SCN1A gain-of-function mutation causing an early onset epileptic encephalopathy

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Loss-of-function SCN1A variants cause Dravet syndrome, a common genetic developmental and epileptic encephalopathy (DEE).
• Emerging evidence indicates SCN1A gain-of-function variants cause distinct neurological disorders.
• The recurrent p.R1636Q variant's specific characteristics require further elucidation.

Purpose of the Study:

• To characterize the clinical, genetic, and functional electrophysiological features of the SCN1A p.R1636Q gain-of-function variant.
• To compare the p.R1636Q variant's effects with other SCN1A-related epilepsies.
• To assess the variant's response to oxcarbazepine.

Main Methods:

• Identified individuals with the SCN1A p.R1636Q variant through diagnostic testing.
• Performed whole-cell voltage-clamp electrophysiology in HEK-293T cells to analyze Na_v1.1 channel properties.
• Analyzed electronic medical records to delineate clinical features and compare with other SCN1A epilepsies.

Main Results:

• All four individuals presented with early-onset DEE, focal tonic seizures, and other seizure types from early infancy.
• Electrophysiology revealed a mixed gain-of-function effect, including hyperpolarized inactivation and slower inactivation kinetics.
• Oxcarbazepine partially corrected the electrophysiological abnormalities, with one individual showing a clinical response.

Conclusions:

• The SCN1A p.R1636Q variant defines a clinical entity with neonatal onset epilepsy and a broader spectrum than previously recognized.
• This variant results in mixed loss- and gain-of-function effects, partially ameliorated by oxcarbazepine.
• The p.R1636Q variant is a significant cause of early-onset SCN1A-related epilepsies with unique treatment and prognostic implications.