Clinical characterization of a novel ATP1A2 p.Gly615Glu mutation in nine family members with familial hemiplegic migraine

Familial hemiplegic migraine type 2 results from pathogenic variants in the ATP1A2 gene, which encodes for a catalytic subunit of sodium/potassium ATPase. This extremely rare autosomal dominant disorder manifests with a spectrum of symptoms, most commonly pure hemiplegic phenotype, epilepsy, and/or intellectual disability. In this study, we detail the clinical features and genetic analysis of nine patients from a large family spanning four generations, with all carrying a previously unreported likely pathogenic variant, p.Gly615Glu, in ATP1A2, compatible with a diagnosis of familial hemiplegic migraine type 2, fully penetrant with variable expressivity. This newly identified likely pathogenic variant primarily presented with psychiatric disturbances and a non-hemiplegic phenotype. Only one patient presented hemiplegic attacks, while seven were diagnosed with migraine with aura, including visual, sensory, and speech/language aura, and one with migraine without aura. The identification of the genes responsible for the more common forms of migraine, both with and without aura, remains a significant challenge in migraine genetics and is critical for advancing personalized medicine.