Genetics of migraine aura: an update

Abstract

Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Various genetic approaches have been applied to identify genetic factors that confer risk for migraine. Initially, so-called candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) tested variants in any gene in an hypothesis-free manner. Whereas GWAS in migraine without aura, or the more general diagnosis migraine have already identified dozens of gene variants, the specific hunt for gene variants in migraine with aura has been disappointing. The only GWAS specifically investigating migraine with aura yielded only one single associated single nucleotide polymorphism (SNP), near MTDH and PGCP, with genome-wide significance. However, interrogation of all genotyped SNPs, so beyond this one significant hit, was more successful and led to the notion that migraine with aura and migraine without aura are genetically more alike than different. Until now, most relevant genetic discoveries related to migraine with aura came from investigating monogenetic syndromes with migraine aura as a prominent phenotype (i.e. FHM, CADASIL and FASPS). This review will highlight the genetic findings relevant to migraine with aura.

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

“…Mutations of ATP1A2 gene have been described in familiar hemiplegic migraine as dominant mutations, usually missense, which are thought to cause loss-of-function [ 1 ]. At least 80 different mutations have been described ( https://databases.lovd.nl/shared/genes/ATP1A2 ), in most cases without ascertainment of their pathogenic role, except for the association with the aura phenotype.…”

“…Hemiplegic migraine (HM) is a rare form of migraine with aura (MA) in which attacks are characterized, among other symptoms, by complex auras including motor disturbances, often lasting several days. A subset of HMs, labelled as familiar HM type 2 (FHM2), are associated with mutations in the ATP1A2 gene [ 1 ]. ATP1A2 encodes for the alpha2-subunit (the catalytic site) of the Na/K ATPase, regulating the excitable properties of muscle and nerve cells [ 1 ].…”

“…A subset of HMs, labelled as familiar HM type 2 (FHM2), are associated with mutations in the ATP1A2 gene [ 1 ]. ATP1A2 encodes for the alpha2-subunit (the catalytic site) of the Na/K ATPase, regulating the excitable properties of muscle and nerve cells [ 1 ]. All mutations are thought to be loss-of-function [ 1 , 2 ], leading to decreased clearance, and thus to increased levels of glutamate in the synaptic cleft: this would facilitate cortical excitability and cortical spreading depression, leading to aura [ 2 ].…”

“…ATP1A2 encodes for the alpha2-subunit (the catalytic site) of the Na/K ATPase, regulating the excitable properties of muscle and nerve cells [ 1 ]. All mutations are thought to be loss-of-function [ 1 , 2 ], leading to decreased clearance, and thus to increased levels of glutamate in the synaptic cleft: this would facilitate cortical excitability and cortical spreading depression, leading to aura [ 2 ]. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe: these latter include permanent neurological signs and MRI abnormalities in the form of vascular lesions [ 3 ].…”

“…Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe: these latter include permanent neurological signs and MRI abnormalities in the form of vascular lesions [ 3 ]. However, studies on genotype-phenotype correlations are still lacking [ 1 , 4 ].…”