Hemiplegic Migraine Associated With PRRT2 Variations

Abstract

Background and objective:PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.Methods:PRRT2 was analyzed in 860 probands with hemiplegic migraine and PRRT2 mutations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with mutations whose clinical manifestations were detailed.Results:PRRT2 mutations were found in 12 of 163 probands previously tested negative for CACNA1A, ATP1A2 and SCN1A mutations, and in 18 of 697 consecutive probands screened simultaneously on the four genes. In this second group, pathogenic variants were found in 105 subjects, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%) and SCN1A (15%). The PRRT2 mutations included seven distinct variants, five of which already described in persons with paroxysmal kinesigenic dyskinesia, and two new variants. Eight probands had a deletion of the whole PRRT2 gene.Among the 49 PRRT2 mutated patients, 26 had pure hemiplegic migraine, 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4) or abnormal movement (3). Three patients had epilepsy without migraine, two had paroxysmal kinesigenic dyskinesia without migraine, and one was asymptomatic.Conclusion:PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine, and screened in any affected patient, together with the three other main genes. Further studies are needed to understand how the same loss of function PRRT2 mutations can lead to a wide range of neurologic phenotypes including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder and hemiplegic migraine.

Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine

“…Nevertheless, while accounting for some HM cases, particularly familial cases with severe phenotypes, we and others have found that <20% of clinically diagnosed cases have pathogenic variants in the FHM genes ( Hiekkala et al, 2018 ; Maksemous et al, 2019 ). Mutations in other genes including PRRT2 , PKND , ATP1A3 , SLC1A3 , SLC2A1 , and SLC4A4 can cause disorders with overlapping symptoms and have been implicated in some cases that present with HM ( Sutherland et al, 2019 ; Riant et al, 2022 ). Nevertheless, despite additional targeted analysis of whole-exome sequencing (WES) data for likely pathogenic variants in these genes, the majority of suspected HM cases remain genetically unsolved ( Pelzer et al, 2018 ; Sutherland et al, 2020 ).…”

Study of variants in genes implicated in rare familial migraine syndromes and their association with migraine in 200,000 exome‐sequenced UK Biobank participants

“…A number of ion‐regulating genes have been implicated in FHM, which is a rare monogenic form of migraine with aura that also includes motor disturbances and hemiparalysis (Goadsby et al., 2017 ). These include CACNA1A , ATP1A2 , SCN1A , and PRRT2 (De Fusco et al., 2003 ; Dichgans et al., 2005 ; Ophoff et al., 1996 ; Pelzer et al., 2014 ; Riant et al., 2012, 2022 ). Variants which have been implicated in FHM differ in their predicted effects, with ATP1A2 and PRRT2 having loss‐of‐function (LOF) variants, CACNA1A having gain‐of‐function variants, and SCN1A variants having a complex impact on protein function (Pietrobon & Moskowitz, 2013 ; Sutherland et al., 2019 ).…”

Genetics of migraine: where are we now?

“…2 ). The PRRT2 gene should be added to the main FHM genes because recent data have shown that PRRT2 is involved at least as frequently as SCN1A [ 29 , 30 ]. For convenience, we will therefore refer to FHM4 for HM associated with PRRT2 mutations.…”