Researchers at the Children’s Hospital of Philadelphia (CHOP) recently discovered a gain-function genetic variant in the SCN1A gene that may be associated with earlier-onset childhood epilepsy. Findings were published in Epilepsia.
SCN1A variants are most commonly associated with Dravet syndrome, the most common genetic epilepsy, which is characterized by seizures that occur in the first year of life and affects childhood development and features on the autism spectrum. Whereas these variants are loss-of-function variants, the variant that was recently discovered was a gain-of-function variant of SCN1A, meaning that the resulting protein carries out additional functions compared with normal.
This discovery suggests a need for new medical definitions of SCN1A, as well as the need for effective treatments for patients with this specific type of variant, who may have otherwise been misdiagnosed and treated for Dravet syndrome.
“A better understanding of what this variant does is critical for us to determine which treatments to choose for affected patients,” senior author, Ingo Helbig, MD, a pediatric neurologist in the Division of Neurology, and co-director of the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP, said in a statement.
In this study, diagnostic testing was used to identify 4 individuals with the identical gain-of-function variant in SCN1A. All 4 individuals had an early-onset developmental and epileptic encephalopathy (DEE), characterized by focal tonic seizures and additional seizure types beginning in the first few weeks of life.
The researchers used electrophysiological analysis to investigate the disease mechanism of SCN14 p.R1636Q, which revealed an overall gain-of-function mechanism. Additionally, SCN1A p.R16363Q was found to be similar to the identical, known disease variants SCN2A, SCN3A, and SCN8A, which also display an overall gain of function.
When given treatment with oxcarbazepine, a sodium channel blocker drug for children and adults, 1 individual clinically responded to treatment, which resulted in partial correction in gain of function and may have explained the reduction of seizures observed in that patient.
Across all individuals with SCN1A-related epilepsies, those with the recurrent SCN1A p.R1636Q variants had the earliest incidences of onset epilepsy. Using data from CHOP’s Epidemiology and Genomics Research Program, the researchers identified 52 individuals with SCN1A-related disorders out of 2356 study participants. The median age at seizure onset was 4.8 months and ranged from 1 day to 4 years. Individuals with SCN1A p.R1636Q were in the second percentile for age at seizure onset compared with all other SCN1A-realted disorders.
This study adds to prior research that had identified 8 individuals with the recurrent p.R1636Q variant, which suggests that this variant may be the most common type of SCN1A function-gain variant and may have been considered as atypical Dravet syndrome.
“Our findings may provide an explanation for why we had previously diagnosed some patients as having atypical Dravet syndrome, as the earlier onset of symptoms associated with this gain-of-function variant allow us to properly distinguish these cases,” author Jérôme Clatot, PhD, director of the ENGIN Ion Channel/Electrophysiology Core at CHOP, said in a statement.
“We hope to raise awareness of this and other potential gain-of-function variants, particularly if common anti-seizure medications may be able to help them,” continued Clatot.
Clatot J, Parthasarathy S, Cohen S, et al. SN1A gain‐of‐function mutation causing an early onset epileptic encephalopathy. Epilepsia. Published online October 26, 2022. doi:10.1111/epi.17444