Exploring the Natural History of SCN8A-Related Disorders in Pediatric Patients

Researchers from the Epilepsy Neurogenetics Initiative (ENGIN) at Children's Hospital of Philadelphia (CHOP) have conducted a significant study on the natural history of SCN8A-related disorders, which encompass a variety of neurological symptoms. This comprehensive investigation utilized retrospective clinical data analyzed through innovative methods to illuminate the range of seizure types and neurodevelopmental characteristics associated with these disorders. The findings have been published in the journal Neurology.

ENGIN is dedicated to assessing and treating children with complex or enigmatic epilepsies, genetic epilepsy syndromes, and other genetic neurodevelopmental disorders. Pathogenic variants within the SCN8A gene are known to cause a diverse array of neurological conditions, such as epilepsy, which can manifest in varying degrees of severity, developmental delays, autism spectrum disorders, and movement disorders.

SCN8A-related disorders rank among the most prevalent genetic epilepsies, yet the treatment of affected children is notably challenging due to the absence of precise treatment options and the limited understanding of the overall progression of these conditions throughout a patient's life. Specifically, the timeline of clinical symptoms, or phenotypes, connected with these disorders has remained largely uncharacterized due to significant variability and previous studies with limited participant numbers.

Since the discovery of SCN8A-related disorders in 2012, there has been a growing interest in this condition due to its frequency and the potential therapeutic avenues it presents. Understanding the natural history of these disorders is crucial for developing targeted outcome measures and identifying critical intervention periods, as emphasized by the senior study author, Dr. Jillian McKee, an epileptologist specializing in neurogenetic disorders at CHOP.

The research team analyzed electronic medical record data from 82 patients diagnosed with SCN8A-related disorders, comparing this information with a larger cohort of 2,833 patients who have other genetic epilepsies. To standardize clinical information across various electronic records, the researchers employed the Human Phenotype Ontology (HPO), a comprehensive dictionary comprising over 15,000 terms to facilitate the analysis of clinical data, thereby expediting the integration of precision medicine into clinical practices.

Significantly, the study revealed that patients with SCN8A-related disorders have over a tenfold increased risk of developing bilateral tonic-clonic seizures by the age of one, a fact that had not been recognized previously. Furthermore, gain-of-function SCN8A variants, which enhance the activity of the sodium channel, were found to elevate the risk of seizures as early as six months and global developmental delays as early as three months when compared to the broader cohort of SCN8A patients. Conversely, patients with loss-of-function variants exhibited a higher likelihood of atypical absence seizures, characterized by episodes of 'blanking out,' by around four years of age.

As children grow older, those with the recurrent p.Arg1617Gln variant of SCN8A are more prone to focal seizures, while those with the p.Asn1877Ser variant tend to experience generalized-onset seizures. Understanding these genotype-phenotype correlations is essential for designing outcome measures and determining participant eligibility for future clinical trials.

The analysis indicated that sodium channel blockers were more effective in managing SCN8A epilepsy in patients with gain-of-function variants and those with variants that had yet to be functionally characterized, implying that some of these variants might also be gain-of-function variants.

Dr. McKee noted that the analysis highlighted the significant developmental challenges associated with SCN8A-related disorders, which possess unique characteristics that differentiate them from other forms of epilepsy. Gaining insights into how these distinct features evolve over time is a critical first step toward preparing for clinical trials aimed at assisting patients with these severe disorders.