Migraine occurs commonly among family members. The existence of genetic factors in migraine is almost certain from linkage analyses and twin studies. Multiple genes are speculated to be involved in the development of migraine. However, the definitive causative genes and susceptibility genes have not been identified.
| Grade B |
Many studies have been conducted with the aim to identify the causative genes and susceptibility genes of migraine. Three causative genes have been identified for familial hemiplegic migraine, but the association of these genes with “normal” migraine has been ruled out. Many association analyses using the candidate gene approach have also been conducted, and some of the findings have been subjected to meta-analysis. In addition, linkage analyses and large-scale genome-wide association studies (GWAS) are ongoing, and multiple chromosomal loci and genes have been reported. However, the detailed pathophysiological mechanisms remain unclear.
Although it has long been noted that migraine commonly occurs within the family, whether this phenomenon is based on genetic factors or environmental factors, or simply due to coincidence because of the high prevalence of migraine has been much debated.
More recently, pedigree analysis1) and twin analyses2)3) suggested that migraine is a multi-factorial genetic disease likely to be associated with a combination of multiple genetic factors and environmental factors. It has been reported that both genetic and environmental factors are involved in migraine without aura, while genetic factors are more strongly associated with migraine with aura, but some reports showed no difference between migraine with and without aura.4)5)
Since the first report of a causative gene found in some families with familial hemiplegic migraine (FHM, a special type of migraine with aura),6) several genes; FHM1, FHM2 and FHM3, have so far been identified (for details, see Comments and Evidence of CQ VIII-4, page 239). All the genes are related to membrane channel function, suggesting a relationship between the excitability of neurons and pathophysiology of migraine.7) These findings were the driving force that promoted the great advances in genetic research on migraine. However, association analyses have ruled out the association between the causative genes of FHM and “normal” migraine.8)
A pedigree analysis focusing on the K+ channel in patients with familial migraine other than FHM reported new finding of a significant relationship with mutation in KCNK18.9)
As for the migraine susceptibility genes, many investigations and verification studies using a candidate gene approach have been conducted, but most yielded inconsistent results. Some of the reports have been subjected to meta-analysis, and a significant relationship has been reported for multiple genes including ACE,10) MTHFR,10)11) ESR-112) and 5-HTT.13)
Linkage analyses have reported multiple chromosomal loci, but the exact genes have not been identified.
Genome-wide association study has revealed associations of PRDM16, TRPM8 and LRP1 with migraine,14) but the contribution of individual genes was low, and the detailed pathophysiology mechanisms remain unclear.
1) Russell MB, Olesen J: Increased familial risk and evidence of genetic factor in migraine. BMJ 1995; 311(7004): 541-544.
2) Ulrich V, Gervil M, Kyvik KO, Olesen J, Russell MB: Evidence of a genetic factor in migraine with aura: a population-based Danish twin study. Ann Neurol 1999; 45(2): 242-246.
3) Russell MB, Ulrich V, Gervil M, Olesen J: Migraine without aura and migraine with aura are distinct disorders. A population-based twin survey. Headache 2002; 42(5): 332-336.
4) Nyholt DR, Gillespie NG, Heath AC, Merikangas KR, Duffy DL, Martin NG: Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities. Genet Epidemiol 2004; 26(3): 231-244.
5) Ligthart L, Boomsma DI, Martin NG, Stubbe JH, Nyholt DR: Migraine with aura and migraine without aura are not distinct entities: further evidence from a large Dutch population study. Twin Res Hum Genet 2006; 9(1): 54-63.
6) Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87(3): 543-552.
7) de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM: Molecular genetics of migraine. Hum Genet 2009; 126(1): 115-132.
8) Nyholt DR, LaForge KS, Kallela M, Alakurtti K, Anttila V, Frkkil M, Hmalinen E, Kaprio J, Kaunisto MA, Heath AC, Montgomery GW, Gbel H, Todt U, Ferrari MD, Launer LJ, Frants RR, Terwindt GM, de Vries B, Verschuren WM, Brand J, Freilinger T, Pfaffenrath V, Straube A, Ballinger DG, Zhan Y, Daly MJ, Cox DR, Dichgans M, van den Maagdenberg AM, Kubisch C, Martin NG, Wessman M, Peltonen L, Palotie A: A high-density association screen of 155 ion transport genes for involvement with common migraine. Hum Mol Genet 2008; 17(21): 3318-3331.
