularly in severe, childhood-onset epilepsy, the patient population in which an underlying causative genetic variant is most likely to be identified. A genetic diagnosis can be explanatory as to etiology, and, in some cases, might suggest a therapeutic approach; yet, a clear path from genetic diagnosis to treatment remains unclear in most cases. Here, we discuss theoretical considerations behind the attempted use of small molecules for the treatment of genetic epilepsies, which is but one among various approaches currently under development. We explore a few salient examples and consider the future of the small molecule approach for genetic epilepsies. We conclude that significant additional work is required to understand how genetic variation leads to dysfunction of epilepsy-associated protein targets, and how this impacts the function of diverse subtypes of neurons embedded within distributed brain circuits to yield epilepsy and epilepsy-associated comorbidities. A syndrome- or even variant-specific approach may be required to achieve progress. Advances in the field will require improved methods for large-scale target validation, compound identification and optimization, and the development of accurate model systems that reflect the core features of human epilepsy syndromes, as well as novel approaches towards clinical trials of such compounds in small rare disease cohorts.

SUBMITTER: Goldberg EM

PROVIDER: S-EPMC8609069 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Rational Small Molecule Treatment for Genetic Epilepsies.

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