Genetics of familial hemiplegic migraine

Familial hemiplegic migraine is an autosomal dominant form of migraine with aura, characterized by the occurrence of a motor deficit during the aura. In 20% of families, permanent cerebellar signs (ataxia or nystagmus) are observed. This condition is genetically heterogeneous. A first gene, CACNA1A, located on chromosome 19 and encoding the main subunit of P/Q type neuronal calcium channel, is implicated in 50% of unselected families and in all families with cerebellar symptoms. Thirteen distinct point mutations of CACNA1A have been identified so far in familial and sporadic cases. A second yet unidentified gene located on chromosome 1 is implicated in 20% of the families. One or more other genes are still to be mapped. Various approaches have been used to understand the mechanisms leading from the CACNA1A mutations to hemiplegic migraine, including in vitro electrophysiological studies as well as detailed analysis of the CACNA1A mutant mice tottering and leaner.     

Molecular genetics and migraine

Migraine carries a significant hereditary determination. Familial hemiplegic migraine (FHM) has been recently linked to mutations in the CACNA1A gene on chromosome 19. CACNA1A codes for a subunit of a neural calcium channel. Other linkage loci on chromosome 1q21-23 and 1q31 have been reported. Several linkage and association studies have been performed to determine the role of the CACNA1A gene, and of other candidate genes implicated in the metabolism of serotonin and dopamine, in the more common types of migraine. Co-morbidity of migraine with vascular events has been analysed versus genetic prothrombotic factors and mitochondrial DNA, and genes involved in the inflammatory cascade have been explored. Though no definite conclusions have emerged from these studies as yet, molecular genetics of migraine can be expected to unravel the complex aetiologies of these fascinating diseases.     

The genetics of migraine

Migraine is currently considered to be a multifactorial disease in that it is modified by environmental and genetic factors and has a polygenic determination. Familial hemiplegic migraine (FHM), a subtype of migraine with aura conforming to simple mendelian transmission, has been shown to result from mutations in the CACNA1A gene, a neural calcium channel gene. FHM is allelic with episodic ataxia type 2 and spinocerebellar ataxia type 6. FHM is genetically heterogeneous, with at least another linkage locus on chromosome 1. Association and linkage studies have also been performed in migraine with and without aura, the so–called typical migraines, without however definite results up to now.     

The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura that is characterized by motor weakness during attacks. FHM1 is associated with mutations in the CACNA1A gene located on chromosome 19. We report a severe, prolonged HM attack in a young pregnant patient who had the S218L FHM1. This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma. The case history we report suggests a specific, severe phenotype and the co-occurrence of HM and epilepsy related to the S218L FHM1 mutation.     

Migraine genetics

The genetics of migraine is a fascinating and moving research area. Familial hemiplegic migraine, a rare subtype of migraine with a Mendelian pattern of inheritance, is caused by mutations in the chromosome 19 CACNA1A gene in approximately 75% of the families. The finding of mutations in an ionchannel subunit defines migraine as a channelopathy (eg, epilepsy). The genetics of the more frequent variants, migraine with and without aura, is more complex. Several loci have been studied in families and case-control studies, but need to be confirmed.     

CACNA1A gene mutations in familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is an autosomal dominant subtpye of migraine with aura. A few years ago, the gene linked to FHM was identified. CACNA1A encodes a voltage-activated, pore-forming α1A subunit of the P/Q-type calcium channel. At present, an increasing number of mutations have been identified in this gene in patients with FHM. Genotype-phenotype comparisons have become feasible only recently. The in vitro functional consequences on channel function of the first mutations have been deciphered. This is the moment to evaluate these recent discoveries and see how they can help us understant the pathophysiology of FHM and the common forms of migraine.     

A novel ATP1A2 gene mutation in an Irish familial hemiplegic migraine kindred

OBJECTIVE: We studied a large Irish Caucasian pedigree with familial hemiplegic migraine (FHM) with the aim of finding the causative gene mutation. BACKGROUND: FHM is a rare autosomal-dominant subtype of migraine with aura, which is linked to 4 loci on chromosomes 19p13, 1q23, 2q24, and 1q31. The mutations responsible for hemiplegic migraine have been described in the CACNA1A gene (chromosome 19p13), ATP1A2 gene (chromosome 1q23), and SCN1A gene (chromosome 2q24). METHODS: We performed linkage analyses in this family for chromosome 1q23 and performed mutation analysis of the ATP1A2 gene. RESULTS: Linkage to the FHM2 locus on chromosome 1 was demonstrated. Mutation screening of the ATP1A2 gene revealed a G to C substitution in exon 22 resulting in a novel protein variant, D999H, which co-segregates with FHM within this pedigree and is absent in 50 unaffected individuals. This residue is also highly conserved across species. CONCLUSIONS: We propose that D999H is a novel FHM ATP1A2 mutation.     

