Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype.

OBJECTIVE: The neuropeptide calcitonin gene-related peptide (CGRP) is a migraine trigger that plays a crucial role in migraine pathophysiology, and CGRP antagonism is efficient in the treatment of migraine attacks. Familial hemiplegic migraine (FHM) is a dominantly inherited subtype of migraine with aura associated with several gene mutations. FHM shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. We tested the hypothesis that the FHM genotype confers a CGRP hypersensitive phenotype. METHODS: We included 9 FHM patients with known mutations in the CACNA1A and ATP1A2 genes and 10 healthy controls. All subjects received i.v. infusion of CGRP (1.5 microg/min). We recorded headache intensity on a verbal rating scale and vascular changes in the middle cerebral artery and the superficial temporal artery. RESULTS: CGRP infusion did not induce an aura in any of the participants. The incidences of reported migraine and migraine-like headache were not different in the two groups, with 22% (2 of 9) reporting migraine in the patient group and 10% (1 of 10) reporting migraine-like headache in the control group (95% CI -0.31 to 0.55; p = 0.58). Headache severity and intensity were not different between the groups. CONCLUSIONS: Familial hemiplegic migraine (FHM) patients do not show hypersensitivity of the calcitonin gene-related peptide (CGRP)-cyclic adenosine 3',5'-monophosphate pathway, as characteristically seen in migraine patients without aura. This indicates that the pathophysiologic pathways underlying migraine headache in FHM may be different from the common types of migraine and questions whether CGRP antagonists would be effective in the treatment of FHM patients.

The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura.

Epidemiological studies indicate that migraine with typical aura (MA) has a major genetic component but the genes for MA have not been identified. However, the autosomal dominantly inherited familial hemiplegic migraine (FHM) is often caused by mutations in the CACNA1A or ATP1A2 genes. The aim of the study was to investigate if the CACNA1A or ATP1A2 genes are involved in MA with an apparently autosomal dominant mode of inheritance. From a clinic population diagnosed by a trained physician we recruited 34 extended families (comprising 174 MA patients) with an apparently autosomal dominant mode of inheritance of MA. We performed a linkage analysis of 161 of 174 MA patients and 79 unaffected relatives using a framework marker set of 44 markers for chromosome 1 and 22 markers for chromosome 19. Linkage analysis was made with a non-parametric or autosomal dominant parametric model, either allowing for heterogeneity or not, using an affected only analysis. We identified no linkage to CACNA1A and ATP1A2 loci on chromosome 19 or 1, respectively. Additionally, at least two patients from each family and 92 healthy, unrelated controls were selected for a sequence analysis. We sequenced the 48 exons of CACNA1A and the 23 exons of ATP1A2, including promoter and flanking intron sequences. No polymorphism was identified in the CACNA1A or ATP1A2 genes with a strong correlation to MA. Our study shows that the CACNA1A or ATP1A2 genes are probably not involved in MA. To identify the genes involved in the common forms of migraine, future genetic studies should focus on MA and migraine without aura (MO) and not FHM.