Gen-Gen yang Berperan dalam Mekanisme Epilepsi Resisten terhadap Obat
DOI:
https://doi.org/10.65310/b1bg2p24Kata Kunci:
drug-resistant epilepsy, ion channel genes, neuroinflammation, pharmacogenetics, epileptogenesis.Abstrak
Drug-resistant epilepsy represents a major clinical challenge due to its complex and multifactorial biological mechanisms. This condition is not solely driven by inadequate pharmacological efficacy but is strongly influenced by genetic alterations affecting drug transport, neuronal excitability, and neuroinflammatory regulation. Genes encoding drug transporters such as ABCB1 and ABCC2 limit antiepileptic drug penetration across the blood–brain barrier, reducing therapeutic concentrations within epileptogenic regions. Meanwhile, mutations in sodium channel genes, particularly SCN1A, SCN2A, and SCN8A, disrupt neuronal excitability by altering action potential dynamics and synaptic balance. In parallel, neuroinflammatory genes including IL1B, TNF, and TLR4 promote chronic inflammatory responses that sustain epileptogenesis and further reduce drug responsiveness. The interaction among these genetic pathways creates a self-reinforcing pathological network that underlies persistent seizure activity despite optimal treatment. Understanding these molecular mechanisms highlights the necessity of precision-based approaches, including pharmacogenetic screening and targeted adjunctive therapies, to improve clinical outcomes in patients with drug-resistant epilepsy.
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Attia, Z. R., Labib, M. E., Kelany, A. K., Alnefaie, R. M., Twab, H. A., Wahsh, E., et al. (2024). Pharmacogenetic insights into ABCB1, ABCC2, CYP1A2, and CYP2B6 variants with epilepsy susceptibility among Egyptian children with drug-resistant epilepsy: A retrospective case–control study. International Immunopharmacology, 142(Pt A), 113073. https://doi.org/10.1016/j.intimp.2024.113073
Bazhanova, E. D., Kozlov, A. A., & Litovchenko, A. V. (2021). Mechanisms of drug resistance in the pathogenesis of epilepsy: Role of neuroinflammation. Brain Sciences, 11(5), 663. https://doi.org/10.3390/brainsci11050663
Brunklaus, A., Brünger, T., Feng, T., Fons, C., Lehikoinen, A., Panagiotakaki, E., et al. (2022). The gain-of-function SCN1A disorder spectrum: Novel epilepsy phenotypes and therapeutic implications. Brain, 145(11), 3816–3831. https://doi.org/10.1093/brain/awac210
Cárdenas-Rodríguez, N., Carmona-Aparicio, L., Pérez-Lozano, D. L., Ortega-Cuellar, D., Gómez-Manzo, S., & Ignacio-Mejía, I. (2020). Genetic variations associated with pharmacoresistant epilepsy: A review. Molecular Medicine Reports, 21(4), 1685–1701. https://doi.org/10.3892/mmr.2020.10999
Cascino, G. D., Sirven, J. I., & Tatum, W. O. (2021). Epilepsy (2nd ed.). Wiley. https://doi.org/10.1002/9781119431893
Daškevičiūtė, A., Zaboras, E., Navalinskas, J., Baronas, K., Jasionis, A., Navickienė, E., & Mameniškienė, R. (2025). A systematic review of ABCB1 polymorphisms and antiseizure medication resistance: Insights from effect size and study power analysis. International Journal of Molecular Sciences, 26(12), 5548. https://doi.org/10.3390/ijms26125548
El-Tallawy, H. N., Abuhamdah, S., Nassar, A. Y., Farghaly, W. M. A., Saleem, T. H., Atta, S. A., et al. (2021). CYP2C9 genetic polymorphisms in patients with pharmacoresistant epilepsy. Pharmacogenomics and Personalized Medicine, 14, 1133–1140. https://doi.org/10.2147/PGPM.S327808
Feng, Y., Wei, Z. H., Liu, C., Li, G. Y., Qiao, X. Z., Gan, Y. J., et al. (2022). Genetic variations in GABA metabolism and epilepsy. Seizure, 101, 22–29. https://doi.org/10.1016/j.seizure.2022.07.007
Gudimella, S. R. L., Mohiuddin, M. K., Mounika, K., Palkonda, S. R., & Devulapalli, K. (2023). Genetic analysis of cytochrome P450 polymorphisms in drug-responsive and drug-refractory epileptic patients in Telangana. The Open Neurology Journal, 17, e1874205X261819. https://doi.org/10.2174/011874205X261819231024053732
Huang, Y., Zhang, Y., & Liang, Y. (2025). Benzodiazepine-resistant epilepsy: Unraveling molecular mechanisms and developing multimodal therapeutic strategies. Frontiers in Neurology, 16, 1615079. https://doi.org/10.3389/fneur.2025.1615079
Johannesen, K. M., Liu, Y., Koko, M., Gjerulfsen, C. E., Sonnenberg, L., Schubert, J., et al. (2022). Genotype–phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain, 145(9), 2991–3009. https://doi.org/10.1093/brain/awab32
Li, M., Zhong, R., Lu, Y., Zhao, Q., Li, G., & Lin, W. (2021). Association between SCN1A and SCN2A polymorphisms and responsiveness to antiepileptic drugs: A meta-analysis. Frontiers in Neurology, 11, 591828. https://doi.org/10.3389/fneur.2020.591828
Li, Z., Cao, W., Sun, H., Wang, X., Li, S., Ran, X., et al. (2022). Potential clinical and biochemical markers for the prediction of drug-resistant epilepsy: A literature review. Neurobiology of Disease, 174, 105872. https://doi.org/10.1016/j.nbd.2022.105872
Liu, J., Zhang, P., Zou, Q., Liang, J., Chen, Y., Cai, Y., et al. (2023). Status of epilepsy in the tropics: An overlooked perspective. Epilepsia Open, 8(1), 32–45.
