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.     

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.     

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.     

A highly polymorphic poly-glutamine stretch in the potassium channel KCNN3 in migraine

Objective: The present study is designed to further elucidate the molecular genetic basis of migraine with and without aura. BACKGROUND: Migraine is a common disease of as yet unknown etiology. Interest in ion channels in migraine has been spurred by molecular genetic findings in familial hemiplegic migraine, since familial hemiplegic migraine type 1 is caused by mutations in the calcium channel gene CACNA1A. METHODS: Given this role of ion channels in migraine, we assessed the potassium channel KCNN3 as a candidate gene for common migraine. We analyzed the highly polymorphic repeat region coding for a poly-glutamine stretch, which constitutes part of the cytoplasmic tail of the channel protein. RESULTS: We found an excess of the allele coding for 15 poly-glutamines in migraine patients. CONCLUSIONS: The potassium channel KCNN3 may thus be of pathophysiological importance in migraine with and without aura.     

Migraine genetics: An update

A growing interest in genetic research in migraine has resulted in the identification of several chromosomal regions that are involved in migraine. However, the identification of mutations in the genes for familial hemiplegic migraine (FHM) forms the only true molecular genetic knowledge of migraine thus far. The increased number of mutations in the FHM1 (CACNA1A) and the FHM2 (ATP1A2) genes allow studying the relationship between genetic findings in both genes and the clinical features in patients. A wide spectrum of symptoms is seen in patients. Additional cerebellar ataxia and (childhood) epilepsy can occur in FHM1 and FHM2. Functional studies show a dysfunction in ion transport as the key factor in the pathophysiology of (familial hemiplegic) migraine that predict an increased susceptibility to cortical spreading depression—the underlying mechanism of migraine aura.     

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.     

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 α2 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.     

Acetazolamide acts on neuromuscular transmission abnormalities found in some migraineurs

Mild subclinical impairment of neuromuscular transmission can be detected with single-fibre electromyography (SFEMG) in subgroups of patients suffering from migraine and could be due to dysfunctioning Ca2+-channels on motor axons controlling stimulation-induced acetylcholine release. Acetazolamide, which is thought to ameliorate ion channel function, was shown effective in familial hemiplegic migraine and episodic ataxia type 2, both of which are associated with mutations of the neuronal Ca2+-channel gene CACNA1A, as well as in aura status. We treated therefore in an open pilot study five non-hemiplegic migraineurs showing mild SFEMG abnormalities with acetazolamide for several weeks. This was followed by a normalization of SFEMG recordings in all patients and by clinical improvement in four. These results support the assumption that the subclinical impairment of neuromuscular transmission found in certain migraineurs might be due to dysfunctioning Ca2+-channels.     

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.     

Migraine genes and the relation to gender

Migraine is an episodic brain disorder that is characterized by recurrent attacks of severe unilateral headache that are accompanied by various neurological symptoms. In addition, many patients have what is called an aura with visual and sensory disturbances. The majority of patients are female, suggesting that female hormones play an important role in the pathophysiology of the disorder. The molecular mechanisms, however, underlying this female preponderance are not well understood. It can be expected that the field of genetics that aims at identifying genetic factors that cause migraine by lowering the threshold for attacks will unravel some of these mechanisms. The 3 best known migraine genes encode ion transporters and were identified in families with familial hemiplegic migraine (FHM), a rare subtype of migraine with aura. FHM gene mutations cause alterations in mechanisms that control and modulate the neurotransmitter balance in the brain. Transgenic mice knock-in with human pathogenic mutations that were shown to exhibit some migraine-relevant features were very helpful in dissecting molecular mechanisms of migraine and pointed to a central role for cortical glutamate. In addition, transgenic mice that overexpress human RAMP1 exist and exhibit an increased sensitivity to calcitonin gene-related peptide. Findings from genetic and animal experiments on gender differences in migraine are discussed. Recently, a role for glutamate also came forward from a genome-wide association study in common migraine. By deciphering genetic and pathogenic migraine pathways, it can be expected that in the near future we will better understand mechanisms behind the female preponderance in migraine.     

The cerebellum and migraine

Clinical and pathophysiological evidences connect migraine and the cerebellum. Literature on documented cerebellar abnormalities in migraine, however, is relatively sparse. Cerebellar involvement may be observed in 4 types of migraines: in the widespread migraine with aura (MWA) and migraine without aura (MWoA) forms; in particular subtypes of migraine such as basilar-type migraine (BTM); and in the genetically driven autosomal dominant familial hemiplegic migraine (FHM) forms. Cerebellar dysfunction in migraineurs varies largely in severity, and may be subclinical. Purkinje cells express calcium channels that are related to the pathophysiology of both inherited forms of migraine and primary ataxias, mostly spinal cerebellar ataxia type 6 (SCA-6) and episodic ataxia type 2 (EA-2). Genetically driven ion channels dysfunction leads to hyperexcitability in the brain and cerebellum, possibly facilitating spreading depression waves in both locations. This review focuses on the cerebellar involvement in migraine, the relevant ataxias and their association with this primary headache, and discusses some of the pathophysiological processes putatively underlying these diseases.     

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.     

