Decoding Seizures: A Look Into How Genetics is Transforming Epilepsy Treatment
Zachary Stayn
Epilepsy is one of the most common neurological disorders, affecting 1-2% of the world population. Characterized by at least two sudden bursts of abnormal electrical brain activity, known as seizures, this disorder can cause excessive staring, involuntary movements, loss of consciousness, and even sudden death. Because epilepsy may be caused by many factors, such as but not limited to genetics, brain trauma, and infections, treatment is challenging (Falco-Walter et al., 2020). Typically, clinicians focus on seizure management and take a trial-and-error approach where patients successively or simultaneously try one or more of 30+ anticonvulsant medications until their seizures and side effects are minimized. These drugs range from Lamotrigine, which binds to inactive sodium and calcium channels to prevent the release of the excitatory neurotransmitter glutamate, to Diazepam, which binds to a receptor to increase the release of the inhibitory neurotransmitter GABA (Sillis and Rogawski, 2020). However, these medications fail to prevent recurrent seizures in 30-40% of patients (Hwang et al., 2024).
Because of this, researchers have recently begun exploring the use of genetic screening with medicinal treatments to precisely target and treat epilepsy (Marini and Giardino, 2021). In this new “precision medicine” approach, patients newly diagnosed with epilepsy or with a family history of the disease undergo exome sequencing, in which researchers compare all gene mutations with a large bank of non-epileptic patients’ genetic sequences to identify variants found in those with epilepsy. Researchers then mutate the corresponding genes in model organisms, such as mice or zebrafish, and assess the animals’ ensuing behavior and brain electrical activity. These assessments help reveal which genes contribute to epilepsy, how a specific mutation may affect the animal’s neurobiology, and, ultimately, which medicine can best help a patient with a particular genetic mutation.
Such experiments with epilepsy genetics have already optimized medicinal treatments for certain patients. For example, patients with mutated TSC1 or TSC2 genes (Tuberous Sclerosis Complex 1 and 2), often infants, are at very high risk for seizures and severe epilepsy. Through clinical studies in patients with TSC mutations, scientists discovered that early targeted use of the drug vigabatrin can block an enzyme that breaks down GABA, thus increasing GABA-mediated inhibitory neuronal transmission, reducing the risk of seizures, and avoiding severe side effects for patients (McGinn et al., 2022, Sillis and Rogawski, 2020). While the exact reason that vigabatrin works better than other drugs for patients with TSC mutations is unknown, simply knowing that vigabatrin can be a successful treatment method allows for a more precise approach to treating epilepsy.
Not all gene mutations link to a clear treatment path, however. For example, many types of epilepsy are now associated with mutations in the sodium channel-encoding gene SCN1A (Sodium Voltage-Gated Channel Alpha Subunit 1), but sodium channel-blocking medications such as carbamazepine may actually worsen seizures (McGinn et al., 2022). Now that epilepsy genetics can identify SCN1A mutations in patients, these patients can avoid trialing multiple anticonvulsant medicines and instead start treatments with valproic acid and clobazam or stiripentol and topiramate or explore ketogenic dieting, all of which have shown promise in treating certain subsets of SCN1A mutations (McGinn et al., 2022). Nonetheless, because over 600 known mutations in SCN1A can cause epilepsy through single base-pair changes, reading frame shifts, deletions, or other methods, there is still a long way to go before there is a best treatment path for each mutation (Knowles et al., 2022).
As researchers continue to investigate such complex mutations, they are increasingly focusing on patients with rarer mutations, for which no treatment guidance exists. In October 2024, a group of over 200 scientists worldwide published the largest-ever genetic study of epilepsy (54,000 people) (Epi25 Collaborative, 2024) in which they honed in on rare mutations in patients from around the globe who had widely varying genetics and compiled likely candidate epilepsy genes, connecting them both to one another as well as known cellular pathways. These new treatment targets spur further research studies and better clinical care for patients who have undergone genetic sequencing.
Similarly, two novel approaches to treat genetic epilepsies were discovered in these large cohort studies. The first approach, gene addition, aims to add genetic material to a patient’s cells to compensate for an epilepsy gene. The second approach, gene editing, uses CRISPR or similar approaches to modify a person’s epilepsy gene. Though exciting, studies using these techniques face challenges, largely because modifying a human genome poses the risk of off-target effects, such as undesired DNA damage, immune response, and cytotoxicity. Nonetheless, as researchers better understand how to use these tools to target specific genes, novel precision medicine treatments may emerge that transform clinical care in epilepsy, improve the lives of many who suffer from it, and serve as a new model for neurological and other therapeutics.
About the Author
Zachary Stayn ('26) is a junior at Harvard College concentrating in neuroscience.
References
Because of this, researchers have recently begun exploring the use of genetic screening with medicinal treatments to precisely target and treat epilepsy (Marini and Giardino, 2021). In this new “precision medicine” approach, patients newly diagnosed with epilepsy or with a family history of the disease undergo exome sequencing, in which researchers compare all gene mutations with a large bank of non-epileptic patients’ genetic sequences to identify variants found in those with epilepsy. Researchers then mutate the corresponding genes in model organisms, such as mice or zebrafish, and assess the animals’ ensuing behavior and brain electrical activity. These assessments help reveal which genes contribute to epilepsy, how a specific mutation may affect the animal’s neurobiology, and, ultimately, which medicine can best help a patient with a particular genetic mutation.
