Elicited Repetitive Daily Blindness Associated With Gain-of-Function SCN1A Variants and Responsiveness to Sodium...

Area of Science:

• Genetics
• Neurology
• Ophthalmology

Background:

• Elicited Repetitive Daily Blindness (ERDB) involves recurrent, daily episodes of reversible vision loss.
• ERDB has been associated with Familial Hemiplegic Migraine 3 (FHM3), caused by pathogenic SCN1A variants.
• Previous reports linked specific SCN1A variants (Q1489H, F1499L) to FHM3 and ERDB, but the association needed further confirmation.

Purpose of the Study:

• To investigate the clinical feature of ERDB in FHM3 patients.
• To identify novel SCN1A variants associated with FHM3 and ERDB.
• To perform functional analysis of SCN1A variants and assess treatment response.

Main Methods:

• Clinical interviews and medical record reviews for four new families with FHM3 and ERDB.
• Genetic analysis of SCN1A variants in affected individuals.
• Electrophysiological studies (patch-clamp) on Na_v1.1 variants (Q1489H, F1499L) in tsA-201 cells and GABAergic neurons.

Main Results:

• Four new families (3-6) presented with FHM3 and ERDB, with blindness episodes starting in infancy.
• Novel heterozygous SCN1A variants (A1343S, V1784F, A1669F) were identified in these families.
• Functional analysis revealed a gain-of-function effect for Q1489H and F1499L variants, with in silico predictions supporting gain-of-function for the novel variants.
• All four probands showed positive response to carbamazepine, with reduced migraine and blindness episodes.

Conclusions:

• ERDB is a confirmed clinical feature in FHM3 patients resulting from gain-of-function Na_v1.1 variants.
• Sodium channel blockers are an effective treatment for FHM3 patients with ERDB.
• This study expands the understanding of SCN1A-related disorders and their management.