Personalized medicine in epilepsy patients

Abstract

The large number of different syndromes and seizure types together with an interindividual variable response to antiepileptic drugs (AEDs) make the treatment of epilepsy challenging. Fortunately, the last few years have been characterized by a huge interest in epilepsy genetics and two methods, genome-wide analyses and next-generation sequencing, have definitely given the possibility to write a new chapter in the book of treatment of epilepsy, the chapter on precision medicine. Epilepsy offers a good opportunity for the personalization of therapy if we consider that at least one third of epileptic patients do not achieve complete seizure control with the currently available pharmacological treatments, treatment is still often empirical and precise therapy, based on the pathogenesis and the mechanism of each AED is not generally possible because this mechanism often remains incompletely known. In addition, new drugs are often not targeted but developed using in vivo seizure models, to be potentially used by the largest number of patients. This method leads to a therapy aimed at treating the symptoms and the seizures rather than the single pathogenic mechanism of each seizure type or syndrome. In this narrative review, we summarize the established evidence regarding pharmacogenomics in epilepsy and discuss the basis of precision medicine.

From Genetic Testing to Precision Medicine in Epilepsy

“…The term precision medicine aims to describe the treatment of patients with therapy targeted to their specific pathophysiology, in other words, a personalization of treatments that ideally should be targeted towards the precise molecular pathogenesis of disease [9,10]. This approach would allow physicians to predict more accurately which treatment and prevention strategies for a particular disease will work in specific groups of people.…”

Identification of the ZEB2 gene as a potential target for epilepsy therapy and the association between rs10496964 and ZEB2 expression

“…Although drug treatment has evolved rapidly in recent years, approximately 30% of patients still suffer from recurrent seizures, resulting in a medically severe and socially disabling condition. 24 , 25 However, the personalization of treatments targeted toward the precise molecular pathogenesis of an illness 26 , 27 may be able to avoid such conditions in the future. A previous study did not find ZEB2 to be a potential target for epilepsy treatment, and did not identify any variants regulating ZEB2 expression.…”

Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters

“…ABCC2 common variants c.1249G>A (p.V417I, rs2273697) and c.3972C>T (p.I1324I, rs3740066) showed no significant associations with the responsiveness to anticonvulsant drugs, especially CBZ, while only c.-24C>T (5′UTR, rs717620) polymorphism was a risk factor for resistance to therapy in epileptic patients [ 124 ]. Indeed, nonsynonymous polymorphism c.1249G>A was associated with reduced CBZ transport but not with drug response in epilepsy patients, while the A-allele of ABCC2 single nucleotide polymorphism c.1249G>A is related to neurological ADRs [ 125 , 126 , 127 ]. In addition, carriers of ABCC2 1249G>A variant were more frequently responders to antiepileptic drugs especially CBZ or oxcarbazepine; conversely, ABCC2 -24C>T and 3972C>T did not influence CBZ response [ 128 , 129 ].…”