Submission Details

Familial Hemiplegic Migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of migraines with aura and associated hemiplegic attacks. Three genes, CACNA1A, ATP1A2, and SCN1A, have been associated with FHM1, FHM2, and FHM3, respectively. Additional phenotypes such as epilepsy and elicited repetitive daily blindness may be present in some FHM3 patients; however, other phenotypes such as ataxia and intellectual disability reported in FHM1-2 are rare in FHM3. The penetrance of FHM3 is close to 100%. FHM was first reported to be associated with SCN1A in 2005 in a study that identified a SCN1A variant segregating with FHM in three families (Dichgans et al. 2005 PMID: 16054936). Since then, 12 missense variants in SCN1A have been reported to be associated with FHM, including one de novo variant (PMID: 27155821). One of the 11 inherited variants (c.3521C>G; p.Thr1174Ser in NM_001165963.1) has a relatively high frequency in the general population, and is considered a benign polymorphism. The remaining 10 inherited variants and the de novo variant are rare variants not observed in gnomAD version 2.11. The 10 inherited rare variants from 16 families have been reported in 11 studies (16054936, 17397047, 19332696, 29145747, 30498473, 19220312, 24707016, 26763045, 26747084, 27919014, 30038559). Of the 16 families, 11 were given points ranging from 0.1 to 0.5 based on case-level and experimental data. A summed LOD score of 8.61 was calculated from the combined three families in the seminal paper as well as two other families (16054936, 17397047, 19332696). Supporting experimental evidence includes expression and biochemical functional studies (17537961). The accepted mechanism of hemiplegic migraine aura is cortical spreading depression, and mouse models of FHM1 and FHM2 support this theory. Since effects of FHM3 variants in SCN1A are often complex and diverse, the exact mechanisms by which defects in SCN1A could cause cortical spreading depression are unclear; however, SCN1A expression in axonal segments such as axon initial segments and the nodes of Ranvier, and the function in maintenance of action potentials are consistent with SCN1A’s role in neuronal activity and brain excitability, processes related to cortical spreading depression. In summary, a score of 6.5 was given to genetic evidence, and 1 to experimental evidence, reaching 7.5 in total. SCN1A’s association with FHM is moderate.