Mohammadzadeh, P., & Nazarbaghi, S. (2022). The prevalence of drug-resistant epilepsy and its associated factors in patients with epilepsy. Clinical Neurology and Neurosurgery, 213, 107086. https://doi.org/10.1016/j.clineuro.2021.107086
Nangoy, E., Mahama, C., & Oktaviani, E. (2024). Epilepsi resisten obat. Jurnal Kesehatan Tambusai, 5(3), 8597–8614. https://doi.org/10.31004/jkt.v5i3.3416
Rheims, S., Sperling, M. R., & Ryvlin, P. (2022). Drug-resistant epilepsy and mortality: Why and when do neuromodulation and epilepsy surgery reduce overall mortality? Epilepsia, 63(12), 3020–3036. https://doi.org/10.1111/epi.17413
Siebenbrodt, K., Willems, L. M., von Podewils, F., Mross, P. M., Strüber, M., Langenbruch, L., et al. (2023). Determinants of quality of life in adults with epilepsy: A multicenter cross-sectional study from Germany. Neurological Research and Practice, 5(1), 41. https://doi.org/10.1186/s42466-023-00265-5
Smolarz, B., Makowska, M., & Romanowicz, H. (2021). Pharmacogenetics of drug-resistant epilepsy: A review. International Journal of Molecular Sciences, 22(21), 11696. https://doi.org/10.3390/ijms222111696
Tang, H. X., Ho, M. D., Vu, N. P., Cao, H. V., Ngo, V. A., Nguyen, V. T., et al. (2024). Association between genetic polymorphisms of SCN1A, GABRA1, and ABCB1 and drug responsiveness in Vietnamese children with epilepsy. Medicina, 60(4), 637. https://doi.org/10.3390/medicina60040637
Tantsura, L. M., Pylypets, O. Y., Tretiakov, D. V., & Tantsura, Y. O. (2023). Variants of the formation and course of drug-resistant epilepsy in children with genetic polymorphisms of CYP2C9, CYP2C19, and CYP3A4. Wiadomości Lekarskie, 76(5 Pt 1), 1007–1013. https://doi.org/10.36740/WLek202305118
Yang, L. Z., Guo, Y., Wang, Z. Q., & Zhang, C. Q. (2024). A population-based analysis of the global burden of epilepsy across all age groups (1990–2021): Utilizing the Global Burden of Disease 2021 data. Frontiers in Neurology, 15, 1448596. https://doi.org/10.3389/fneur.2024.1448596
Zan, X., Yue, G., Hao, Y., & Sima, X. (2021). A systematic review and meta-analysis of the association of ABCC2/ABCG2 polymorphisms with antiepileptic drug responses in epileptic patients. Epilepsy Research, 175, 106678. https://doi.org/10.1016/j.eplepsyres.2021.106678
Zhao, T., Li, H. J., Yu, J., Zhang, H. L., Feng, J., Wang, T. T., et al. (2023). ABCB1 gene polymorphisms are closely associated with drug-resistant epilepsy: Evidence based on 377 Chinese pediatric patients. Clinical Neuropharmacology. https://doi.org/10.1097/WNF.0000000000000555
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Hak Cipta (c) 2025 Shinta Nurhaliza, Roro Rukmi Windi Perdani, Intan Kusumaningtyas, Rasmi Zakiah Oktarlina (Author)
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