Such experiments with epilepsy genetics have already optimized medicinal treatments for certain patients. For example, patients with mutated TSC1 or TSC2 genes (Tuberous Sclerosis Complex 1 and 2), often infants, are at very high risk for seizures and severe epilepsy. Through clinical studies in patients with TSC mutations, scientists discovered that early targeted use of the drug vigabatrin can block an enzyme that breaks down GABA, thus increasing GABA-mediated inhibitory neuronal transmission, reducing the risk of seizures, and avoiding severe side effects for patients (McGinn et al., 2022, Sillis and Rogawski, 2020). While the exact reason that vigabatrin works better than other drugs for patients with TSC mutations is unknown, simply knowing that vigabatrin can be a successful treatment method allows for a more precise approach to treating epilepsy.
Not all gene mutations link to a clear treatment path, however. For example, many types of epilepsy are now associated with mutations in the sodium channel-encoding gene SCN1A (Sodium Voltage-Gated Channel Alpha Subunit 1), but sodium channel-blocking medications such as carbamazepine may actually worsen seizures (McGinn et al., 2022). Now that epilepsy genetics can identify SCN1A mutations in patients, these patients can avoid trialing multiple anticonvulsant medicines and instead start treatments with valproic acid and clobazam or stiripentol and topiramate or explore ketogenic dieting, all of which have shown promise in treating certain subsets of SCN1A mutations (McGinn et al., 2022). Nonetheless, because over 600 known mutations in SCN1A can cause epilepsy through single base-pair changes, reading frame shifts, deletions, or other methods, there is still a long way to go before there is a best treatment path for each mutation (Knowles et al., 2022).
As researchers continue to investigate such complex mutations, they are increasingly focusing on patients with rarer mutations, for which no treatment guidance exists. In October 2024, a group of over 200 scientists worldwide published the largest-ever genetic study of epilepsy (54,000 people) (Epi25 Collaborative, 2024) in which they honed in on rare mutations in patients from around the globe who had widely varying genetics and compiled likely candidate epilepsy genes, connecting them both to one another as well as known cellular pathways. These new treatment targets spur further research studies and better clinical care for patients who have undergone genetic sequencing.
Similarly, two novel approaches to treat genetic epilepsies were discovered in these large cohort studies. The first approach, gene addition, aims to add genetic material to a patient’s cells to compensate for an epilepsy gene. The second approach, gene editing, uses CRISPR or similar approaches to modify a person’s epilepsy gene. Though exciting, studies using these techniques face challenges, largely because modifying a human genome poses the risk of off-target effects, such as undesired DNA damage, immune response, and cytotoxicity. Nonetheless, as researchers better understand how to use these tools to target specific genes, novel precision medicine treatments may emerge that transform clinical care in epilepsy, improve the lives of many who suffer from it, and serve as a new model for neurological and other therapeutics.
About the Author
Zachary Stayn ('26) is a junior at Harvard College concentrating in neuroscience.
References
- Chen, S., Abou-Khalil, B. W., Afawi, Z., Ali, Q. Z., Amadori, E., Anderson, A., Anderson, J., Andrade, D. M., Annesi, G., Arslan, M., Auce, P., Bahlo, M., Baker, M. D., Balagura, G., Balestrini, S., Banks, E., Barba, C., Barboza, K., Bartolomei, F., … Epi25 Collaborative. (2024). Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes. Nature Neuroscience, 27(10), 1864–1879. https://doi.org/10.1038/s41593-024-01747-8
- Falco-Walter, J. (2020). Epilepsy—Definition, classification, pathophysiology, and epidemiology. Seminars in Neurology, 40(06), 617–623. https://doi.org/10.1055/s-0040-1718719
- Hwang, S., Shin, Y., Sunwoo, J.-S., Son, H., Lee, S.-B., Chu, K., Jung, K.-Y., Lee, S. K., Kim, Y.-G., & Park, K.-I. (2024). Increased coherence predicts medical refractoriness in patients with temporal lobe epilepsy on monotherapy. Scientific Reports, 14(1), 20530. https://doi.org/10.1038/s41598-024-71583-0
- Knowles, J. K., Helbig, I., Metcalf, C. S., Lubbers, L. S., Isom, L. L., Demarest, S., Goldberg, E. M., George, A. L., Lerche, H., Weckhuysen, S., Whittemore, V., Berkovic, S. F., & Lowenstein, D. H. (2022). Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia, 63(10), 2461–2475. https://doi.org/10.1111/epi.17332
- Marini, C., & Giardino, M. (2022). Novel treatments in epilepsy guided by genetic diagnosis. British Journal of Clinical Pharmacology, 88(6), 2539–2551. https://doi.org/10.1111/bcp.15139
- McGinn, R. J., Von Stein, E. L., Summers Stromberg, J. E., & Li, Y. (2022). Chapter Six—Precision medicine in epilepsy. In D. B. Teplow (Ed.), Progress in Molecular Biology and Translational Science (Vol. 190, pp. 147–188). Academic Press. https://doi.org/10.1016/bs.pmbts.2022.04.001
- Sills, G. J., & Rogawski, M. A. (2020). Mechanisms of action of currently used antiseizure drugs. Neuropharmacology, 168, 107966. https://doi.org/10.1016/j.neuropharm.2020.10796