Researchers from the Epilepsy Neurogenetics Initiative (ENGIN) at Children’s Hospital of Philadelphia (CHOP) have completed a comprehensive natural history study of SCN8A-related disorders, which represent a spectrum of neurological symptoms.

The study, using retrospective clinical information analyzed through novel data analysis methods, revealed a range of seizure types and neurodevelopmental features, and identified potential targets for future clinical trials. The findings are published in Neurology.

Engin evaluates and cares for children with difficult-to-treat or unexplained epilepsies, genetic epilepsy syndromes and other genetic neurodevelopmental disorders. Variants in certain genes have been linked to epilepsy syndromes and other disorders. Pathogenic variants in the SCN8A gene cause a spectrum of neurological conditions, including epilepsy ranging in severity from mild to severe seizures, developmental delays, autism spectrum disorder, and movement disorders.

SCN8A-related disorders are among the most common genetic epilepsies and treatment of children with these conditions is challenging due to the lack of precision treatments and because the overall history of these conditions across the lifespan is poorly understood. In particular, the time course of clinical symptoms, or phenotypes, associated with these disorders remain largely uncharacterized because of the wide range of variability and limited population sizes previously studied.

“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,” said senior study author Jillian McKee, MD, PhD, an ENGIN Epileptologist specialized 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.”

In this study, researchers utilized electronic medical record data from 82 patients with SCN8A-related disorders and compared that information to a cohort of 2,833 patients with other genetic epilepsies. To help standardize clinical information across electronic medical records, the researchers employed the Human Phenotype Ontology (HPO), a dictionary of more than 15,000 terms, to help standardize how clinical information can be analyzed, accelerating the integration of precision medicine into clinical practice.

The study found that patients with SCN8A-related disorders had more than 10-fold risk of developing bilateral tonic-clonic seizures as early as one year old, a fact that was previously not appreciated. Gain-of-function SCN8A variants, which increase the activity of the sodium channel, lead to an increased risk of seizures as early as 6 months old and global developmental delay as early as 3 months old when compared to the broader cohort of SCN8A patients.

Patients with loss-of-function variants, on the other hand, were more likely to have atypical absence seizures, which involve instances of “blanking out,” at around four years old.

In later childhood, patients with the recurrent p.Arg1617Gln variant of SCN8A were more likely to have focal seizures, whereas patients with the p.Asn1877Ser variant were more likely to experience generalized-onset seizures. An understanding of these genotype-phenotype correlations will be critical when designing outcome measures and selecting participants for future clinical trials.

Additionally, using sodium channel blockers to help manage SCN8A epilepsy was more effective in patients with gain-of-function variants as well as patients whose variants were not yet functionally characterized, suggesting that some of these variants may also be 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 said. “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.”