9) Lafrenire RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenire F, McLaughlan S, Dub MP, Marcinkiewicz MM, Ramagopalan S, Ansorge O, Brais B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G, Rouleau GA: A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med 2010; 16(10): 1157-1160.
10) Schrks M, Rist PM, Kurth T: MTHFR 677C>T and ACE D/I polymorphisms in migraine: a systematic review and meta-analysis. Headache 2010; 50(4): 588-599.
11) Samaan Z, Gaysina D, Cohen-Woods S, Craddock N, Jones L, Korszun A, Owen M, Mente A, McGuffin P, Famer A: Methylenetetrahydrofolate reductase gene variant (MTHFR C677T) and migraine: a case control study and meta-analysis. BMC Neurol 2011; 11: 66.
12) Schrks M, Rist PM, Kurth T: Sex hormone receptor gene polymorphisms and migraine: a systematic review and meta-analysis. Cephalalgia 2010; 30(11): 1306-1328.
13) Liu H, Liu M, Wang Y, Wang XM, Qiu Y, Long JF, Zhang SP: Association of 5-HTT gene polymorphisms with migraine: a systematic review and meta-analysis. J Neurol Sci 2011; 305(1-2): 57-66.
14) Chasman DI, Schrks M, Anttila V, de Vries B, Schminke U, Launer LJ, Terwindt GM, van den Maagdenberg AM, Fendrich K, Vlzke H, Ernst F, Griffiths LR, Buring JE, Kallela M, Freilinger T, Kubisch C, Ridker PM, Palotie A, Ferrari MD, Hoffmann W, Zee RY, Kurth T: Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 2011; 43(7): 695-698.
• Search database: PubMed (2011/10/07)
Search was conducted using the same search terms as for Chronic Headache VIII-1 in the Clinical Practice Guidelines 1st edition, narrowed to after 2004 only.
migraine
& association 877
& genetics 897
& polymorphisms 213
& (genetic factor OR genetic factors) 287
& genetic influence 44
& familial occurrence 239
& inheritance 59
& twin 48
& segregation 6
& adoption 3
& linkage 108
Cluster headache occurs significantly more commnly among family members, and the involvement of genetic factors is highly probable. Due to the coexistence of environmental factors and the genetic heterogeneity, the causative genes and susceptibility genes for cluster headache have not been identified.
| Grade B |
Family-based and twin studies have reported the involvement of genetic factors in cluster headache, but the mode of inheritance and other details remain unclear. Some reports have indicated the involvement of gene polymorphism, but analysis is difficult due to the clinical diversity and the low prevalence of cluster headache.
Summarizing reports of genetic epidemiological surveys on cluster headache, first-degree relatives of patients with cluster headache are 5 to 18 times, and second-degree relatives are 1 to 3 times more likely to have cluster headache than the general population, suggesting that in addition to environmental factors, genetic predispositions are involved in the development of cluster headache.1)
Many studies have investigated the causative genes and susceptible genes of cluster headache.
In relation to the pathophysiological hypothesis of cluster headache, research has focused on orexin (hypocretin), a physiologically active peptide closely associated with the hypothalamus. It has been shown that patients with cluster headache have a significantly higher frequency of GG genotype of 1246G>A polymorphism [rs2653349] in the hypocretin receptor 2 gene (HCRTR2: MIM ID 602393). A meta-analysis of two reports that confirmed such association2) and one report that found no such association3) verified an association between cluster headache and HCRTR2.4)
A genetic study also reported two-fold higher frequency of GG genotype of 925A>G polymorphism [rs1126671] in exon 7 of the alcohol dehydrogenase 4 gene (ADH4: MIM ID 103740) in patients with cluster headache.5)
In relation to treatment, carriers of CT genotype of 825C>T polymorphism [rs5443] in the guanine nucleotide-binding protein β3 gene (GNB3: MIM ID 139130) was three times more responsive to triptan compared to carriers of CC genotype.6)
Further clinical genetic data have to be accumulated to determine whether these genes are the causative genes or susceptibility genes of cluster headache. One genome-wide association study of cluster headache was conducted, and found no significant genes associated with cluster headache.3)
1) Russell MB: Epidemiology and genetics of cluster headache. Lancet Neurol 2004; 3(5): 279-283.
