Neurological Sciences

, Volume 29, Supplement 1, pp 47–51 | Cite as

Migraine: a genetic disease?

Headache Controversies


Migraines carry a substantial genetic liability, and in families affected with the typical migraines (migraine with, MA, and without aura, MO) linkage to some chromosomal loci has been reported. As yet however, no genes are known for MA/MO, while the three genes discovered as responsible for familial hemiplegic migraine (FHM) are not involved in the typical migraines. Accordingly, we propose to consider FHM as a syndromic migraine and not as a variety of MA. Moreover, we suggest that epigenetic mechanisms play a role in the determination of the typical migraines, and that the primary headaches represent behavioural responses (sickness behaviour, fight-or-flight responses), having adaptive advantage and having been evolutionary conserved, in which pain represents a signal of homeostatic imbalance. Epigenetic mechanisms and this proposed genetic behavioural model could be usefully incorporated into headache genetic research.


Migraine Genetics Epigenetics Linkage Genetic association 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Russell MB, Iselius L, Olesen J (1996) Migraine without aura and migraine with aura are inherited disorders. Cephalalgia 16:305–309PubMedCrossRefGoogle Scholar
  2. 2.
    Russell MB, Ulrich V, Gervil M, Olesen J (2002) Migraine without aura and migraine with aura are distinct disorders. A population-based twin survey. Headache 42:332–336PubMedCrossRefGoogle Scholar
  3. 3.
    Devoto M, Lozito A, Staffa G et al (1986) Segregation analysis of migraine in 128 families. Cephalalgia 6:101–105PubMedCrossRefGoogle Scholar
  4. 4.
    Mochi M, Sangiorgi S, Cortelli P et al (1993) Testing models for genetic determination in migraine. Cephalalgia13:389–394PubMedCrossRefGoogle Scholar
  5. 5.
    Ulrich V, Gervil M, Kyvik KO et al (1999) The inheritance of migraine with aura estimated by means of structural equation modelling. J Med Genet 36:225–227PubMedGoogle Scholar
  6. 6.
    Ulrich V, Russell MB, Ostergaard S, Olesen J (1997) Analysis of 31 families with an apparently autosomal-dominant transmission of migraine with aura in the nuclear family. Am J Med Genet 74:395–397PubMedCrossRefGoogle Scholar
  7. 7.
    Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders. Cephalalgia 24:1–160Google Scholar
  8. 8.
    Wessman M, Kallela M, Kaunisto MA et al (2002) A susceptibility locus for migraine with aura, on chromosome 4q24. Am J Hum Genet 70:652–662PubMedCrossRefGoogle Scholar
  9. 9.
    Bjornsson A, Gudmundsson G, Gudfinnsson E et al (2003) Localization of a gene for migraine without aura to chromosome 4q21. Am J Hum Genet 73:986–993PubMedCrossRefGoogle Scholar
  10. 10.
    Carlsson A, Forsgren L, Nylander PO et al (2002) Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1. Neurology 59:1804–1807PubMedCrossRefGoogle Scholar
  11. 11.
    Cader ZM, Noble-Topham S, Dyment DA et al (2003) Significant linkage to migraine with aura on chromosome 11q24. Hum Mol Genet 12:2511–2517PubMedCrossRefGoogle Scholar
  12. 12.
    Russo L, Mariotti P, Sangiorgi E et al (2005) A new susceptibility locus for migraine with aura in the 15q11–q13 genomic region containing three GABA-A receptor genes. Am J Hum Genet 76:327–333PubMedCrossRefGoogle Scholar
  13. 13.
    Soragna D, Vettori A, Carraro G et al (2003) A locus for migraine without aura maps on chromosome 14q21.2–q22.3. Am J Hum Genet 72:161–167PubMedCrossRefGoogle Scholar
  14. 14.
    Nyholt DR, Dawkins JL, Brimage PJ et al (1998) Evidence for an X-linked genetic component in familial typical migraine. Hum Mol Genet 7:459–463PubMedCrossRefGoogle Scholar
  15. 15.
    Nyholt DR, Curtain RP, Griffiths LR (2000) Familial typical migraine: significant linkage and localization of a gene to Xq24–28. Hum Genet 107:18–23PubMedCrossRefGoogle Scholar
  16. 16.
    Ophoff RA, Terwindt GM, Vergouwe MN et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552PubMedCrossRefGoogle Scholar
  17. 17.
    De Fusco M, Marconi R, Silvestri L et al (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33:192–196PubMedCrossRefGoogle Scholar
  18. 18.
    Dichgans M, Freilinger T, Eckstein G et al (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366:371–377PubMedCrossRefGoogle Scholar
  19. 19.
    Zhuchenko O, Bailey J, Bonnen P et al (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–69PubMedCrossRefGoogle Scholar
  20. 20.
    Jouvenceau A, Eunson LH, Spauschus A et al (2001) Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358:801–807PubMedCrossRefGoogle Scholar
  21. 21.
    Vanmolkot KR, Kors EE, Hottenga JJ et al (2003) Novel mutations in the Na+,K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 54:360–366PubMedCrossRefGoogle Scholar
  22. 22.
    Kors EE, Melberg A, Vanmolkot KR et al (2004) Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation. Neurology 63:1136–1137PubMedGoogle Scholar
  23. 23.
    Beauvais K, Cave-Riant F, De Barace C et al (2004) New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus. Eur Neurol 52:58–61PubMedCrossRefGoogle Scholar
  24. 24.
