Cracking the Genetic Code: A New Way to Diagnose Infantile Epilepsy

By Suhanee Mitragotri 

When your infant wakes up from a nap, all you want is to be able to hold them close and give them all of your love. While being able to wake up peacefully from naptime is a normal thing for most infants, some babies are awakened by a violent series of spasms and seizures (Boston Children’s Hospital, n.d.). Infantile spasms are a form of epilepsy that present in the first year of a child’s life but can impact their quality of life forever (Smith et al., 2023). The disorder may be relatively rare, with an incidence rate of 1.6 to 4.5 per 10,000 births, but can be quite severe (Smith et al., 2023). Neurologists often will diagnose an infant with epilepsy by using an electroencephalogram (EEG) or other brain imaging techniques such magnetic resonance imaging (MRI) (Smith et al., 2023). Once an infant is diagnosed with epilepsy, they are given a treatment which often consists of antiepileptic drugs. While these medications can reduce the number of seizures an infant has, they cannot cure epilepsy and many patients remain treatment-resistant (NHS, n.d.). For adult patients that are resistant to treatment for epilepsy, doctors may offer more invasive therapies, such as removing the section of the brain where seizures originate or implanting a device into the brain that releases electric impulses to control seizure activity (Liu et al., 2017; Boon et al, 2009). However, these invasive procedures are recommended for less than 1% of patients, and are generally not performed in infants because their brains are still developing (Engel, 2018).

Epilepsy can be diagnosed at any age, but it generally is diagnosed in childhood or after the age of 60 (NHS, n.d.). While epilepsy holds its own challenges in any age group, infants and children have the unique risk of facing developmental delays due to the condition (Yuskaitis et al., 2018). In this way, the effects of infantile epilepsy can have lifelong effects on an individual’s ability to learn and grow. Unfortunately, studies have shown that late diagnosis is common among children showing symptoms for epilepsy, and these delays are associated with significant impacts on development and cognitive ability later in childhood (Berg et al., 2014). While there are many contributing factors, it seems that delayed diagnoses are often due to parents not fully recognizing the symptoms or their severity, as well as not being able to get the child to the right clinical specialist in a timely manner (Berg et al., 2014). So, how can we develop more efficient strategies to diagnose infantile epilepsy?

Alissa D’Gama, PhD and others set out to answer just that. In their study, the team of researchers evaluated the ways in which genome sequencing could be used to diagnose infants with epilepsy (D’Gama et al., 2023). Between September of 2021 and August of 2022, the researchers enrolled 100 infants from around the world, all of whom had already been diagnosed with epilepsy. The biological parents of these children underwent bloodwork for genome sequencing, allowing the researchers to identify the genotype underlying epilepsy in 43 of the 100 infants. The genetic diagnoses of the infants revealed that different genes were responsible for epilepsy across the patient population. 34 unique DNA regions were found to be correlated with epilepsy diagnosis, with a large number of the variants being due to a single letter change in the child’s DNA. These diagnoses were used to inform treatment and evaluation options, and about half of these diagnoses were used to develop personalized therapy for the patients (e.g., antiseizure medication selection). In 86% of the infants, the genetic diagnosis helped doctors understand the future progression of the disease, beyond what one would typically know based on a standard epilepsy diagnosis.

This study demonstrated the power that genome sequencing could have in infantile epilepsy diagnosis. Dr. Annapurna Poduri, a clinician-scientist who worked on the study, has seen many patients and families dealing with infantile epilepsy without having answers as to why or how it came to be. In sharing her perspective, she explained that the results of this study show promise in offering “diagnostic certainty to provide support for what wasn’t as definitive before, because a precise diagnosis can be something around which families and patients can anchor with their treating team.” Dr. Poduri is excited to continue working with the patients in the study and assess their long-term outcomes.

There’s still a long way to go. The researchers identified many genes that could be useful in epilepsy diagnosis, but the extent to which each gene impacts the severity of epileptic seizures or other symptoms is still mostly a mystery. Additionally, this study focused on short-term testing, but it will be essential to also understand how accelerated diagnoses may improve clinical outcomes and quality of life in the long term. This study is only the beginning of precision medicine, as genetic testing will require more evaluation before it is considered for application in clinical settings. However, genome sequencing could transform the future of epilepsy diagnosis and be used to optimize therapeutic interventions. In the long run, this could improve the growth and development of infants and children with epilepsy, which is ultimately all a caregiver could ask for.

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Written by Suhanee Mitragotri

Illustrated by Katie Cooke

Edited by Liza Chartampila, Justin McMahon, and Dhruv Mehrota

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References

Berg, A. T., Loddenkemper, T., & Baca, C. B. (2014). Diagnostic delays in children with early onset epilepsy: impact, reasons, and opportunities to improve care. Epilepsia, 55(1), 123–132. https://doi.org/10.1111/epi.12479

Boon, P., Raedt, R., de Herdt, V., Wyckhuys, T., & Vonck, K. (2009). Electrical stimulation for the treatment of epilepsy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 6(2), 218–227. https://doi.org/10.1016/j.nurt.2008.12.003

D’Gama, A. M., Mulhern, S., Sheidley, B. R., Boodhoo, F., Buts, S., Chandler, N. J., Cobb, J., Curtis, M., Higginbotham, E. J., Holland, J., Khan, T., Koh, J., Liang, N. S. Y., McRae, L., Nesbitt, S. E., Oby, B. T., Paternoster, B., Patton, A., Rose, G., Scotchman, E., … McTague, A. (2023). Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study. The Lancet. Neurology, 22(9), 812–825. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00246-6/fulltext

Engel J., Jr (2018). The current place of epilepsy surgery. Current opinion in neurology, 31(2), 192–197. https://doi.org/10.1097/WCO.0000000000000528

Infantile spasms. Boston Children’s Hospital. (n.d.). https://www.childrenshospital.org/conditions/infantile-spasms

Liu, G., Slater, N., & Perkins, A. (2017). Epilepsy: Treatment Options. American family physician, 96(2), 87–96. https://www.aafp.org/pubs/afp/issues/2017/0715/p87.html

NHS. (n.d.). NHS choices. https://www.nhs.uk/conditions/epilepsy/treatment/

Smith, M. S., Matthews, R., & Mukherji P. Infantile Spasms. (2023). StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK537251/

Yuskaitis, C. J., Ruzhnikov, M. R. Z., Howell, K. B., Allen, I. E., Kapur, K., Dlugos, D. J., Scheffer, I. E., Poduri, A., & Sherr, E. H. (2018). Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation. Pediatric neurology, 87, 48–56. https://doi.org/10.1016/j.pediatrneurol.2018.04.012