2) Schrks M, Kurth T, Geissler I, Tessman G, Diener HC, Rosskopf D: Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology 2006; 66(12): 1917-1919.
3) Baumber L, Sjstrand C, Leone M, Harty H, Bussone G, Hilert J, Trembath RC, Russell MB: A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 2006; 66(12): 1888-1893.
4) Rainero I, Rubino E, Valfr W, Gallone S, De Martino P, Zampella E, Pinessi L: Association between the G1246A polymorphism of the hypocretin receptor 2 gene and cluster headache: a meta-analysis. J Headache Pain 2007; 8(3): 152-156.
5) Rainero I, Rubino E, Gallone S, Fenoglio P, Negro E, De Martino P, Savi L, Pinessi L: Cluster headache is associated with the alcohol dehydrogenase 4 (ADH4) gene. Headache 2010; 50(1): 92-98.
6) Schrks M, Kurth T, Stude P, Rimmbach C, de Jesus J, Junjic M, Diener HC, Rosskopf D: G protein beta3 polymorphism and triptan response in cluster headache. Clin Pharmacol Ther 2007; 82(4): 396-401.
• Search database: PubMed (2011/10/11)
Search was conducted using the same search terms as for Chronic Headache VIII-2 in the Clinical Practice Guidelines 1st edition, narrowed to after 2004 only.
cluster headache
& association 73
& genetics 60
& polymorphisms 14
& (genetic factor OR genetic factors) 21
& genetic influence 4
& familial occurrence 24
& inheritance 4
& twin 9
& segregation 0
& adoption 0
& linkage 7
Environmental factors are considered to be strongly associated with the development of tension-type headache. However, the presence of genetic factors in some subtypes is possible.
| Grade C |
There is less research on the genetic factors for tension-type headache compared to migraine and cluster headache. Reports are limited to some twin studies. Although environmental factors are mainly involved in the development of tension-type headache, the involvement of genetic predisposition has been reported for frequent episodic tension-type headache.
A study using the New Danish Twin Register of 5,360 twins found no significant difference in concordance of tension-type headache in both monozygotic and dizygotic twin pairs.1) The report concluded that genetic factor, if it exits, has minor effect.
In a subsequent study using the same Register, of 11,199 twin pairs with tension-type headache and no migraine, the concordance rate of frequent episodic tension-type headache was higher in monozygotic than in dizygotic twin pairs.2) The concordance rate of infrequent episodic tension-type headache was significantly higher in monozygotic than in dizygotic twin pairs in women only, and the difference was small in men. The report concluded that genetic factors play a role in frequent episodic tension-type headache, while infrequent episodic tension-type headache is caused primarily by environmental factors, and that no firm conclusion could be drawn for chronic tension-type headache.
Further accumulation of clinical genetic data for different regions and various races is required to elucidate whether genetic element is involved in tension-type headache.
1) Ulrich V, Gervil M, Olesen J: The relative influence of environment and genes in episodic tension-type headache. Neurology 2004; 62(11): 2065-2069.
2) Russell MB, Saltyte-Benth J, Levi N: Are infrequent episodic, frequent episodic and chronic tension-type headache inherited? A population-based study of 11 199 twin pairs. J Headache Pain 2006; 7(3): 119-126.
• Search database: PubMed (2011/10/11)
Search was conducted using the same search terms as for Chronic Headache VIII-3 in the Clinical Practice Guidelines 1st edition, narrowed to after 2004 only.
tension-type headache
& association 102
& genetics 30
& polymorphisms 11
& (genetic factor OR genetic factors) 27
& genetic influence 2
& familial occurrence 42
& inheritance 1
& twin 9
& segregation 0
& adoption 1
& linkage 2
Familial hemiplegic migraine type 1, type 2 and type 3 have been reported to be familial migraine caused by single gene mutations. In addition, single gene disorders that may coexist with migraine include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary hemorrhagic telangiectasia type 1 (HHT1), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged-red fibers (MERRF).
| Grade A |
Genetic diseases causing migraine due to single gene mutations exist, and the causative genes have been identified in recent years.
