Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Terwindt, G.M.; Ophoff, RA; Haan, Joost; La, Sandkuijl; Frants, R.R.; Ferrari, Michel D.

doi:10.1038/sj.ejhg.5200206

Cited by 80 publications

(52 citation statements)

References 79 publications

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“…CACNA1A codes for a voltagedependent, P/Q-type, alpha-1A subunit calcium channel and ATP1A2 for a Na + , K + -ATPase alpha-2 subunit. These findings lead to the hypothesis that migraine could be a channelopathy, something that resides in the neuronal membrane, making it more excitable [3,4]. Similar breakthroughs are awaited for the more common migraine forms, migraine with and without aura.…”

Section: Introductionmentioning

confidence: 99%

Comorbidity in Finnish migraine families

Artto

Wessman

Nissilä³

et al. 2006

J Headache Pain

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The objective of the study was to investigate comorbidity of migraine in Finnish migraine families. One thousand consecutive participants in the Finnish Migraine Gene Project reported their medical illnesses in addition to migraine and headache. Migraine patients (n=678) reported significantly more hypotension (OR 1.43, CI 95% 1.02-2.01), allergy (OR 1.83, CI 95% 1.34-2.51) and psychiatric disorders (OR 4.09, CI 95% 2.11-7.92) compared to their family members without migraine (n=322). Subgroup analyses demonstrated that especially women and the group fulfilling the criteria for both migraine with and without aura were likely to have additional disorders besides their migraine. Interestingly, male migraineurs with aura reported a significant association with stroke and epilepsy. Familial migraine is comorbid with hypotension, allergy and psychiatric disorders. The association between migraine with aura and stroke and epilepsy among men of the studied families warrants further study. Clinical, pathophysiological and genetic implications of these results are discussed.

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Section: Introductionmentioning

confidence: 99%

Comorbidity in Finnish migraine families

Artto

Wessman

Nissilä³

et al. 2006

J Headache Pain

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“…myasthenia gravis, Lambert Eaton myasthenic syndrome and acquired neuromyotonia (Isaac's disease) . Often termed autoimmune channelopathies, these contrast with genetic channelopathies in which a loss or decrease in function is conferred by gene mutation with similar phenotypic consequences (Terwindt et al 1998). …”

Section: 'Classical' Antibody-mediated Neurological Diseasesmentioning

confidence: 99%

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

Hubball

Martin

Lang

et al. 2009

Progress in Neurobiology

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Dysfunction of the gastrointestinal neuromuscular apparatus (including interstitial cells ofCajal) is presumed to underlie a heterogeneous group of disorders collectively termed gastrointestinal neuromuscular diseases (GINMDs). Humoral (antibody)-mediated autoimmunity directed against ligand-or voltage-gated ion channels or associated proteins involved in neuromuscular transmission is associated with several acquired neuromuscular diseases of the periphery and is now implicated in an increasing number of less well-characterised diseases. Anti-channel antibodies have been reported in small numbers of patients with GINMD, particularly in those with GI dysfunction secondary to an underlying disease such as neoplasia or infection. However, little is known of humoral autoimmunity in primary GINMDs.This thesis investigated the association between anti-channel antibodies and GINMD, and the human GI tract as a potential target of anti-channel antibodies. The presence of antivoltage-and ligand-gated antibodies was investigated in the serum of patients with primary achalasia, enteric dysmotility and intestinal pseudo-obstruction, and in those with GINMD secondary to Chagas' disease. The functional effect of sera from some of these patients on colonic smooth muscle contractility was also characterised. Finally, the distribution of six voltage-gated potassium channels (VGKCs), which serve essential roles in the peripheral and central nervous systems and are known targets of pathological autoantibodies, were investigated in all layers of the human GI tract.Our findings suggest that currently recognised anti-channel antibodies are not a common pathogenic factor in primary GINMDs. Anti-channel antibodies, in particular anti-VGKC antibodies, were however found in a significant number of individuals with Chagas' disease. Furthermore, circulating factors in patients with chagasic GI disease altered GI smooth muscle contractility in vitro which may have pathological relevance to GI

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“…They found that sibling pairs with MA inherited the same 19p13 CACNA1A containing region significantly more frequently than expected by chance, consistently with an important involvement of this region in migraine, especially MA. Such results had led previously to the contention that the typical migraines could be conceptualized as calcium channelopathies, a concept useful also in explaining their co-morbidity with ataxia and epilepsy, and applicable also to the animal models displaying mutations in the murine homologue of the human CACNA1A gene [13].…”

Section: Migraine As a Channelopathymentioning

confidence: 99%

The “typical” migraines: genetic studies and some practical considerations

2003

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"Typical" migraine as a complex disease: genetic epidemiology, twin and segregation analysis studies That migraine runs in families is an ancient observation. Familiarity however is not synonymous with heritability, especially given the wide prevalence of migraine and the possibility that familial occurrence is due to chance. In order to assess the heritability of migraine, e.g. the rate of variance attributable to genetic factors, the disease risk of relatives of migraine probands is determined and compared to that found in the general population. Several surveys indicated that first-and sometimes also seconddegree relatives of migraine probands show increased risk for migraine: a two-fold increased risk for migraine without aura (MO) and 1.4 for migraine with aura (MA) in the case of first-degree relatives of MO probands, and a 4-fold risk for MA in the case of first-degree relatives of MA probands [1]. An increased disease risk does not however prove heritability, since it may result from shared environmental factors. It is therefore interesting to note that at least one genetic epidemiology survey found an increased disease risk for migraine in first-degree relatives compared to spouses of migraine probands, who presumably share environmental factors at least for some time in their lives. Notably however, the relative risk for spouses was increased compared to the general population, which implies some degree of assorted mating or shared environmental influences [1]. Studies of heritability performed according to disease risk comparisons came to high rates of genetic determination, e.g. 60%-80% for MO and MA [2].Better ways of analysing heritability of migraine are studies of monozygotic versus dizygotic twins, especially when reared-together and reared-apart (adopted) identical twins are considered. Several twin studies have been performed in migraine Pasquale Montagna Pietro Cortelli Mirella MochiAbstract Epidemiological genetic, family and twin studies show that the typical migraines carry a substantial genetic risk; they are currently conceptualized as complex genetic diseases. Several genetic association and linkage studies have been performed in the typical migraines. Candidate gene studies based on "a priori" pathogenic models of migraine (migraine as a calcium channelopathy; a mitochondrial DNA disorder; a disorder in the metabolism of serotonin or dopamine; in vascular risk factors or in the inflammation cascade; etc.) did not result in uniformely accepted findings. Linkage and genome wide scans gave evidence for several genetic susceptibility loci, still however in need of confirmation. Careful dissection of the clinical phenotypes and trigger factors shall greatly help future efforts in the quest for the genetic basis of the typical migraines.

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Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Cited by 80 publications

References 79 publications

Comorbidity in Finnish migraine families

Comorbidity in Finnish migraine families

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

The “typical” migraines: genetic studies and some practical considerations

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