R583Q CACNA1A variant in SHM1 and ataxia: case report and literature update

Familial hemiplegic migraine (FHM) type 1 is a rare monogenic dominant autosomal disease due to CACNA1A gene mutations. Besides the classical phenotype, mutations on CACNA1A gene are associated with a broader spectrum of clinical features including cerebellar ataxia, making FHM1 a complex channelopathy. We report the case of a patient carrying the p.Arg583Gln mutation affected by hemiplegic migraine and late onset ataxia and we performed a literature review about the clinical features of p.Arg583Gln. Although p.Arg583Gln mutations are associated with a heterogeneous phenotype, carriers present cerebellar signs which consisted generally in ataxia and dysmetria, with intention tremor appearing mostly in advanced age, often progressive and permanent. The heterogeneous spectrum of CACNA1A gene mutations probably causes sporadic hemiplegic migraine (SHM) to be misdiagnosed. Given the therapeutic opportunities, SHM/FHM1 should be considered in differential diagnosis of patients with cerebellar ataxia and migraine with aura.     

Familial hemiplegic migraine presenting as recurrent encephalopathy in a Native Indian family

BACKGROUND: Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, which can result from mutations in the CACNA1A (FHM1) and ATP1A2 (FHM2) genes. Typically, FHM presents with an aura of hemiplegia accompanied by a moderate-to-severe headache. FHM can be associated with other neurological findings including coma and seizures. METHODS: We describe the clinical and genetic features of a two-generation, seven-member Native Indian family with recurrent encephalopathy and FHM. RESULTS: Two of the three affected family members presented initially with encephalopathy, the third family member presented with classic episodes of migraine and hemiparesis. The CACNA1A gene locus was excluded in this family by haplotype analysis and no mutations were identified in the coding region of the ATP1A2 gene by direct sequencing. CONCLUSIONS: This emphasizes the genetic and clinical heterogeneity in familial hemiplagic migraine FHM and highlights the need to consider the diagnosis of FHM in cases of recurrent encephalopathy.     

No involvement of the calcium channel gene (CACNA1A) in a family with cluster headache

It is very likely that genetic factors play a role in the pathophysiology of cluster headache (CH). As CH shares its paroxysmal character with migraine, and migraine has been described in coexistence with CH in some families, we hypothesized that both diseases might share a genetic aetiology. In this study, we tested whether the migraine CACNA1A gene on chromosome 19 is involved in CH in an extended pedigree. Haplotype analysis did not reveal an obvious disease haplotype, and SSCP analysis of all 47 exons of the CACNA1A gene did not reveal a causative mutation. CH in this family is not caused by mutations in the CACNA1A gene.     

Migraine Genetics: Part II

Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21‐23. The defect is a new mutation in the α2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an α1 subunit of a neuronal voltage‐gated Na+ channel. Genome‐wide association studies have identified many non‐coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two‐pore domain potassium channel, TWIK‐related spinal cord potassium channel. TWIK‐related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.     

CACNA1A Nonsense Mutation is Associated With Basilar-Type Migraine and Episodic Ataxia Type 2

Mutations in the CACNA1A gene on chromosome 19 have been associated with a variety of clinical disorders, including familial hemiplegic migraine type 1 and episodic ataxia type 2 (EA2). We report a patient with 2 distinct attack types, one representing EA2 and the other, basilar-type migraine. Genetic testing revealed a novel nonsense mutation in the CACNA1A gene at codon position 583. Treatment with acetazolamide relieved both types of attacks. We hypothesize that the CACNA1A gene mutation may contribute to both typical EA2 and typical basilar-type migraine, extending the spectrum of clinical manifestations associated with CACNA1A mutations.     

The molecular genetics of migraine

Within the past decade it has been possible to identify susceptibility gene loci that predispose to migraine using genetic markers distributed across the human genome. Five new loci with significant linkage to common types of migraine--migraine with or without aura--have been identified on four different chromosomes using a genome-wide screen approach. So far, only the locus on 4q has been replicated but no specific, disease-causing mutations have been described in these common forms of migraine. The best genetic evidence providing molecular insight into migraine still comes from the mutations detected in a rare Mendelian form of migraine with aura--familial hemiplegic migraine (FHM). In 50%-70% of FHM families, mutations in the calcium channel gene CACNA1A in chromosome 19p13 have been identified. In some families, mutations in the ATP1A2 gene encoding the alpha2 subunit of the Na+, K+-ATPase are associated with FHM, linked to 1q23. Here we discuss the current knowledge of the heritability of migraine and rare migraine variants as models for understanding the pathophysiology of common migraine and animal models that might contribute to understanding common forms of migraine.     