1. Familial migraine caused by single gene mutations
The causative gene of FHM1, CACNA1A, is located on chromosome 19p13 and encodes Cav2.1, the α1 subunit of P/Q type voltage-gated calcium channel.1) CACNA1A is also known to be the causative gene of spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and progressive cerebellar ataxia (PCA). FHM1 is complicated with diverse symptoms including disturbance of consciousness, fever, and cerebella ataxia. Among the mutations, the frequency of p.T666M point mutation (substituting methionine for threonine at codon 666) is high.
The causative gene of FHM, ATP1A2, is located on chromosome 1q21-23 and encodes the α2 subunit of ATP-dependent Na,K-ATPase.2) Unlike FHM1, most of the FHM2 patients manifest a clinical picture of pure hemiplegic migraine, although some cases are complicated with cerebellar ataxia, epilepsy and mental retardation.
The causative gene of FHM3, SCN1A, is located on chromosome 2q24 and encodes Nav1.1, the α1 subunit of voltage-gated sodium channel.3) SCN1A is also known to be the causative gene of generalized epilepsy febrile seizures plus (GEFS+) or Dravet syndrome. Apart from pure familial hemiplegic migraine, cases of FHM3 are complicated with epilepsy and elicited repetitive transient daily blindness (ERDB) have been reported.
2. Genetic diseases with concurrent migraine
The causative gene of CADASIL is NOTCH3 located on chromosome 19p13.4) Twenty to 30% of CADASIL patients manifest migraine with aura concurrently. With onset at 30 to 50 years of age, CADASIL is characterized by recurrent subcortical infarction and transient ischemic attack, as well as diverse symptoms including impaired cognitive function, psychiatric symptoms, and pseudobulbar palsy. CADASIL is an autosomal dominant disease. On brain MRI, characteristic hyperintense signals in external capsule and temporal pole white matter on T2-weighted and FLAIR images are observed.
The causative gene of RVCL is TREX1, located on chromosome 19p13.5) RVCL is an autosomal dominant disorder. With onset symptoms of retinal vasculopathy and progressive visual disturbance at 30 to 40 years of age, migraine is added to the clinical picture together with diverse neurological symptoms including cognitive decline due to multiple infarcts in cerebral cortex, convulsion, spastic paralysis and dysarthria, as well as systemic symptoms including Raynaud symptom, renal disease and cirrhosis. On brain MRI, multiple contrast-enhancing lesions in cerebral subcortical white matter and surrounding edema are observed.
So far four genetic loci (HHT1 to 4) have been reported, and the causative genes for HHT1 and HHT2 have been identified. Approximately 40% of patients with HHT1 manifest migraine concurrently. The causative gene of HHT1 (MIM ID 187300) is ENG, located on chromosome 9q34.6) HHT1 is an autosomal dominant disease previously known as Osler-Rendu-Weber disease. The disorder is characterized by arteriovenous malformations in the lung, brain, liver and spinal cord, as well as multiple telangiectases and hemorrhages in the skin, mucous and internal organs.
Migraine has been reported to occur concurrently with subtypes of mitochondrial disorder: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) characterized by episodic vomiting, headache, convulsion and stroke-like symptoms, and MERRF (myoclonic epilepsy associated with ragged-red fibers) with myoclonus, cerebellar ataxia and myopathy as main symptoms. Eighty percent of MELAS cases are caused by A3243G mutation of MTTL1 that encodes mitochondrial tRNA-leucine.7) Mutations of ND5 that encodes the subunit 5 of electron transport complex 1 are also known. On the other hand, the major causative mutation in MERRF is A8344G mutation of MTTK that encodes mitochondrial tRNA-lysine.
3. Other genes associated with familial migraine
Using candidate gene approach or pedigree analysis, mutations in various other genes such as EAAT 1,8) SLC4A4,9) and KCNK1810) have been reported in pedigrees with familial migraine. To determine whether these genes are causative genes of migraine, further accumulation of clinical genetic data is necessary.
1) Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87(3): 543-552.
2) De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G: Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003; 33(2): 192-196.
3) Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM: Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005; 366(9483): 371-377.
4) Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Ccillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383(6602): 707-710.
5) Richards A, van den Maagdenberg AM, Jen JC, Kavanagh D, Bertram P, Spitzer D, Liszewski MK, Barilla-Labarca ML, Terwindt GM, Kasai Y, McLellan M, Grand MG, Vanmolkot KR, de Vries B, Wan J, Kane MJ, Mamsa H, Schfer R, Stam AH, Haan J, de Jong PT, Storimans CW, van Schooneveld MJ, Oosterhuis JA, Gschwendter A, Dichgans M, Kotschet KE, Hodgkinson S, Hardy TA, Delatycki MB, Hajj-Ali RA, Kothari PH, Nelson SF, Frants RR, Baloh RW, Ferrari MD, Atkinson JP: C-terminal truncations in human 3’-5’ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 2007; 39(9): 1068-1070.
6) McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, et al: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994; 8(4): 345-351.
7) Goto Y, Nonaka I, Horai S: A mutation in the tRNA (Leu) (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990; 348(6302): 651-653.
8) Jen JC, Wan J, Palos TP, Howard BD, Baloh RW: Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 2005; 65(4): 529-534.
9) Suzuki M, Van Paesschen W, Stalmans I, Horita S, Yamada H, Bergmans BA, Legius E, Riant F, De Jonghe P, Li Y, Sekine T, Igarashi T, Fujimoto I, Mikoshiba K, Shimadzu M, Shiohara M, Braverman N, Al-Gazali L, Fujita T, Seki G: Defective membrane expression of the Na+-HCO3—cotransporter NBCe1 is associated with familial migraine. Proc Natl Acad Sci U S A 2010; 107(36): 15963-15968.
10) Lafrenire RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenire F, McLaughlan S, Dub MP, Marcinkiewicz MM, Ramagopalan S, Ansorge O, Brais B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G, Rouleau GA: A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med 2010; 16(10): 1157-1160.
• Search database: PubMed (2011/12/21)
Migraine & CACNA1A 253
Migraine & ATP1A2 115
Migraine & SCN1A 41
Migraine & Notch 3104
TREX 168
Migraine & HHT 10
Migraine & MELAS 70
Migraine & MERRF 7
Migraine & genome-wide association study 29
Genetic diagnosis of familial hemiplegic migraine may be possible by analyzing CACNA1A, ATP1A2 and SCN1A. While it is rare to find causative mutations in sporadic hemiplegic migraine patients, genetic diagnosis is possible in some young-onset cases. Although migraine susceptibility genes have been identified by genome-wide association study, the contribution of individual gene is low and not useful for genetic diagnosis.
| Grade B |
With advances made in the identification of causative genes for familial hemiplegic migraine, genetic diagnosis of this disorder has become possible. For common migraine also, susceptibility genes are gradually being identified.
In general, for conducting genetic diagnosis, detailed explanations and various supports such as genetic counseling have to be provided to the subjects, according to the guideline for genetic diagnosis of neurological diseases (2009). In addition, since the causative genes of hemiplegic migraine; CACNA1A, ATP1A2 and SCN1A1)2) are relatively large genes, it is inefficient to conduct genetic diagnosis on all the cases. Careful consideration of the indication for genetic diagnosis is recommended, by reviewing genetic epidemiological and clinical information including frequency of disease, age of onset and associated symptoms.
Among the causative genes for hemiplegic migraine, the mutation frequencies of CACNA1A and ATP1A2 are high, and that of SCN1A is low. Therefore, in conducting genetic diagnosis, analyzing CACNA1A and ATP1A2 first, and then proceeding to SCN1A is recommended.
In a large-scale epidemiological survey of the whole Danish population of 5.2 million people, a total of 44 families with familial hemiplegic migraine (FHM) were identified.3) When mutation analyses of all exons of CACNA1A and ATP1A2 as well as p.Q1489K mutation of SCN1A were conducted in 43 families, 14% of the families were positive for these mutations. The mutation frequencies for CACNA1A and ATP1A2 were similar, and no SCN1A mutation was detected. In the same population, 105 individuals with sporadic hemiplegic migraine were identified.4) Mutation analysis was conducted in 100 individuals, and causative gene mutations were found in only 2 individuals.
