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.