IRCCS Mondino Foundation, via Mondino 2, 27100, Pavia, Italy.
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
J Headache Pain. 2021 Mar 12;22(1):12. doi: 10.1186/s10194-021-01221-x.
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.
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.
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.
家族性偏瘫性偏头痛 2 型（FHM2）基因型-表型相互作用的机制仍不清楚。已经描述了不同的 ATP1A2 突变，表型谱从轻度到重度不等。尚未尝试进行基因型-表型相关性研究。
我们描述了一个意大利家族性偏瘫性偏头痛和一个以前未描述的错义 ATP1A2 变体（L425H）。所有受影响的成员的临床症状都很轻微。
该变体与先兆症状的共分离在这个家族中是完全的，提示 100%的外显率。计算机蛋白预测软件表明，该变体可能会改变位于两个中央跨膜螺旋之间的细胞质环上的 ATPA1A2 的 3D 结构。在文献中很少报道更轻微的 FHM 表型，可能是因为病例报告偏向于最严重的表型，而更轻微的形式可能被误诊为散发性偏头痛伴先兆（MAs），甚至是复杂先兆。进一步的研究考虑到家族内的变异性和对通道蛋白的功能后果，可能有助于阐明基因型-表型相关性。