    Cevoli S, Pierangeli G, Monari L et al (2002) Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family. Neurol Sci 23:7–10PubMedCrossRefGoogle Scholar
  25. 25.
    Jurkat-Rott K, Freilinger T, Dreier JP et al (2004) Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants. Neurology 62:1857–1861PubMedGoogle Scholar
  26. 26.
    Vanmolkot KR, Stroink H, Koenderink JB et al (2006) Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation. Ann Neurol 59:310–314PubMedCrossRefGoogle Scholar
  27. 27.
    Spranger M, Spranger S, Schwab S et al (1999) Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis. Eur Neurol 41:150–152PubMedCrossRefGoogle Scholar
  28. 28.
    Giffin NJ, Benton S, Goadsby PJ (2002) Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation. Dev Med Child Neurol 44:490–493PubMedCrossRefGoogle Scholar
  29. 29.
    Swoboda KJ, Kanavakis E, Xaidara A et al (2004) Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol 55:884–887PubMedCrossRefGoogle Scholar
  30. 30.
    Maselli RA, Kong DZ, Bowe CM et al (2000) Presynaptic congenital myasthenic syndrome due to quantal release deficiency. Neurology 57:279–289CrossRefGoogle Scholar
  31. 31.
    Terwindt GM, Ophoff RA, Haan J et al (1998) Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Dutch Migraine Genetics Research Group. Eur J Hum Genet 6:297–307PubMedCrossRefGoogle Scholar
  32. 32.
    Pietrobon D, Striessnig J (2003) Neurobiology of migraine. Nat Rev Neurosci 4:386–398PubMedCrossRefGoogle Scholar
  33. 33.
    Hovatta I, Kallela M, Färkkilä M, Peltonen L (1994). Familial migraine: exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p. Genomics 23:707–709PubMedCrossRefGoogle Scholar
  34. 34.
    Monari L, Mochi M, Valentino ML et al (1997) Searching for migraine genes: exclusion of 290 cM out of the whole human genome. Ital J Neurol Sci 18:277–282PubMedCrossRefGoogle Scholar
  35. 35.
    Noble-Topham SE, Dyment DA, Cader MZ et al (2002) Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13. Neurology 59:1099–1101PubMedCrossRefGoogle Scholar
  36. 36.
    Jones KW, Ehm MG, Pericak-Vance MA et al (2001) Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus. Genomics 78:150–154PubMedCrossRefGoogle Scholar
  37. 37.
    Brugnoni R, Leone M, Rigamonti A et al (2002) Is the CACNA1A gene involved in familial migraine with aura? Neurol Sci 23:1–5PubMedCrossRefGoogle Scholar
  38. 38.
    Wieser T, Mueller C, Evers S et al (2003) Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing. Clin Chem Lab Med 41:272–275PubMedCrossRefGoogle Scholar
  39. 39.
    von Brevern M, Ta N, Shankar A et al (2006) Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4. Headache 46:1136–1141CrossRefGoogle Scholar
  40. 40.
    Netzer C, Todt U, Heinze A et al (2006) Haplotype-based systematic association studies of ATP1A2 in migraine with aura. Am J Med Genet B Neuropsychiatr Genet 141:257–260Google Scholar
  41. 41.
    Kirchmann M, Thomsen LL, Olesen J (2006) The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura. Am J Med Genet B Neuropsychiatr Gen 141:250–256CrossRefGoogle Scholar
  42. 42.
    Kim JS, Yue Q, Jen JC et al (1998) Familial migraine with vertigo: no mutations found in CACNA1A. Am J Med Genet 79:148–151PubMedCrossRefGoogle Scholar
  43. 43.
    Jen JC, Kim GW, Dudding KA, Baloh RW (2004) No mutations in CACNA1A and ATP1A2 in probands with common types of migraine. Arch Neurol 61:926–928PubMedCrossRefGoogle Scholar
  44. 44.
    Curtain RP, Lea RA, Tajouri L et al (2005) Analysis of chromosome 1 microsatellite markers and the FHM2-ATP1A2 gene mutations in migraine pedigrees. Neurol Res 27:647–652PubMedCrossRefGoogle Scholar
  45. 45.
    Luedi PP, Dietrich FS, Weidman JR et al (2007) Computational and experimental identification of novel human imprinted genes. Genome Res 17: 1723–1730PubMedCrossRefGoogle Scholar
  46. 46.
    Oommen AM, Griffin JB, Sarath G, Zempleni J (2005) Roles for nutrients in epigenetic events. J Nutr Biochem 16:74–77PubMedCrossRefGoogle Scholar
  47. 47.
    Craig AD (2003) A new view of pain as a homeostatic emotion. Trends Neurosci 26:303–307PubMedCrossRefGoogle Scholar
  48. 48.
    Johnson RW (2002) The concept of sickness behavior: a brief chronological account of four key discoveries. Vet Immunol Immunopathol 87:443–450PubMedCrossRefGoogle Scholar
  49. 49.
    Bracha HS, Ralston TC, Matsukawa JM et al (2004) Does “fight or flight” need updating? Psychosomatics 45:448–449PubMedCrossRefGoogle Scholar
  50. 50.
    Loder E (2002) What is the evolutionary advantage of migraine? Cephalalgia 22:624–632PubMedCrossRefGoogle Scholar
  51. 51.
    Montagna P (2008) The primary headaches: genetics, epigenetics and a behavioural genetic model. J Headache Pain 9:57–69PubMedCrossRefGoogle Scholar
  52. 52.
    Montagna P, Cortelli P (2008) Migraine and the autonomic nervous system. In: Low PA (ed) Clinical autonomic disorders: evaluation and management. Lippincott, Williams and Wilkins (in press)Google Scholar

Copyright information

© Springer-Verlag Italia 2008

Authors and Affiliations

  1. 1.Department of Neurological SciencesUniversity of Bologna Medical SchoolBolognaItaly

Personalised recommendations