Genetics of headaches.

Insight into the molecular mechanisms involved in primary headaches is important to identify drug targets for improving treatment of patients, but essentially lacking. Genetic research is increasingly successful in pinpointing these mechanisms. Most progress has been made for Familial Hemiplegic Migraine, a rare subtype of migraine with aura. Three genes (CACNA1A, ATP1A2 and SCN1A) have been identified that all encode ion transporters. Cellular and transgenic mouse studies suggest that neuronal hyperexcitability and increased susceptibility to cortical spreading depression, the correlate of migraine aura, are important molecular mechanisms in migraine. Investigating monogenic diseases in which migraine is a prominent feature such as CADASIL, which is caused by mutations in the NOTCH3 gene, can help understanding the pathology of migraine. Candidate gene association studies and linkage studies in the common forms of migraine were less successful. Except for the MTHFR gene no gene variant has been identified yet. Convincingly demonstrated genetic findings in other primary headaches such as cluster headache and tension-type headache are even rarer. However, with current technical possibilities of massive genotyping and international efforts to collect large well-phenotyped patient cohorts, the first gene variants for various primary headache types are likely to be discovered in the coming decade.