Pharmacogenomics and epilepsy

Epilepsy can manifest in various ways and may not respond to ASMs in the same way for everyone. This highlights the importance of personalized treatment strategies. Pharmacogenomics makes it possible to customize ASM therapy based on an individual’s genetic profile, leading to better treatment outcomes and signaling a new era in epilepsy care [6]. This is particularly important for patients with DRE. Studies have shown the crucial role of genetic factors in determining ASM effectiveness and safety, making pharmacogenomics a key player in customizing epilepsy management [4].

The literature on epilepsy’s pathophysiology shows that it is a complex condition with a strong genetic component [7]. Therefore, epilepsy care should adopt a precision medicine approach that takes into account an individual’s unique genetic makeup. Genome-wide association studies have identified genetic markers that influence how patients respond to ASMs in genetically generalized epilepsies [3]. This highlights the potential of pharmacogenomics to revolutionize epilepsy treatment by enabling personalized drug therapy.

Polymorphisms versus disease-associated mutations

Understanding the difference between polymorphisms and disease-associated mutations is essential to comprehend genetic influences on drug response and disease susceptibility. Polymorphisms, which are prevalent in over 1% of the population, are single or multiple nucleotide variations that significantly affect drug action due to their genetic substrates. In contrast to these prevalent variations, mutations are infrequent but can produce a diverse range of phenotypic manifestations, affecting protein function and subsequently influencing drug interactions. This complexity highlights both the challenges and potential of genetically driven pharmacology for developing tailored treatments [8].

DRE challenges a significant fraction of epilepsy patients, with about one-third not responding to multiple ASMs. The exploration of genetic variations, including those in the ABCB1 and CACNA1H genes, reveals the complex genetic basis of DRE and emphasizes the need for individualized approaches [9]. As research continues to uncover the genetic factors associated with the response to ASMs, the integration of pharmacogenomic data into clinical practice is becoming increasingly important. This presents opportunities for pharmacogenomics to guide the development of targeted therapies for epilepsy, especially in the context of DRE [10].

Neuroprotective pharmacotherapies through pharmacogenomics

Pharmacogenomics has made significant progress in promoting neuroprotection for epilepsy patients. The goal is to not only improve seizure management but also preserve neurological function. Metformin is a promising example of a drug that has demonstrated neuroprotective effects in epilepsy. By activating AMP-activated protein kinase (AMPK) and possessing antioxidant properties, it has the potential to be an effective treatment beyond traditional ASMs [11]. Moreover, targeting neuroinflammatory pathways in epileptogenic brain areas suggests a new direction in overcoming the limitations of current medications [12]. Novel therapeutic strategies like rhein, known for its anti-inflammatory properties, demonstrate anticonvulsant and neuroprotective effects by inhibiting specific signaling pathways and reducing cytokine secretion [13]. These developments underline the revolutionary potential of pharmacogenomics in evolving epilepsy treatment into a more individualized and neuroprotective approach.

Metabolism

The metabolism of ASMs is profoundly affected by genetic polymorphisms in the CYP2C9 and CYP2C19 genes, with significant implications for drug levels, efficacy, and adverse effects [14]. Recent studies have highlighted the influence of CYP2C93 and CYP2A64 variants on plasma concentrations of valproic acids, suggesting that carriers of these alleles might require dosage adjustments to maintain therapeutic efficacy and avoid toxicity as shown in Table 1.

Research conducted on the metabolism of phenytoin among Middle Eastern and North African populations found that the CYP2C9*2 and CYP2C9*3 variants significantly reduced the rate of metabolism. However, the effects of the CYP2C19*2 and CYP2C9*3 variants on metabolism were not clear, indicating that the function of CYP2C9 variants plays a crucial role in determining the pharmacokinetics of phenytoin [15, 16]. Furthermore, recent studies have emphasized the importance of genetic testing in optimizing phenytoin therapy. It has been revealed that individuals who are homozygous or heterozygous carriers of CYP2C19 mutations require significantly reduced maintenance doses. In addition, a meta-analysis focused on the relationship between the CYP2C93 variant and the risk of phenytoin-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) has highlighted the clinical significance of CYP2C9 genotyping in minimizing the risk of severe cutaneous adverse reactions. Table 1 depicts the overall summary of genetic determinants of valproic acid, along with their specific genetic polymorphism and implications [17].

Drug transporters

The ABCB1 gene, encoding P-glycoprotein, influences the efflux of several ASMs from the central nervous system. Polymorphisms such as 3435C>T have been associated with varying drug transportation activity, leading to differences in drug response among patients with epilepsy. This particularly impacts drugs like carbamazepine (CBZ) and lamotrigine [18]. A comprehensive analysis encompassing 18 studies was conducted with 3,293 epilepsy patients, revealing the significant role of ABCB1 c.3435C>T polymorphism in CBZ metabolism and resistance. It was found that individuals carrying the T allele had adjusted concentrations of CBZ significantly different from those with the C allele. This indicated that this polymorphism directly affects CBZ plasma levels and in turn, its efficacy and side-effect profile. Moreover, the EPHX1 c.416A>G polymorphism was linked to the metabolism of CBZ, specifically its conversion to CBZ-10,11-trans-dihydrodiol (CBZD). These findings emphasize the complex genetic factors that influence ASM metabolism and resistance, highlighting the need for a more personalized approach to epilepsy treatment that takes into account individual genetic profiles (Table 2) [19].

