Nav1.6. It has been several years since I last wrote a blog post about SCN8A. A wide range of clinical presentations have been described since, and significant progress has been made towards understanding the disease mechanism. However, SCN8A-related disorders have not become less puzzling. In a recent publication, we tried to understand whether SCN8A-related disorders have a unique clinical profile by harmonizing the electronic medical record data of 82 individuals across more than 600 patient years. Here is what we found.
Figure 1. The use of real-world data in SCN8A-related disorders. In our publication by Magielski and collaborators, we harmonized the electronic medical record data of 82 individuals with SCN8A-related disorders and compared this information to 2,833 individuals with known or presumed genetic epilepsies. Surprisingly, we found a unique seizure profile for SCN8A-related disorders that became prominent in the first year of life. The inset provides an overview of the seizure dynamics in SCN8A [modified from Magielski et al., 2025].
Profiling SCN8A. One of the first patients with an SCN8A-related disorder I met was referred to us through a neuromuscular specialist because of profound hypotonia. While the pattern of low muscle tone is conceptually different in individuals with developmental and epileptic encephalopathies (DEE) compared to those with muscle disorders, this distinction can sometimes be difficult to discern in very young children. But is hypotonia a specific feature for SCN8A, and are there other features that might even be more typical of this condition compared to other genetic epilepsies? The answers to these questions seem intuitive for clinicians caring for individuals with SCN8A-related disorders. However, the solution is complex.
Real-world data. Understanding the unique aspects of specific genetic epilepsies is important. With many genetic neurodevelopmental conditions on the brink of clinical trials for disease-modifying therapies, endpoints critically depend on understanding the natural history of each disease. Drawing conclusions from developmental and epileptic encephalopathies more broadly can be misleading and potentially counterproductive. Likewise, existing publications on SCN8A-related disorders frequently focus on specific clinical aspects and often cannot outline the entirety of the disease trajectory over time. This is where real-world data comes in.
EMR. In our publication by Magielski and collaborators, we tried to make data speak. In collaboration with Citizen Health, we took the entirety of the electronic medical record (EMR) data for 82 individuals with SCN8A-related disorders and compared this information to the EMR data of 2,833 individuals with known or presumed genetic epilepsies across the entire age range. In order to accomplish this, we used the framework of the Human Phenotype Ontology (HPO), a data dictionary we have used extensively in the past and helped to refine. This comparison allowed us to see features linked to SCN8A-related disorders which may have otherwise gone unnoticed.
Infancy. One of the main findings of our study was a feature we did not expect. Bilateral tonic-clonic seizures are roughly 10x more common in SCN8A-related disorders than other genetic epilepsies. Yes, hypotonia is also more common than in other known or presumed genetic epilepsies, but it does not stand out in infancy. In fact, the late persistence of hypotonia—with a 10x increase compared to other genetic epilepsies at the age of 4 years—is the most prominent muscle tone finding, not the hypotonia in infancy. In contrast, the most striking feature in the first year of life is the significantly higher frequency of bilateral tonic-clonic seizures in SCN8A. This example highlights the difference between clinical intuition and data-driven evidence. Even though we are highly familiar with the seizure pattern in SCN8A, comparisons across diseases are challenging, and the various cognitive biases that we are subject to tend to skew our intuition. In fact, nobody can meaningfully hold clinical data across more than 600 patient years in mind.
ASM response. In addition to our longitudinal comparison, we specifically looked at the prescription patterns in SCN8A and evidence for gene-specific medication responses. What stood out prominently was the “switch” towards sodium-channels blockers after the genetic diagnosis was made. This suggestion is not only a theoretical concept, but we could demonstrate that this happens in real life across the entire patient population, beyond just tertiary medical centers. Likewise, when combined with seizure frequency data, we were able to demonstrate that oxcarbazepine, phenytoin, and topiramate were more effective at keeping patients seizure-free than other anti-seizure medications. In summary, there is real-world evidence that sodium-channel blockers are effective in treating SCN8A-related epilepsy, and these strategies are already widely employed. Despite this relative efficacy, good seizure control is not achieved in more than 50% of individuals across the entire age span.
What you need to know. We can understand specific clinical features of SCN8A-related disorders by systematically comparing real-world data derived from the EMR. This data shows a 10x increase in bilateral tonic-clonic seizures and hypotonia persisting into childhood. Though we find strong evidence for the use of sodium-channel blockers (SCBs), these treatments are often ineffective at achieving lasting seizure control – 50% of individuals have seizures at any given age. Taken together, these insights enhance our understanding of SCN8A-related disorders and will inform future clinical trial design. than we had before.
