Elicited Repetitive Daily Blindness Associated With Gain-of-Function <i>SCN1A</i> Variants and Responsiveness to Sodium Channel Blockers
Background and Objectives: variants. The proband in each family was commenced on sodium channel blocker medication. We performed functional analysis of the previously reported Q1489H and F1499L variants, including the overall effect in GABAergic neurons. Methods: 1.1 voltage-gated sodium channel with either wild type (WT), Q1489H, or F1499L variants. Results: gene for family 3 (c.4027G > T/p.[A1343S]), 4 (c.5350G > T/p.[V1784F]), 5 (c.5006C > T/p.[A1669F]) and 6 (c.5006C > T/p.[A1669F]). Electrophysiologic testing revealed an overall gain-of-function on Nav1.1-mediated currents for the previously reported variants Q1489H and F1499L when compared with WT, particularly when they were expressed in cortical GABAergic neurons. In silico tools predicted gain-of-function in the 3 novel variants. All 4 probands responded well to treatment with carbamazepine reporting fewer migraines and blindness episodes. Discussion: 1.1 variants. Patients in this report responded to sodium channel blocker medications.
Authors
- Fenella J. Kirkham (ORCID: https://orcid.org/0000-0002-2443-7958)
- Alexander James Harper (ORCID: https://orcid.org/0000-0001-7532-4219)
- Andreas Brunklaus (ORCID: https://orcid.org/0000-0002-7728-6903)
- Iain Horrocks
- Sameer M. Zuberi (ORCID: https://orcid.org/0000-0002-4489-4697)
- Massimo Mantegazza (ORCID: https://orcid.org/0000-0002-1070-7929)
- Sandra Dhifallah
- Jaspal Singh (ORCID: https://orcid.org/0000-0001-8690-2192)
- Sandrine Cestèle (ORCID: https://orcid.org/0000-0002-5982-1562)
- Joseph D. Symonds (ORCID: https://orcid.org/0000-0002-2141-4216)
- Nathalie Leroudier
- Raffaella Rusconi
- I Morgan
- Sebastian Marra (ORCID: https://orcid.org/0009-0004-8325-2074)
- Daniel John Stobo (ORCID: https://orcid.org/0009-0006-8858-2659)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Great Ormond Street Hospital (GB)
- Royal Hospital for Children (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- Groupe de Recherche en Droit, Économie, Gestion (FR)
- NIHR Southampton Respiratory Biomedical Research Unit (GB)
- Queen Elizabeth University Hospital (GB)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
- University of Southampton (GB)
- University College London (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Neurology Genetics
- Published
- 2026-04-22
- DOI
- https://doi.org/10.1212/nxg.0000000000200352
- Primary Topic
- Advanced Memory and Neural Computing
- Type
- article
- Field-Weighted Citation Impact
- 0.00