Involvement of the
            <i>CACNA1A</i>
            gene containing region on 19p13 in  migraine with and without aura

Terwindt, Gisela M.; Ophoff, Roel A.; Eijk, Ronald van; Vergouwe, Monique N.; Haan, Joost; Frants, Rune R.; Sandkuijl, L. A.; Ferrari, Michel D.

doi:10.1212/wnl.56.8.1028

Cited by 125 publications

(85 citation statements)

References 19 publications

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“…Indeed, there is evidence for low Mg 2+ levels in brain during (Ramadan et al 1989) and between (Lodi et al 1997) migraine attacks. As mentioned above, Ca 2+ seems to be involved in the pathogenesis of migraine as mutations in P/Q-type Ca 2+ channels are related to FHM (Ophoff et al 1996) and, possibly, also to migraine with and without aura (Terwindt et al 2001). Further, L-type Ca 2+ channels modulate the release of CGRP in trigeminal neurons innervating the cranial vasculature (Akerman et al 2003).…”

Section: Ion Channelsmentioning

confidence: 94%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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Section: Ion Channelsmentioning

confidence: 94%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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“…This gene, SCN1A, has previously been implicated in epilepsy. Some studies suggest that the CACNA1A gene may also play a role in the typical migraines (May et al, 1995;Nyholt et al, 1998;Terwindt et al, 2001), but negative findings have also been reported (Hovatta et al, 1994;Jones et al, 2001). Considering the clinical heterogeneity of migraine, and the fact that a variety of mutations in at least three different genes are implicated in a rare and specific subtype of migraine, it seems likely that many genes are involved in the pathogenesis of more common migraine types.…”

Section: Genetics Of Migrainementioning

confidence: 99%

Migraine With Aura and Migraine Without Aura Are Not Distinct Entities: Further Evidence From a Large Dutch Population Study

et al. 2006

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It is often debated whether migraine with aura (MA) and migraine without aura (MO) are etiologically distinct disorders. A previous study using latent class analysis (LCA) in Australian twins showed no evidence for separate subtypes of MO and MA. The aim of the present study was to replicate these results in a population of Dutch twins and their parents, siblings and partners (N = 10,144). Latent class analysis of International Headache Society (IHS)-based migraine symptoms resulted in the identification of 4 classes: a class of unaffected subjects (class 0), a mild form of nonmigrainous headache (class 1), a moderately severe type of migraine (class 2), typically without neurological symptoms or aura (8% reporting aura symptoms), and a severe type of migraine (class 3), typically with neurological symptoms, and aura symptoms in approximately half of the cases. Given the overlap of neurological symptoms and nonmutual exclusivity of aura symptoms, these results do not support the MO and MA subtypes as being etiologically distinct. The heritability in female twins of migraine based on LCA classification was estimated at .50 (95% confidence intervals [CI] .27 – .59), similar to IHS-based migraine diagnosis (h2 = .49, 95% CI .19–.57). However, using a dichotomous classification (affected–unaffected) decreased heritability for the IHS-based classification (h2 = .33, 95% CI .00–.60), but not the LCA-based classification (h2 = .51, 95% CI .23–.61). Importantly, use of the LCA-based classification increased the number of subjects classified as affected. The heritability of the screening question was similar to more detailed LCA and IHS classifications, suggesting that the screening procedure is an important determining factor in genetic studies of migraine.

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“…The ATP1A2 gene on chromosome 1q23 (FHM2) [De Fusco et al, 2003;Vanmolkot et al, 2003], the SCN1A gene on chromosome 2q24 , and the CACNA1A gene on 19p13 (FHM1) [Joutel et al, 1993;Ophoff et al, 1996] have been implicated in this autosomal dominantly inherited disorder. Evidence is accumulating that the chromosome 1 and 19 loci may also be involved in the common migraines, although more research is required to confirm these findings [Hovatta et al, 1994;May et al, 1995;Ophoff et al, 1997;Nyholt et al, 1998Nyholt et al, , 2005Jones et al, 2001;Terwindt et al, 2001;Todt et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

Ligthart

Nyholt

Hottenga

et al. 2008

American J of Med Genetics Pt B

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Latent class analysis was performed on migraine symptom data collected in a Dutch population sample (N ¼ 12,210, 59% female) in order to obtain empirical groupings of individuals suffering from symptoms of migraine headache. Based on these heritable groupings (h 2 ¼ 0.49, 95% CI: 0.41-0.57) individuals were classified as affected (migrainous headache) or unaffected. Genomewide linkage analysis was performed using genotype data from 105 families with at least 2 affected siblings. In addition to this primary phenotype, linkage analyses were performed for the individual migraine symptoms. Significance levels, corrected for the analysis of multiple traits, were determined empirically via a novel simulation approach. Suggestive linkage for migrainous headache was found on chromosomes 1 (LOD ¼ 1.63; pointwise P ¼ 0.0031), 13 (LOD ¼ 1.63; P ¼ 0.0031), and 20 (LOD ¼ 1.85; P ¼ 0.0018). Interestingly, the chromosome 1 peak was located close to the ATP1A2 gene, associated with familial hemiplegic migraine type 2 (FHM2). Individual symptom analysis produced a LOD score of 1.97 (P ¼ 0.0013) on chromosome 5 (photo/ phonophobia), a LOD score of 2.13 (P ¼ 0.0009) on chromosome 10 (moderate/severe pain intensity) and a near significant LOD score of 3.31 (P ¼ 0.00005) on chromosome 13 (pulsating headache). These peaks were all located near regions previously reported in migraine linkage studies. Our results provide important replication and support for the presence of migraine susceptibility genes within these regions, and further support the utility of an LCA-based phenotyping approach and analysis of individual symptoms in migraine genetic research. Additionally, our novel ''2-step'' analysis and simulation approach provides a powerful means to investigate linkage to individual trait components.

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Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura

Abstract: The increased allele sharing in the CACNA1A gene region on 19p13 is consistent with an important involvement of this region in migraine, especially migraine with aura.

Cited by 125 publications

References 19 publications

Current and prospective pharmacological targets in relation to antimigraine action

Current and prospective pharmacological targets in relation to antimigraine action

Migraine With Aura and Migraine Without Aura Are Not Distinct Entities: Further Evidence From a Large Dutch Population Study

A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

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