Children’s Hospital of Philadelphia (CHOP) researchers have identified a particular genetic variant in SCN1A, the most common genetic epilepsy, that contributes to an earlier start of epilepsy with clinical features different from other epilepsies. The scientists also discovered a viable treatment approach. The observations were published in the journal Epilepsia recently.
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The majority of SCN1A genetic variants are linked to Dravet syndrome. Dravet syndrome is a type of genetic epilepsy marked by seizures that commence in the first year of life, as well as impairments in childhood development and autism spectrum disorder features.
In these circumstances, SCN1A has a loss-of-function variant, which means that the resultant protein is unable to perform its normal functions. However, this research concentrates on an SCN1A gain-of-function variant, which suggests the resulting protein performs additional functions in potentially detrimental ways.
This genetic change does exactly the opposite of what it should do, which in turn causes a peculiar clinical presentation. A better understanding of what this variant does is critical for us to determine which treatments to choose for affected patients.”
Ingo Helbig MD, Study Senior Author and Pediatric Neurologist, Division of Neurology, Children’s Hospital of Philadelphia
Ingo Helbig is also the co-director of the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP.
Researchers performed diagnostic testing to find four patients who shared the same gain-of-function variant in SCN1A. All four patients had early-onset developmental and epileptic encephalopathy (DEE), a condition marked by seizures and developmental impairments.
Patients in these cases had focal tonic seizures, which induce rigidity of the body in one specific area, as well as other seizure types beginning in the first few weeks of life. The researchers also discovered that patients with this recurrent gain-of-function variant in SCN1A-related epilepsies had a faster onset of disease than patients with loss-of-function variants.
The research also identified that oxcarbazepine, a seizure control medication for adults and children, might help patients. One of the patients responded to treatment with the medication, and the variant exhibited sensitivity to the drug.
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. 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.”
Jérôme Clatot PhD, Study First Author and Director, ENGIN Ion Channel/Electrophysiology Core, Children’s Hospital of Philadelphia
Clatot, J., et al. (2022) SCN1A gain-of-function mutation causing an early onset epileptic encephalopathy. Epilepsia. doi.org/10.1111/epi.17444.