SCN1A Philadelphia Variant – a Recurrent Gain-of-function Variant Causing an Early-onset Epileptic Encephalopathy Distinct from Dravet Syndrome
Abstract number :
1.03
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2022
Submission ID :
2204364
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Jerome Clatot, PhD – CHOP; Sridhar Parthasarathy, Data Scientist – The Children Hospital of Philadelphia; Stacey Cohen, Licensed Genetic Counselor – The Children's Hospital of Philadelphia; Jillian McKee, PL-6 Fellow – CHOP; Shavonne Massey, MD – CHOP; Ala Somarowthu, PhD – CHOP; Ethan Goldberg, MD. PhD. – CHOP; Ingo Helbig, MD – CHOP
Rationale: Genetic variation in SCN1A is the most common monogenic cause of developmental and epileptic encephalopathies, and loss-of-function variants are associated with GEFS+ and Dravet syndrome. We recently identified a recurrent SCN1A p.Arg1636Gln variant in three unrelated patients with developmental and epileptic encephalopathy of neonatal onset. Here, we aim to define the clinical, genetic, and functional electrophysiological features of this recurrent variant, which is clearly distinct from Dravet syndrome.
Methods: Three individuals with the recurrent SCN1A p.Arg1636Gln variant were recruited at our center and underwent deep phenotyping. Whole-cell voltage-clamp electrophysiological recording was performed in HEK-293T cells expressing WT or Nav1.1-Arg1636Gln along with both Navb1 and Navb2 subunits. To fully delineate the clinical distinction between the patients reported here from over 50 individuals with SCN1A-related epilepsies, we performed an analysis of the electronic medical record (EMR).
Results: All three individuals with the recurrent SCN1A p.Arg1636Gln variant exhibited an early-onset developmental and epileptic encephalopathy characterized by focal tonic seizures and other seizures types starting in the first two weeks of life, progressing to intractable epilepsy in two of three individuals. Electrophysiological analysis showed a mixed gain- and loss-of-function effect. We observed normal current density and a leftward (hyperpolarized) shift in the voltage dependence of activation and of steady-state inactivation, with slower inactivation kinetics with increased persistent sodium (Na+) current (INaP). Both WT and variant exhibited sensitivity to block by oxcarbazepine. The observed functional changes closely parallel effects of known paralogous disease-associated variants in the epilepsy genes SCN3A and SCN8A. Across 51 individuals with SCN1A-related epilepsies in our cohort, the patients reported here with the recurrent p.Arg1636Gln variant had among the earliest age of epilepsy onset.
Conclusions: In contrast to Dravet syndrome, the recurrent variant p.Arg1636Gln is associated with a distinct clinical presentation with neonatal-onset epilepsy. Functional consequences of this variant include a mixed gain and loss of channel function albeit with normal current density and prominent impairment of fast inactivation with increased persistent Na+ current. Na+ channel blockers did not fully correct the identified electrophysiological abnormalities in vitro, but may offer some therapeutic clinical benefit with early administration.
Funding: This work was supported by The Hartwell Foundation Individual Biomedical Research Award and NIH NINDS K02 NS112600 to I.H., NIH NINDS U54 NS108874 (PI, Alfred L. George), NIH NINDS R01 NS110869 and the Burroughs Wellcome Fund Career Award for Medical Scientists to E.M.G.
Basic Mechanisms