Abstract
BACKGROUND AND OBJECTIVES: Elicited Repetitive Daily Blindness (ERDB) is a debilitating condition resulting in recurrent, daily episodes of reversible visual loss. ERDB has been described in individuals with Familial Hemiplegic Migraine 3 (FHM3), caused by pathogenic SCN1A variants. Two families with cosegregation of FHM3 and ERDB (families 1-2) have previously been reported associated with SCN1A variants c.4467G > C/p.(Q1489H) and c.4495T > C/p.(F1499L). However, F1499L was also identified in a separate FHM3 family without ERDB. Thus, it is uncertain whether ERDB is a clinical feature in FHM3 besides the 2 identified families. We present 4 new families with cosegregation of FHM3 and ERDB resulting from 3 novel SCN1A 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: Data were collated through clinical interview and review of medical records for the probands of 4 new families with FHM3 and ERDB. Genetic analysis was performed for probands and, where possible, their parents. Whole-cell patch-clamp experiments were performed to measure sodium currents. Measurements were taken from transfected temperature sensitive SV40 Large T-antigen (tsA-201) cells and cortical GABAergic neurons in primary culture expressing the human Na(v)1.1 voltage-gated sodium channel with either wild type (WT), Q1489H, or F1499L variants. RESULTS: Four new pedigrees are described with typical FHM3 and ERDB (families 3-6). Blindness attacks commenced from infancy to 9 years of age. Episodes occurred 3-10 times per day, lasting up to 30 seconds. Genetic testing revealed novel heterozygous variants in the SCN1A 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: Our study demonstrates that ERDB is a clinical feature in FHM3 patients because of gain-of-function Na(v)1.1 variants. Patients in this report responded to sodium channel blocker medications.