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The Genetic Basis of Migraine: How Much Do We Know?

Published online by Cambridge University Press:  02 December 2014

Kathy Gardner
Kathy Gardner*
Affiliation:
Department of Neurology, University of Pittsburgh, PA, USA
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Abstract

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Migraine with and without aura is thought to be genetically complex with aggregation in families due to a combination of environmental and genetic tendencies. Twin studies are most important in establishing the multifactorial nature of migraine with heritability approaching 50%. Familial hemiplegic migraine (FHM) on the other hand is an autosomal dominant, highly penetrant, though rare form of migraine with strong genetic tendency. Fifty percent of families with FHM are linked to chromosome 19p13 and mutations demonstrated for some in a brain expressed calcium channel alpha 1A subunit, CACNL1A4. Other FHM loci have been identified on chromosome 1q and further genetic heterogeneity is likely. The exact role of the mutated calcium channel in the pathway leading to hemiplegic migraine is yet to be established. Changes in the electrophysiologic properties of the mutated forms of the CACNL1A4 calcium channel expressed in heterologous systems help establish the functional significance of the mutations and suggest that chromosome 19p-linked FHM, an episodic disorder, represents a CNS channelopathy. Additional candidate genes causative for migraine might include other calcium channel subunits and related proteins important for neuronal membrane stability. Delineating the cascade of biochemical events leading to hemiplegic migraine will serve as a model for understanding the pathophysiology of more common forms of migraine. The evidence suggesting that some families of migraine with and without aura might also be related to the chromosome 19p locus, chromosome Xq28 locus, or DRD2 receptor polymorphisms is reviewed.

Résumé

RÉSUMÉ

On pense généralement que la migraine avec et sans aura est complexe au point de vue génétique et que l’agrégation de cas dans les familles est due à une combinaison de tendances environnementales et génétiques. Les études sur les jumeaux sont très importantes pour établir la nature multifactorielle de la migraine dont l’héritabilité est de près de 50%. D’autre part, la migraine hémiplégique familiale (MHF), une maladie autosomale dominante dont la pénétrance est élevée, est une forme de migraine rare à forte tendance génétique. Chez cinquante pourcent des familles atteintes de MHF la maladie est liée au chromosome 19, en 19p13, et chez certaines familles, des mutations ont été démontrées dans la sous-unité 1A d’un canal calcique exprimé dans le cerveau, CACNL1A4. D’autres loci ont été identifiés sur le chromosome 1, en1q, et il existe sans doute une grande hétérogénéité génétique. Le rôle exact du canal calcique muté dans la voie qui est atteinte dans la MHF n’a pas encore été établi. Les changements dans les propriétés électrophysiologiques des formes mutées du canal calcique CACNL1A4 exprimé dans les systèmes hétérologues aident à établir la signification fonctionnelle des mutations et suggèrent que la MHF liée au chromosome 19, en 19p, un trouble épisodique, représente une canalopathie du SNC. Les gènes d’autres sous-unités de canaux calciques et de protéines associées, qui sont importants pour la stabilité de la membrane des neurones, pourraient être des gènes candidats dans l’étiologie de la migraine. La définition de la cascade d’événements biochimiques conduisant à la MHF servira de modèle pour comprendre la physiopathologie de formes plus communes de migraine. Les observations suggérant que dans certaines familles atteintes de migraine avec et sans aura la maladie pourrait également être liée aux loci sur le chromosome 19, en 19p, sur le chromosome X, en Xq28, ou aux polymorphismes du récepteur DRD2 sont revues.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 26 , Issue 3 , November 1999 , pp. 37 - 43
Copyright
Copyright © The Canadian Journal of Neurological 1999

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