Involvement of a Ca 2+ Channel Gene in Familial Hemiplegic Migraine and Migraine With and Without Aura

A gene for familial hemiplegic migraine, a subtype of migraine with aura, was assigned to chromosome 19p13. In this region, we identified a brain-specific P/Q-type calcium channel α1a-subunit gene, CACNA1A, with 47 exons covering 300 kb. Sequencing of all exons and their flanking surroundings revealed polymorphic variations, including a (CA)0-repeat anti a (CAG)n-repeat in the 34 untranslated region. In patients with familial hemiplegic migraine, we found four different missense mutations in conserved functional domains. One of the mutations has occurred on two different haplotypes in unrelated familial hemiplegic migraine families. Moreover, in episodic ataxia type 2, we found two mutations disrupting the reading frame. Thus, familial hemiplegic migraine and episodic ataxia type 2 can be considered as allelic channelopathies. Involvement of this familial hemiplegic migraine locus in migraine with and without aura was demonstrated by sib-pair analysis. We showed an increase of shared marker alleles of locus D19S394 , which is tightly linked to the gene. The association between the α1A calcium channel and familial hemiplegic migraine, and the increase of shared alleles in migraine-affected sib-pairs, have uncovered a new pathway for the pathophysiology of migraine. This finding may provide a rationale for the development of specific prophylactic therapy for migraine and other (paroxysmal) cerebral disorders.     

CACNA1A mutation linking hemiplegic migraine and alternating hemiplegia of childhood

Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.     

Alternating hemiplegia of childhood: no mutations in the familial hemiplegic migraine CACNA1A gene

INTRODUCTION: Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterized by attacks of hemiplegia and mental retardation. It has been often associated with migraine. The CACNA1A gene on chromosome 19 is involved in familial hemiplegic migraine and other episodic cerebral disorders, but also with progressive neuronal damage. METHODS: We performed mutation analysis in this gene in four AHC patients, using single strand conformation polymorphism analysis. RESULTS: We found nine polymorphisms, but no mutations in any of the 47 exons. CONCLUSIONS: Other cerebral ion channel genes remain candidate genes for AHC.     

Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide

Familial hemiplegic migraine type 1 (FHM-1) is a dominantly inherited subtype of migraine with aura and transient hemiplegia associated with mutations in the CACNA1A gene. FHM-1 shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. Experimental studies have established that activation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that CACNA1A mutations in patients with FHM-1 are associated with hypersensitivity to NO-cGMP pathway. We included eight FHM-1 patients with R583Q and C1369Y mutations and nine healthy controls, who received intravenous infusions of 0.5 microg kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by Dermascan. One patient reported migraine without aura 5 h after start of the GTN infusion. No aura was reported. The AUC(headache) in the immediate phase was more pronounced in patients than in controls (P = 0.01). In the 14 h following GTN infusion, there was no difference in the AUC(headache) between patients and controls (P = 0.17). We found no difference in the AUC(VmeanMCA) (P = 0.12) or AUC(STA) (P = 0.71) between FHM-1 patients and controls. None of the control persons reported migraine-like headache. FHM-1 patients do not show hypersensitivity of the NO-cGMP pathway, as characteristically seen in migraine patients with and without aura. This indicates that the pathophysiological pathways underlying migraine headache in FHM-1 may be different from the common types of migraine.     

Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing.

Mutations in the gene CACNA1A have been known to cause familial hemiplegic migraine (FHM); it has been suggested, based on indirect genetic studies, that this gene may also be involved in common forms of migraine. To obtain data from direct gene analysis to test this hypothesis, we investigated 143 patients with common migraine, irrespective of their family history, for the presence of mutations known to result in the FHM phenotype; the mutations V714A, R192Q, R583Q, T666M, V1457L, and 11811L were absent in our patient sample. Furthermore, exons 4, 16, 17, and 36 were completely screened by single-strand conformation polymorphism (SSCP), and no other, hitherto unknown, mutations were detected. Bearing in mind that, in particular, the T666M mutation contributes to a large proportion of FHM linked to chromosome 19, we conclude that common migraine is distinct from FHM in its molecular basis and, therefore, most likely also in its pathophysiology. The possibility, however, of the existence of allelic disorders, with mutations located in other regions of the CACNA1A gene, cannot be ruled out. Molecular testing, therefore, is at present not a feasible option for the diagnosis and classification of migraine.     

Familial Hemiplegic Migraine and Recurrent Episodes of Psychosis: A Case Report

Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with motor aura. We present a case report of a father and son with very similar attacks of hemiplegic migraine and recurrent episodes of accompanying psychoses. Previously, such episodes led to hospitalization and extended clinical examinations, which further worsened the psychoses. Since the episodes were recognized as related to the hemiplegic migraine, a treatment strategy combining sleep and sedation was initiated and progression onto psychosis was almost completely avoided in both father and son. Genetic analyses found no causal gene mutation in the three known FHM genes, suggesting that the phenotype is caused by a yet unidentified mutation.