Authors :
Presenting Author: Jerome Clatot, PhD – The Children's Hospital of Philadelphia
Natalie Ginn, MGC, LCGC – The Children's Hospital of Philadelphia
Anna Prentice, MS, LCGC – CHOP
Ingo Helbig, MD – Children's Hospital of Philadelphia
Ethan Goldberg, MD, PhD – CHOP
Rationale:
SCN1A – encoding the voltage-gated sodium channel subunit Nav1.1 – represents the most common monogenic cause of epilepsy, with loss-of-function variants linked to GEFS+ and Dravet Syndrome. We identified five de novo heterozygous pathogenic variants in SCN1A, p.L209R, p.S872Y, p.G891R, p.I1347V, p.R1636Q, in 11 patients presenting with early-onset phenotypes that included refractory epilepsy, global developmental delay/intellectual disability, and hypotonia, with or without arthrogryposis or movement disorder. Here, we aim to characterize the electrophysiological features of the identified pathogenic variants to better define the genotype-phenotype relationship in a single-center cohort of early-onset SCN1A spectrum disorders.Methods:
Methods: HEK-293T cells were co-transfected with WT or variant SCN1A construct, along with a tricistronic construct SCN1B/SCN2B/FusionRed. Whole-cell voltage-clamp electrophysiological recording was performed to delineate the biophysical characteristics of pathogenic SCN1A variants relative to WT.
Results:
Results: All individuals identified to carry a pathogenic variant presented with medication-resistant epilepsy within the first year of life, with 8/11 individuals (73%) presenting in the first three months of life. Global developmental delay/intellectual disability was observed in all individuals and ranged from mild to severe. Hypotonia was present in 7/11 individuals (64%). Additional clinical features varied and included arthrogryposis (4/11; 36%), movement disorder (4/11; 36%), abnormal neuroimaging (4/11; 36%) and nystagmus (2/11; 18%). Electrophysiological analysis revealed a combination of gain- and loss-of-function effects. All variants led to a significantly decreased peak current density, as well as a hyperpolarizing shift of the voltage dependence of activation and steady-state inactivation.
Conclusions:
Conclusions: Unlike loss of function pathogenic variants seen in patients with a later disease onset and clinical spectrum from GEFS+ to Dravet syndrome, early-onset SCN1A-related disorders are defined by gain of function or mixed gain/loss that commonly includes a hyperpolarized shift of the voltage-gated dependence of activation.
Funding:
Funding: This work was supported by the Dravet Syndrome Foundation (PI, I. Helbig / E. Goldberg) and a Cell & Gene Therapy Seed Grant from the Children’s Hospital of Philadelphia (PI, E. Goldberg / J. Clatot).