Researchers at the Epilepsy Neurogenetics Initiative (ENGIN) of the Children’s Hospital of Philadelphia (CHOP) have finished a detailed study on the natural history of SCN8A-related disorders. These disorders manifest across a spectrum of neurological symptoms. The study, which analyzed retrospective clinical data through innovative analysis techniques, identified seizure varieties and neurodevelopmental traits, setting goals for future clinical trials. The research was published on April 14, 2025, in Neurology, the journal of the American Academy of Neurology.
ENGIN provides evaluation and care for children facing difficult-to-treat epilepsies, genetic epilepsy syndromes, and other neurodevelopmental disorders. Variants in genes, such as SCN8A, link to a range of epilepsy syndromes and related conditions, from mild to severe seizures, developmental delays, autism spectrum disorder, and movement disorders.
SCN8A-related disorders are common among genetic epilepsies. Treatment remains challenging due to a lack of precise treatments and insufficient understanding of these disorders’ history throughout life. The disorders’ clinical symptoms and their progression are still largely uncharacterized due to variability and past studies focusing on limited population sizes.
“Since the initial discovery in 2012, SCN8A-related disorders have received significant attention given the frequency of the condition and because SCN8A represents a potential therapeutic target,” stated Jillian McKee, MD, PhD, a senior study author and ENGIN Epileptologist specializing in neurogenetic disorders at CHOP. “However, in order to move toward our goal of launching clinical trials for these patients, an understanding of the natural history of these disorders is critical for developing outcome measures and identifying the key time periods for intervention.”
The study involved electronic medical records from 82 patients with SCN8A disorders, compared against 2,833 patients with other genetic epilepsies. Researchers standardized clinical information using the Human Phenotype Ontology (HPO), effectively integrating precision medicine into practice.
Findings indicated a significantly increased risk (over 10-fold) of bilateral tonic-clonic seizures in patients as young as one year. Gain-of-function SCN8A variants have been associated with earlier seizure onset at six months and developmental delay by three months, compared to the broader SCN8A patient cohort. In contrast, loss-of-function variants linked to atypical absence seizures appear around four years.
Dr. Ingo Helbig, a leading figure in this field, notes that specific SCN8A variants contribute to varied seizure types in later childhood. Patients with the p.Arg1617Gln variant experienced more focal seizures, while those with p.Asn1877Ser faced generalized-onset seizures. These genotype-phenotype correlations are crucial for defining outcome measures and identifying suitable candidates for forthcoming clinical trials. Furthermore, sodium channel blockers proved more effective for patients with gain-of-function variants.
“Our analysis found that there is a significant developmental burden in SCN8A-related disorders with unique features that set these conditions apart from other epilepsies,” McKee stated. “Knowing how unique features of SCN8A-related disorders develop over time is the first step towards readiness for clinical trials, so we can help our patients with these severe conditions.”
This research was supported by the CURE Epilepsy Rare Epilepsy Partnership Award for SCN8A, co-funded by The Cute Syndrome Foundation, National Institute of Neurological Disorders, and Stroke grants, and CHOP’s intramural funds through ENGIN.
Magielski et al., “Deciphering the natural history of SCN8A-related disorders.” Neurology. Online April 14, 2025. DOI: 10.1212/WNL.0000000000213533
