Identifying mutations in epilepsy genes: Impact on treatment selection

Piero Perucca, Emilio Perucca

Research output: Contribution to journalReview articlepeer-review


The last decade saw impressive advances not only in the discovery of gene mutations causing epilepsy, but also in unraveling the molecular mechanisms underlying the clinical manifestations of the disease. Increasing evidence is emerging that understanding these mechanisms is relevant for selection of the most appropriate treatment in the affected individual(s). The present article discusses the therapeutic implications of epilepsy-causing variants affecting a broad range of targets, from ion channels to genes controlling cellular metabolism and cell signaling pathways. Identification of a precise genetic etiology can direct physicians to (i) prescribe treatments that correct specific metabolic defects (e.g., the ketogenic diet for GLUT1 deficiency, or pyridoxine for pyridoxine-dependent epilepsies); (ii) avoid antiepileptic drugs (AEDs) that can aggravate the pathogenic defect (e.g., sodium channel blocking drugs in SCN1A-related Dravet syndrome), or (iii) select AEDs that counteract the functional disturbance caused by the gene mutation (e.g., sodium channel blockers for epilepsies due to gain-of-function SCN8A mutations). In some instances, different pathogenic variants of the same gene can have opposite functional effects, which determines whether certain treatments can be beneficial or deleterious (e.g., gain-of-function versus loss-of-function variants in SCN2A determine whether sodium channel blockers improve or worsen seizure control). There are also cases where functional disturbances caused by the gene defect may not be corrected by existing AEDs, but can be countered by medications already available in the market for other indications (e.g., memantine has been used to treat the epileptic encephalopathy caused by a specific gain-of-function GRIN2A mutation), thus making 'drug repurposing' a valuable tool for personalized epilepsy therapies. As our understanding of pathogenic mechanisms improve, opportunities arise for development of treatments targeting the specific gene defect or its consequences. Everolimus, an mTOR inhibitor approved for the treatment of focal seizures associated with tuberous sclerosis complex, is an example of a medication targeting the etiological mechanisms of the disease. Several treatments aimed at correcting specific pathogenic defects responsible for rare genetic epilepsies are currently in development, and range from traditional small molecules to novel approaches involving peptides, antisense oligonucleotides, and gene therapy.

Original languageEnglish
Pages (from-to)18-30
Number of pages13
JournalEpilepsy Research
Publication statusPublished - May 2019


Dive into the research topics of 'Identifying mutations in epilepsy genes: Impact on treatment selection'. Together they form a unique fingerprint.

Cite this