July 5, 2022

The SCN1A Philadelphia Variant – a Gain-of-Function Mutation Causing an Early-Onset Epileptic Encephalopathy

Abstract found in BioRxiv

 Objective: Loss-of-function variants in SCN1A cause Dravet Syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center.

Methods: Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole-cell voltage-clamp electrophysiological recording in HEK-293T cells was performed to compare the properties of sodium channels containing wild-type Nav1.1 or Nav1.1-R1636Q along with both Nav?1 and Nav?2 subunits, including response to oxcarbazepine. To delineate differences to other SCN1A-related epilepsies, we analyzed electronic medical records.

Results: All four individuals had an early-onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current (INa). The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wildtype and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages of onset.

Interpretation: The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by ultra early-onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss- and gain-of-function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early-onset SCN1A-related epilepsies with separate treatment and prognosis implications.