Familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

Abstract

Background The mechanisms of genotype-phenotype interaction in Familiar Hemiplegic migraine type 2 (FHM2) are still far from clear. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe. No genotype-phenotype correlations have been attempted. Case presentation We describe an Italian family with FHM and a missense ATP1A2 variant (L425H) not previously described. The clinical picture was mild in all the affected members. Conclusions Co-segregation of the variant with the aura phenotype was complete in this family, suggesting a 100% penetrance. In silico protein prediction softwares indicate that this variant may change the 3D structure of ATPA1A2 at the cytoplasmic loop between the two central transmembrane helices. Milder FHM phenotypes are rarely reported in literature, likely because case reports are biased towards the most severe phenotypes, with milder forms possibly misdiagnosed as sporadic migraine with aura forms (MAs), even with complex auras. Further studies taking into account intra-familiar variability and functional consequences on the channel protein may help clarify genotype-phenotype correlations.

Familial hemiplegic migraine type 2: a case report of an adolescent with ATP1A2 mutation

“…Following an extended depolarization period, water permeated from the cellular interior to the extracellular space, leading to a delayed occurrence of heightened perfusion ( 16 ). Brain enhancement MRI findings in patients with ATP1A2 exhibit two characteristics: (i) normal findings, primarily observed in patients with mild hemiplegic migraine (HM) ( 17 , 18 ), and (ii) hypoperfusion in the initial stage of the hemisphere opposite to the hemiplegia, followed by widespread diffusion-weighted imaging hyperintense signals in the subsequent stage, often accompanied by cortical swelling in certain patients ( 15 , 17 ). Regrettably, the brain CTA of the boy conducted 3 hours after the onset of symptoms yielded normal results, with no findings of hypoperfusion.…”

A novel heterozygous ATP1A2 pathogenic variant in a Chinese child with MELAS‐like alternating hemiplegia

“…ATP1A1 is widely expressed in most tissues, whereas ATP1A2 is more restricted to astrocytes, ATP1A3 is more restricted to neurons (Calame et al, 2021; Sweadner et al, 2019), ATP1A4 is only expressed in male germ cells (Syeda et al, 2020). According to reports, pathogenic variants of ATP1A2 are usually associated with familial hemiplegic migraine type 2 (FHM‐2) (Antonaci et al, 2021; Moya‐Mendez et al, 2021), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE) (Parrini et al, 2017), transient cytotoxic edema (Kornbluh & Chung, 2020) and so on.…”