Abstracts

Rationale: SCN8A encodes the NaV1.6 channel, which is highly expressed in the central nervous system with a major role in regulating excitatory networks in the brain. SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset cognitive impairment, developmental delay, and intractable seizures. Variants in SCN8A have also been reported in patients with a broader phenotypic spectrum with varying degrees of severity. In this study, data from a no-charge, targeted epilepsy gene panel program (Invitae’s Behind the Seizure® [BTS]) were analyzed to better understand the demographics, disease presentation, seizure history, and treatment of pediatric patients with SCN8A-related epilepsies.

Methods: US- and Canada-based children under 8 years old who had ≥ 1 unprovoked seizure were eligible for no-charge genetic testing and counseling through the BTS program. Ordering clinicians submitted a form detailing a patient’s demographics and clinical history, as well as a specimen for sequencing and deletion/duplication analysis of up to 302 genes associated with syndromic and non-syndromic causes of epilepsy. In this analysis, demographic and clinical history data were analyzed descriptively from patients tested between 2017 and May 2022 who had SCN8A variants that were classified as pathogenic (P) or likely pathogenic (LP).

Results: Of 17,843 patients tested, 36 (0.2%) had an SCN8A variant that was classified as P/LP. Of 24 unique P/LP SCN8A variants identified, 14 were classified as pathogenic and 10 were likely pathogenic. In patients with a P/LP SCN8A variant, mean (±SD) age at seizure onset was 16.3 (±17.0) months and mean age at testing was 2.1 (±2.4) years. The most common seizure type reported was generalized onset motor (50.0% of patients), followed by focal onset (30.6%) and generalized onset nonmotor (absence) seizures (13.9%). The most common developmental delays reported were language delays (30.6%), limited or absent speech (22.2%), and intellectual disability/motor development delays (both 16.7%). Over half (58.3%) of patients were reported to have experienced ≥ 1 convulsive seizure in the last month and 44.4% of patients had ≥ 1 prolonged (> 5 min) seizure over the past six months. At screening, 77.8% of patients were reported to be taking 1 to 3 antiseizure medications (ASMs) and almost one-fifth (19.4%) had previously discontinued 1 to 3 ASMs.

Conclusions: Overall, patients with P/LP SCN8A variants were heterogenous in terms of seizure types and developmental delays and reported a high seizure burden. Genetic screening-based studies such as this one may inform clinical trial design and provide insights into the clinical characteristics of patients with specific molecular diagnoses. Further analysis will clarify the role that variants identified in two or more epilepsy-associated genes play in shaping these results.

Funding: Neurocrine Biosciences, Inc.