The pharmacogenomics of epilepsy

Abstract

Genetic factors contribute to the high interindividual variability in response to antiepileptic drugs. However, most genetic markers identified to date have limited sensitivity and specificity, and the value of genetic testing in guiding antiepileptic drug (AED) therapy is limited. The best defined indication for testing relates to HLA-B*15:02 genotyping to identify those individuals of South Asian ethnicity who are at high risk for developing serious adverse cutaneous reactions to carbamazepine. The indication for HLA-A*31:01 testing to identify individuals at risk for skin reactions from carbamazepine, or for CYP2C9 genotyping to identify individuals at risk for serious skin reactions from phenytoin is less compelling. The use of genetic testing to guide epilepsy treatment is likely to increase in the future, as better understanding of the function of epilepsy genes will permit the application of precision medicine targeting the biological mechanisms responsible for epilepsy in the specific individual.

Keywords:

• adverse drug reactions
• antiepileptic drugs
• efficacy
• epilepsy
• genetics
• pharmacogenomics
• pharmacoresistance

Financial & competing interests disclosure

E Perucca has received research grants from the EU, the Italian Medicines Agency, the Italian Ministry of Health and the Italian Ministry for Education, University and Research. E Perucca has also received speaker’s or consultancy fees from Biopharm Solutions, Eisai, GW Pharma, Sun Pharma, Takeda and UCB Pharma. V Franco is a former employee of Eisai. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Genetic factors contribute to the wide variability in response to AEDs.

• Genetic influences on AED pharmacokinetics relate primarily to polymorphisms of drug metabolizing enzymes.

• The CYP2C9 polymorphism impacts particularly on response to phenytoin, with individuals carrying defective CYP2C9 allele variants being more susceptible to phenytoin-induced serious cutaneous reactions.

• Despite intensive research, no reliable genetic marker predictive of AED resistance has been identified.

• Several HLA alleles identify individuals at high risk for developing Stevens–Johnson syndrome and Toxic Epidermal Necrolysis induced by carbamazepine, the most important being HLA-B*15:02 and HLA-A*31:01.

• Screening for HLA-B*15:02 is recommended in candidates to carbamazepine therapy from Han Chinese and South Asian ethnic groups, in whom this allele is frequent.

• Carbamazepine should be avoided in HLA-B*15:02-positive individuals, who are also at higher risk of developing serious cutaneous reactions to oxcarbazepine, phenytoin and lamotrigine.

• The need for systematic screening for HLA-A*31:01 before initiating carbamazepine therapy has not been comprehensively assessed.

• An increasing number of epilepsy genes are being discovered, which collectively are responsible for causing epilepsy in a sizeable proportion of individuals.

• Unraveling the molecular mechanisms of genetic epilepsies will permit effective personalized therapies targeting the relevant specific functional defect.

Notes