Neurotology of Migraine

Neurotologic symptoms are common with migraine, yet relatively little is known about the pathophysiology of such symptoms. Motion sensitivity with bouts of motion sickness occurs in about two thirds of patients with migraine. Episodes of vertigo occur in about one fourth of patients and, in some, vertigo is the only symptom (so-called "migraine equivalent"). Phonophobia is the most common auditory symptom, but fluctuating hearing loss and acute permanent hearing loss occur in a small Percentage. Migraine can mimic Meniere's disease and so-called "vestibular Meniere's disease" is usually associated with migraine. The recent discovery of a mutation in a brain calcium-channel gene in families with hemiplegic migraine and in families with episodic vertigo and ataxia suggests a possible mechanism for neurotologic symptoms in patients with more common varieties of migraine. A defective calcium channel, primarily expressed in the brain and inner ear, could lead to reversible hair cell depolarization and auditory and vestibular symptoms. This hypothesis is currently being investigated in other families with migraine headaches and neurotologic symptoms. Hopefully, such studies will lead to improved diagnosis and better treatments in the future.     

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.     

Migraine update

Migraine is one of the common diseases suffering 8.4 million patients in Japan. The pathophysiology of migraine remains unclear. The genetic and basic studies of the familial hemiplegic migraine, a specific subtype of migraine with aura, have demonstrated the dysfunction of mutant brain-expressed calcium ion channel and/or the Na+/K+ ion transporter and suggested the association between cortical spreading depression (CSD) and migraine with aura. It is suggested that the CSD, neurogenic inflammation and vasodilatation caused by unknown triggers may activate the 'brainstem migraine generator' and amplified back way. In consequence, headache and/or aura will be appeared and strengthened. Our etiological data of headache in Daisen located in Western Japan clarified as follows; 1) Overall prevalence of migraine in Daisen was 6.0%. Women observed a 5.9-fold higher risk of migraine than men. 2) Fatigue, mental stress, and lack of sleep were the main headache triggers. 3) Only 7.3% of those with migraine with aura and 5.3% of those with migraine without aura had consulted a physician. 4) Migraineurs consume significantly more fatty/oily foods, coffee, and tea than nonheadache subjects of the same community. Migraineurs consume significantly fewer fish than nonheadache residents. As a conclusion, only a few Japanese migraineurs receive benefits of medical services and recent advances of headache medicine. The Japanese guideline for chronic headache treatment has declared in 2002. The International Classification of headache disorders has reedited to the 2nd edition. Public education concerning headaches is one of the most urgent issues in Japan.     

Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4

BACKGROUND: Migrainous vertigo (MV) is increasingly recognized as a common cause of episodic vertigo. MV displays several clinical similarities with familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA-2), which have been linked to mutations in 3 genes, CACNA1A, encoding a neuronal calcium channel alpha subunit, ATP1A2, encoding a catalytic subunit of a Na(+)/K(+)-ATPase, and most recently the voltage-gated sodium channel SCN1A. The present study explored the hypothesis that mutations in CACNA1A, ATP1A2, SCN1A, and the calcium channel beta(4) subunit CACNB4 confer susceptibility to MV. METHODS: Mutation analysis of the coding exons and exon/intron junctions of CACNA1A, ATP1A2, SCN1A, and CACNB4 was performed in 14 unrelated MV patients by conformation sensitive gel electrophoresis and automated sequence analysis. RESULTS: Analysis of the 4 candidate genes in the 14 MV patients resulted in the identification of a total of 26 sequence variants. The silent substitution D29D in CACNB4 was observed in 2 MV patients and was not present in 46 ethnically matched control DNA samples. The remaining variants were also observed in control DNA samples and the allele frequencies of variants that resulted in amino acid substitutions were not significantly different between patients and controls. CONCLUSIONS: Based on this group of patients there is no evidence that the genes causing FHM and EA-2 represent major susceptibility loci for MV.     

A single-fibre EMG study of neuromuscular transmission in migraine patients

It is known that mutations of CACNA1A, which encodes a neuronal P/Q Ca(2+) channel, are present in patients with familial hemiplegic migraine, and possibly in other types of migraine as well. This calcium channel is also involved in neuromuscular transmission. To assess if the single-fibre EMG (SFEMG) method can demonstrate a neuromuscular transmission deficit in migraine, a group of 26 patients with different types of migraine and 20 healthy control subjects were studied. The migraine patients were divided into three groups: 8 patients with migraine without aura (MoA), 12 with migraine with aura excluding visual aura (MA) and 6 with visual aura (VA). A SFEMG of the voluntarily activated extensor digitorum communis muscle was performed. The SFEMG results were normal in the healthy controls and the MoA group (migraine without aura). Slight neuromuscular transmission disturbances were present in 6/12 (50%) of patients with MA and in 1/6 (17%) of patients with VA. We suggest that abnormal neuromuscular transmission detectable by SFEMG may reflect a genetically determined dysfunction of the P/Q Ca(2+) channels in a subgroup of migraineurs with aura.     

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.     

Familial Hemiplegic Migraine: A New Case

SYNOPSIS
The definition of familial hemiplegic migraine is still unsettled. We report the case of a young man who has had hemiplegic migraine attacks for ten years. CT of the brain was abnormal with a low density in the temporal lobe, suggesting infarction and probably having no relation to the attacks. There was a clear family history of hemiplegic migraine, possibly with the same type of attack. Ergotamine tartrate seemed to be effective in preventing headache. This case challenges the current clinical definition of familial hemiplegic migraine, in that while the attack pattern was hereditary, the hemiplegia occurred as an aura rather than accompanying and outlasting the headache.