Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Dutch Migraine Genetics Research Group.
TL;DR: The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.
Abstract: Clinical and genetic heterogeneity as well as influence of environmental factors have hampered identification of the genetic factors which are involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subtypes, may help to unravel the pathogenesis of the more common forms. Recently, different types of mutation in the brain-specific P/Q type calcium channel alpha 1A subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebellar ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and without aura. In the tottering and leaner mouse, which are characterised by epilepsy and ataxia, similar mutations were identified in the mouse homologue of the calcium channel alpha 1A subunit gene. These findings add to the growing list of episodic (and now also chronic) neurological disorders, which are caused by inherited abnormalities of voltage-dependent ion channels. The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.
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TL;DR: Site-directed mutagenesis has identified sites on voltage-activated calcium channels, which interact specifically with other proteins, inhibitors and ions, which are an essential part of many excitable and non-excitable mammalian cells.
Abstract: Voltage-activated calcium channels regulate the intracellular calcium concentration and contribute thereby to calcium signalling in numerous cell types These channels are widely distributed in the animal kingdom and are an essential part of many excitable and non-excitable mammalian cells The opening of these channels is primarily regulated by the membrane potential, but is also modulated by a wide variety of hormones, protein kinases, protein phosphatases, toxins and drugs Site-directed mutagenesis has identified sites on these channels, which interact specifically with other proteins, inhibitors and ions This article will focus on these recent developments The older findings have been summarized in several excellent reviews (Striessnig et al 1993; Hofmann et al 1994; Catterall 1995; De Waard et al 1996a)
339 citations
TL;DR: Different evidences and hypotheses which suggest a link between SD and clinical disorders are collected to increase the understanding of SD associated disorders and improve the fundamental research strategies.
305 citations
TL;DR: A systematic search for familial cases of migraine with an aura that included motor weakness in the Danish population was performed in order to generate non-selected material of as many FHM cases as possible and to compare this material with already available population-based clinical descriptions of headache with typical aura (MA).
Abstract: Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine with aura. The clinical characteristics of FHM have been described previously in selected materials or case studies, but population-based studies are important in order to analyse the full spectrum of the disorder. The aim of the present study was to perform a systematic search for familial cases of migraine with an aura that included motor weakness in order to generate non-selected material of as many FHM cases as possible in the Danish population of 5.2 million inhabitants, and to compare this material with already available population-based clinical descriptions of migraine with typical aura (MA). Due to the rarity of FHM, traditional population-based methods were not feasible. Therefore, the search strategy employed a computer search of the National Patient Register, screening >27 000 case records from headache clinics and private neurologists, and advertisements. A total of 147 affected FHM patients from 44 families were identified. FHM patients most often had all four 'typical' aura symptoms (visual, sensory, aphasic and motor symptoms) and all had at least two of these aura symptoms during FHM attacks. The motor, sensory and visual aura symptoms were all similar in type to the motor, sensory and visual aura symptoms in MA, but FHM had a statistically significantly longer duration of the visual and sensory aura symptoms, and these and other aura symptoms often fulfilled the criteria of the International Headache Society for prolonged aura. In addition, 69% had basilar migraine (BM) symptoms during FHM attacks. The order of the aura symptoms was usually visual, followed by sensory, aphasic, motor and, lastly, basilar-type migraine symptoms. Headache was present in 99% of FHM patients during FHM attacks, whereas the aura symptoms more often occurred without headache in MA. Headache duration was significantly longer in FHM compared with MA. Based on these data, we suggest more precise diagnostic criteria for FHM and a more clear clinical distinction between FHM and BM. Our results have significant implications for case finding in genetic studies and for clinical migraine differential diagnosis.
223 citations
Additional excerpts
...…Stevens, 1977; Zifkin et al., 1980; Jensen et al., 1981; O'Hare et al., 1981; Haan et al., 1994, 1995; Rajput and Kramer, 1995; Ahmed et al., 1996; Terwindt et al., 1996, 1998b; Kramer et al., 1997; Hayashi et al., 1998; Echenne et al., 1999; Ducros et al., 2000, 2001) and probably why…...
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TL;DR: There is effective therapy for the common problem of migraine-associated dizziness, and 100% of the patients in the migraine without active headache group received substantial relief of their vertigo or disequilibrium symptoms with migraine therapy.
Abstract: ObjectiveTo determine patient characteristics and effectiveness of therapy for migraine-associated dizziness.Study DesignRetrospective chart review.SettingTertiary referral center.PatientsPatients were identified through a code query of billing records for the diagnosis of migraine-associated vertig
159 citations
Cites background from "Migraine, ataxia and epilepsy: a ch..."
...Diet alone 13 69 (9) 31 (4) 0 0 Diet + TCA 31 39 (12) 39 (12) 19 (6) 3 (1) Diet + other 37 16 (6) 41 (15) 35 (13) 8 (3) Totals 81 33 (27) 38 (31) 23 (19) 5 (4)...
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...This makes migraine similar in pathophysiology to other episodic disorders such as epilepsy, periodic paralyses, and episodic movement disorders (30,31)....
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TL;DR: The authors identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis and isolated 48 single-nucleotide polymorphisms within the locus, of which they genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls.
130 citations
References
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TL;DR: Specific standards designed to maintain rigor while also promoting communication are proposed for the interpretation of linkage results in genetic studies under way for many complex traits.
Abstract: Genetic studies are under way for many complex traits, spurred by the recent feasibility of whole genome scans. Clear guidelines for the interpretation of linkage results are needed to avoid a flood of false positive claims. At the same time, an overly cautious approach runs the risk of causing true hints of linkage to be missed. We address this problem by proposing specific standards designed to maintain rigor while also promoting communication.
5,317 citations
TL;DR: A brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons is characterized, revealing polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG) n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2.
2,264 citations
TL;DR: The characterization of the human Notch3 gene, which was previously mapped to the CADASIL critical region, is reported, indicating that Notch 3 could be the defective protein in CADASil patients.
Abstract: Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.
1,917 citations
TL;DR: Southern blot analyses and genomic cloning demonstrates the existence of related genes, raising the possibility that similar abnormalities in related genes may give rise to diseases similar to Machado-Joseph disease.
Abstract: We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68-79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.
1,704 citations
TL;DR: There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.
Abstract: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.
1,586 citations