FAMILIAL hemiplegic migraine may have a newly recognised genetic driver after researchers linked rare SCN2A mutations to inherited and sporadic cases, broadening understanding of a severe migraine disorder marked by temporary one-sided paralysis during attacks.
Familial Hemiplegic Migraine Genetics
Familial hemiplegic migraine is a rare autosomal dominant migraine subtype characterised by aura with transient motor weakness or paralysis. Existing genes including CACNA1A, ATP1A2, SCN1A, and PRRT2 explain fewer than 20% of genetically diagnosed cases. Researchers therefore investigated whether additional variants might account for unresolved familial hemiplegic migraine presentations.
Genetic Sequencing Strategy
Investigators conducted whole-genome linkage analysis and partial exome sequencing in a four-generation pedigree affected by familial hemiplegic migraine. After identifying SCN2A as a candidate gene, they screened six additional pedigrees with multiple affected members and 594 unrelated probands with familial or sporadic hemiplegic migraine lacking known FHM gene mutations. Functional consequences of identified variants were tested using heterologous expression systems and automated patch clamp recording. Computational neuron models were used to assess electrophysiological effects. Primary outcomes were variant identification, segregation with disease phenotype, and functional evidence of pathogenicity. Completion numbers for all screened cohorts were not separately reported.
SCN2A Variants Identified Across Affected Cases
Researchers identified a heterozygous missense mutation c.4438A>G, p.Lys1480Glu in SCN2A that co-segregated with familial hemiplegic migraine in the index pedigree. Two further variants, c.769T>A, p.Phe257Ile and c.3955C>G, p.Arg1319Gly, were found in a second family and one sporadic case, respectively. All variants were absent from the gnomAD population database. All ten individuals carrying an SCN2A variant experienced typical hemiplegic migraine beginning in childhood. Two children heterozygous for p.Phe257Ile also had self-limited infantile seizures in the first year of life. No affected individuals had permanent cerebellar ataxia, intellectual disability, or recurrent febrile coma. Confidence intervals and P values were not reported.
Clinical Implications and Future Testing Pathways
These findings suggest SCN2A should be considered in genetic testing panels for familial hemiplegic migraine and unresolved sporadic cases. Earlier molecular diagnosis may improve counselling, family screening, and management planning. Further studies are needed to define prevalence, genotype-phenotype correlations, and whether sodium channel-targeted therapies could benefit selected patients with this disabling migraine syndrome.
Reference
Riant F et al. SCN2A variants are associated with familial and sporadic hemiplegic migraine. Brain. 2026;awag109.
Featured image: Celt Studio on Adobe Stock
