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Page 2 of 18                                                    Orsini et al. J Transl Genet Genom 2018;2:16. I  https://doi.org/10.20517/jtgg.2018.14
                                                      [2]
               (AEDs) with different mechanisms of action , which can only provide control of symptoms (seizures).
               It is ineffective in a large percentage of patients and can sometimes also worsen seizures or cause adverse
                       [3]
               reactions . The heterogeneous etiology of epilepsy, the large number of different syndromes and seizure
               types, together with an individually variable response to AEDs, make the treatment of this condition still
                         [4,5]
               challenging . Moreover, adverse drug effects can be severe and life-threatening and some AEDs can even
                                                            [6]
               worsen seizure control and induce new seizure types . It is now well established that genetic factors are the
                                                                         [5]
               explication of the interindividual variability in the response to AEDs ; different genes can be mutated thus
               affecting drug pharmacokinetics, drug pharmacodynamics or causing epilepsy itself. In addition, studies have
                                                                                        [7]
               shown that epigenetic mechanisms are involved in brain modifications due to epilepsy . The term precision
               medicine aims to describe a personalization of treatments that ideally have to be targeted towards the precise
                                            [8]
               molecular pathogenesis of disease . Perhaps, the best realization of precision medicine is, to date, achieved
               in oncology specialties, which is called cancer precision medicine, a Barack Obama initiative in terms of
               funding. Epilepsy offers a good and challenging opportunity for the personalization of treatments for different
                                                                                                   [9]
               reasons: it affects ~1% of worldwide populations at the age of 20 years and 3% at the age of 75 years , many
               patients are still not seizure-free or have adverse drug reactions, and the genetic bases of many epileptic
               syndromes are well studied nowadays while new genes are discovered every day.

               To write this manuscript, a literature search was conducted through the PubMed database using the terms
               “epilepsy”, “pharmacogenomics”, “antiepileptic drugs”, “pharmacogenetics” and “diagnostic sequencing”
               from 1997 to 2018. Additional information was found in the reference lists of selected articles.


               PHARMACOGENOMICS IN EPILEPSY
               Genetic mutation can alter response to AEDs at both pharmacokinetic (e.g., polymorphism in gene involved
               in drug metabolism) and pharmacodynamic level (e.g., polymorphism in brain AED targets, such as ion
               channels). Other mechanisms involved are mutations in genes causing epilepsy or the modification of the
               expression of enzymes and other molecules involved in the pathogenesis of pharmacoresistance or adverse
               drug reactions [10,11] . Pharmacogenomics is the science that studies how these genetic differences affect drug
                                                                                [11]
               response both in terms of efficacy and susceptibility to adverse drug reactions . It is in the last two decades
               that advances in genetic testing have led to a systematic search for gene variations that could predict drug
               response and ultimately improve the efficacy and safety of epilepsy therapies. As we already know, adverse
               drug effects can be severe and life-threatening and some AEDs can even worsen seizure control and induce
                              [6]
               new seizure types .

               Genetic influences on AED metabolism
               It is now well established that the clearance of most AEDs is linked to cytochrome P450 (CYP) enzymes
               activity. Polymorphisms of the gene encoding CYP enzymes can alter their activity, thus affecting serum
                                                       [12]
               AED concentrations and lead to drug toxicity  [Table 1]. A good example is phenytoin (first generation
               AED) which is metabolized primarily by CYP2C9 and also by CYP2C1. Some individuals have CYP2C9
               polymorphisms, which cause a reduced activity of the enzyme thus leading to low phenytoin clearance,
               higher serum phenytoin concentrations and a greater risk of central nervous system adverse effects.
               CYP2C9*2 (rs1799853) and CYP2C9*3 [rs1057910(C)] are the best documented of these polymorphisms [13,14] .
               To the best of our knowledge, pre-treatment testing for CYP2C9 variants is not considered as routine practice
               in any center. In our opinion, the best practice remains the clinical monitoring of signs of toxicity and of
                                                                                                       [15]
               serum drug levels and it is also important to consider drug interactions if patients are taking other AEDs .

               Another AED that has shown reduction of clearance due to genetic polymorphisms is phenobarbital (first
               generation AED). The enzyme involved is CYP2C19, with a difference of up to about 20%-50% in the re-
                                 [16]
               duction of clearance . To the best of our knowledge, there is no evidence that genetic testing improves
               the outcome of phenobarbital therapy compared with clinical observation and monitoring of serum drug
                           [17]
               concentration . A Japanese study showed that CYP2C19 and CYP3A5 polymorphisms are involved in the
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