Therefore, FHM is a genetically heterogeneous disease, and so far genetic diagnosis has not identified mutations in the majority of the affected families. This point has to be explained when obtaining informed consent for genetic diagnosis.
Causative mutations identified in FHM are rarely detected in patients with SHM. However, when analysis was conducted in early-onset SHM only, de novo mutation was identified in 19 of 25 (76%) SHM patients aged 16 years or younger.5) Therefore genetic diagnosis has clinical significance in early-onset SHM. However, whether amino acid substitutions identified in SHM represent true causative mutations has to be examined carefully.
No large-scale genetic epidemiological study on hemiplegic migraine has been conducted in Japan, and the frequency of mutation in Japanese remains unknown. As of November 2011, reports of mutations in hemiplegic migraine among Japanese included two families with p.T666M mutation in CACNA1A, one family with p.S218L mutation in CACNA1A, and one family with p.H916L mutation in ATP1A2.
Regarding the involvement of FHM-related causative mutations in common migraine, linkage analysis, association study and direct sequencing analysis yielded negative results.6) Therefore analysis of FHM-related genes in common migraine has no relevance. As for migraine susceptibility genes, candidate gene approach suggested an association with MTHFR7) and 5-HTT.8) Genome-wide association study reported an association with TRPM8 and LRP1.9) However, the odds ratios were 1.3 to 1.5 at the highest, not sufficiently accounting for the heritability of migraine. Therefore, at this time, they are not useful for genetic diagnosis.
1) Russell MB, Ducros A: Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol 2011; 10(5): 457-470.
2) de Vries B, Frants R, Ferrari M, van den Maagdenberg A: Molecular genetics of migraine. Hum Genet 2009; 126(1): 115-132.
3) Thomsen LL, Kirchmann M, Bjornsson A, Stefansson H, Jensen RM, Fasquel AC, Petursson H, Stefansson M, Frigge ML, Kong A, Gulcher J, Stefansson K, Olesen J: The genetic spectrum of a population-based sample of familial hemiplegic migraine. Brain 2007; 130(Pt 2): 346-356.
4) Thomsen LL, Oestergaard E, Bjornsson A, Stefansson H, Fasquel AC, Gulcher J, Stefansson K, Olesen J: Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients. Cephalalgia 2008; 28(9): 914-921.
5) Riant F, Ducros A, Ploton C, Barbance C, Depienne C, Tournier-Lasserve E: De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology 2010; 75(11): 967-972.
6) Noble-Topham SE, Dyment DA, Cader MZ, Ganapathy R, Brown JD, Rice GPA, Ebers GC: Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13. Neurology 2002; 59(7): 1099-1101.
7) Samaan Z, Gaysina D, Cohen-Woods S, Craddock N, Jones L, Korszun A, Owen M, Mente A, McGuffin P, Farmer A: Methylenetetrahydrofolate reductase gene variant (MTHFR C677T) and migraine: a case control study and meta-analysis. BMC Neurol 2011; 11: 66.
8) Schurks M, Rist PM, Kurth T: 5-HTTLPR polymorphism in the serotonin transporter gene and migraine: A systematic review and meta-analysis. Cephalalgia 2010; 30(11): 1296-1305.
9) Chasman DI, Schrks M, Anttila V, de Vries B, Schminke U, Launer LJ, Terwindt GM, van den Maagdenberg AM, Fendrich K, Vlzke H, Ernst F, Griffiths LR, Buring JE, Kallela M, Freilinger T, Kubisch C, Ridker PM, Palotie A, Ferrari MD, Hoffmann W, Zee RY, Kurth T: Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 2011; 43(7): 695-698.
• Search database: PubMed (2011/12/21)
hemiplegic migraine AND epidemiology 38
(hemiplegic migraine) AND Japanese 24
familial hemiplegic migraine AND sporadic 77
(common migraine) AND (CACNA1A OR ATP1A2 OR SCN1A) 206
(migraine) AND (susceptibility gene) 294
• Japanese Society of Neurology (ed.): Guideline for Genetic Diagnosis of Neurological Diseases 2009. Igakushoin 2009.