Studies further elaborated on the relationship between ABCB1 polymorphisms and CBZ metabolism through a meta-analysis of 12 studies involving 2,126 epilepsy patients. This analysis highlighted the TC genotype of the rs1045642 polymorphism as significantly associated with decreased CBZ plasma concentration, suggesting an alteration in the drug’s efflux mechanism that could impact its therapeutic efficacy. It was also found that the AG genotype of the rs2032582 polymorphism correlated with increased CBZ concentration, pointing towards genetic variants that modulate the pharmacokinetics of CBZ integration of pharmacogenetic testing in the clinical management of epilepsy to achieve optimal treatment outcomes (Figure 2) [20].

Display full size

Figure 2. 

Genetic polymorphism, drug transporter, and drug response. This figure highlights genetic influences on drug response, emphasizing P-glycoprotein’s role as a vital drug transporter. Polymorphisms in P-glycoprotein can affect carbamazepine metabolism, requiring dose adjustments and genetic testing for safe and effective antiseizure medication use. Notably, the 3435C>T variant of the ABCB1 gene influences P-glycoprotein expression, impacting drug response and necessitating consideration of individual genetic makeup

A study investigated the influence of the ABCB1 C3435T polymorphism on anticonvulsant drug resistance. The study emphasized the role of the gene in regulating drug efflux across the blood-brain barrier. The meta-analysis suggested that individuals with the 3435CC genotype may experience a higher efflux of anticonvulsants from brain tissue, which could contribute to pharmaco-resistant. This finding highlights the importance of genetic testing in identifying patients at risk of DRE [21].

In silico functional network analysis

In 2023, Khatri and colleagues [24] conducted a study that used an in silico-based approach to identify new targets associated with the SCN1A gene that could potentially be used to develop ASM with minimal side effects and maximum efficacy. The study examined 157 genes related to epilepsy and, through network analysis, identified proteins encoded by the SCN9A, HCN2, and FGF12 genes as potential targets. This investigation offers a unique perspective on identifying targets for ASM and highlights the potential of using genetic and network analyses to uncover new treatment options for epilepsy [24].

Expanding the drug spectrum

Newer medications such as levetiracetam, lacosamide, and perampanel are being researched in addition to the already mentioned ASMs. For instance, genetic factors that influence SV2A (the synaptic vesicle glycoprotein targeted by levetiracetam) and collagen-related genes that impact lacosamide’s modulation of sodium channels provide new possibilities for personalized epilepsy therapy [25].

Epilepsy genes and precision medicine in epilepsy

Personalized medicine has increasingly influenced the management of epilepsy. A deeper understanding of epilepsy genetics, coupled with advancements in in vivo and in vitro genetic frameworks, has propelled the use of genetic approaches in devising targeted therapies. Identifying genetic factors underlying epilepsy has significantly expanded our knowledge of epileptogenic mechanisms. However, achieving positive outcomes through this approach is complex. The interaction of genetic variants within the entirety of the genome and the presence of adaptive and compensatory changes can render the direct correction of the identified dysfunction challenging. This highlights a critical consideration in precision medicine. Therefore, treatments must target the mechanisms directly associated with causative genetic alterations.

Recent investigations into precision medicine therapies have provided promising directions. For instance, patients with GLUT1 deficiency have shown remarkable improvement on a ketogenic diet, which addresses the transport dysfunction by providing an alternative energy source through ketogenesis, thereby managing seizures and paroxysmal activities. Similarly, pyridoxine-dependent epilepsy, linked to antiquities deficiency, responds well to vitamin B6 therapy, showing the direct impact of tailored nutrient supplementation on genetic epilepsies. Moreover, the application of sodium channel blockers in cases with KCNQ2, SCN1A, and SCN2A mutations, and the use of mTOR-inhibitors in mTORopathies, exemplify the repurposing of available treatments based on genetic insights as shown in Table 3 [30].

Several studies have highlighted the role of advanced diagnostic tools, such as exome and genome sequencing, in enhancing genotype-phenotype correlations. These findings support the use of pyridoxine supplementation in managing seizures across various genetic epilepsies and suggest ganaxolone as a novel therapeutic agent for certain syndromes, signaling a leap toward personalized treatment modalities [31]. The quinidine uses in KCNT1-related epileptic disorders and analysis of treatment approaches in KCNQ2-related epilepsy further elaborate the precision medicine in epilepsy. These studies illustrate the potential of genotype-directed therapies, highlighting the crucial balance between efficacy and safety in the development of new treatments [32, 33] also summarized in Table 3.