Epilepsy comprises a series of chronic neurological disorders characterized by seizures. Epileptic seizures are related to abnormal and uncontrolled neuronal activity of the brain. It is the most common neurological disorder after stroke 1. Seizures are normally recurrent with no immediate primary cause, but genetic abnormalities could be one of the possible causes 2. Genetic mutations can lead to the onset of epilepsy 3. Epilepsy can occur as the result injuries to the nervous system, stroke, tumors or infection 4. Epidemiological studies have shown that over 50 million people are affected by epilepsy worldwide 5 and the treatment focus initially on seizure suppression or prorogation 6.

One of the most important pathophysiology of epilepsy is the blood brain barrier (BBB) permeability. It is known that BBB contributes to epileptogenesis in symptomatic epilepsies. Genetic components that predict epilepsy predisposition and antiepileptic drugs response would lead to the development of promising treatment and a better prognosis of the disease 7. The onset of epilepsy can be directly or indirectly linked to genetic disorders. It could be related to a single gene, a combination of genetics and environmental factors, mutations in the nuclear or mitochondria DNA or chromosomes anomalies. Around a third of all patients with epilepsy present a drug-refractory response, which is likely related to a genetic multifactorial feature. The up-regulation of drug transporters at the blood-brain barrier reduces anti-epileptic drugs accumulation favoring drug resistance in epilepsy treatment. Moreover, the complex trait of epilepsy and the anti-epileptic drugs response are also influenced by epigenetic, developmental, and environmental factors 8.

Epilepsy syndromes are frequently linked to metabolic abnormalities such as those related to mitochondrial metabolism, dysfunction in the regulation of essential metabolites, for example, folate, cholesterol, and amino acids. The identification of metabolic anomalies in patients with epilepsy may lead to a more efficient treatment and prognosis 5. The epilepsy diagnosis syndrome can be a difficult medical task. The most used methods for diagnosing epilepsy today is electroencephalogram; complete blood count and chemistry panel are complimentary to the diagnosis. Regarding the treatment, it is based on seizure medications such as anticonvulsant, ketogenic Diet, nerve stimulation and surgery 7.

Polymorphisms in genes that code for neurotransmitters and neuropeptides may be involved in the pathophysiology of epilepsy as well. It has been shown that anomalies in glutamatergic and GABAergic synaptic transmission in the origin of the paroxysmal depolarization shifts is related to the onset of epileptic seizures. Several genes and their variants are under investigation whether they could affect the onset of epilepsy 9,10,11,12,13. The brain-derived neurotrophic factor (BDNF) gene regulates processes related to brain development, synaptic activity, cognition and memory 9. BDNF is target of studies regarding the gradual process by which a normal brain develops epilepsy 10. Other factors are closely associated to the anti-epileptic drug resistance, such as the p-glycoprotein, a drug efflux transporter encoded by ATP-binding cassette subfamily B member 1 (ABCB1) 11, a highly polymorphic gene with more than 50 variants within the coding region. In addition, polymorphisms in N-acetyltransferase-2 (NAT2) 12 or thiopurine-S-methyltransferase (TPMT) 13 are well-investigated and they play a role in drug resistance in a variety of diseases, including neurological ones. The most common method for identifying genetic polymorphisms related to epilepsy is based on polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism analysis and followed by gel electrophoresis 11.

Drug response is governed by interactions of several genes and environmental factors. CYP2C19 and CYP2C9are polymorphic drug metabolizing enzymes also associated to drug response. Heterozygous CYP2C9 was down-regulated in Caucasians epileptic patients that do not respond to anti-epileptic drug treatment 14 . It has been suggested that CYP2C9 contribute to a lower risk of developing drug resistance in epileptic patients 15. Another gene implicated in the epilepsy susceptibility is the gamma-aminobutyric acid A receptor (GABRG2) 16. GABRG2 acts as an inhibitory neurotransmitter in the central nervous system and polymorphism within its sequence increases susceptibility to idiopathic epilepsy 17.

Here, we explore the features of the multifactorial genetic basis of epilepsy and its resistance against anti-epileptic drugs. Polymorphisms in relevant genes related to epilepsy are highlighted in order to discuss possible risk factors for the disease and point out alternatives to improve prognosis, therapy and the quality of life of patients. To achieve this goal, the present review focuses on the role of genetic polymorphisms of the ABCB1, BDNF and CYP2C9 genes (Figure 1). The scientific literature databases PubMed, EMBASE, and Google Scholar were searched using keywords “epilepsy gene polymorphism” “ABCB1 and epilepsy” “BDNF and epilepsy” “CYP2C9 and epilepsy” “epilepsy and drug resistance”.

Early identification of risk factors for epilepsy should optimize treatment and prognosis. The characterization of genetic polymorphism contribute to the selection of the most promising antiepileptic therapy and avoidance of drug resistance. The necessity of developing biomarkers to estimate the risk of inducing drug resistance is real once variation in drug metabolizing genes have a clinical impact on the anti-epileptic drug therapy.

The author declares no financial support was sought in this project and there is no conflicts of interest.