Skip to main content

Genetics of Cluster Headache and Other Trigeminal Autonomic Cephalalgias

  • Chapter
  • First Online:

Part of the book series: Headache ((HEAD))

Abstract

Cluster headache and other trigeminal autonomic cephalalgias (TACs) are rare and often severe primary headache disorders. Family and twin studies in cluster headache have demonstrated a clear genetic component, but the mode of transmission and the amount of heritability remain to be determined. A few familial cases of other TACs have been reported, but it is at present unknown to what extent these disorders are genetic. As a consequence, all genetic studies to date have focussed on the identification of genetic factors in cluster headache, foremost the testing of single nucleotide polymorphisms (SNPs) in candidate genes that were selected on presumed knowledge of the pathophysiology, but this did not result in any robust associations. More recently, the first genome-wide association study (GWAS) was conducted, albeit with limited success. Here we will (1) present current knowledge of the genetics of cluster headache and other TACs and (2) discuss factors potentially explaining why genetic studies were less successful in TACs than in migraine. Learning from the past, genetic studies in cluster headache and other TACs may hopefully be more fruitful in the future.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   49.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   64.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   89.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain. 1997;120:193–209.

    Article  PubMed  Google Scholar 

  2. May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet. 2005;366:843–55.

    Article  PubMed  Google Scholar 

  3. Nesbitt AD, Goadsby PJ. Cluster headache. Br Med J. 2012;344:e2407.

    Article  CAS  Google Scholar 

  4. Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629–808.

    Article  Google Scholar 

  5. Goadsby PJ. Trigeminal autonomic cephalalgias. Pathophysiology and classification. Rev Neurol. 2005;161:692–5.

    Article  CAS  PubMed  Google Scholar 

  6. Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009;8:755–64.

    Article  PubMed  Google Scholar 

  7. Barloese MCJ. The pathophysiology of the trigeminal autonomic cephalalgias, with clinical implications. Clin Auton Res. 2018;28(3):315–24.

    Article  PubMed  Google Scholar 

  8. May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352:275–8.

    Article  CAS  PubMed  Google Scholar 

  9. May A, Goadsby PJ. The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab. 1999;19:115–27.

    Article  CAS  PubMed  Google Scholar 

  10. Malick A, Strassman RM, Burstein R. Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat. J Neurophysiol. 2000;84:2078–112.

    Article  CAS  PubMed  Google Scholar 

  11. Sjostrand C. Genetic aspects of cluster headache. Expert Rev Neurother. 2009;9:359–68.

    Article  PubMed  Google Scholar 

  12. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: 2nd edition. Cephalalgia. 2004;24(Suppl 1):9–160.

    Google Scholar 

  13. Salvesen R. Cluster headache sine headache: case report. Neurology. 2000;55:451.

    Article  CAS  PubMed  Google Scholar 

  14. Leone M, Rigamonti A, Bussone G. Cluster headache sine headache: two new cases in one family. Cephalalgia. 2002;22:12–4.

    Article  CAS  PubMed  Google Scholar 

  15. Favier I, van Vliet JA, Roon KI, Witteveen RJ, Verschuuren JJ, Ferrari MD, et al. Trigeminal autonomic cephalgias due to structural lesions: a review of 31 cases. Arch Neurol. 2007;64:25–31.

    Article  PubMed  Google Scholar 

  16. Leroux E, Ducros A. Cluster headache. Orphanet J Rare Dis. 2008;3:20.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders. 3rd edition. ICHD-3. Cephalalgia. 2018;38(1):1–211.

    Article  Google Scholar 

  18. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8:1–96.

    Article  Google Scholar 

  19. Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol. 2004;3:279–83.

    Article  PubMed  Google Scholar 

  20. Goadsby PJ, Cittadini E, Cohen AS. Trigeminal autonomic cephalalgias: paroxysmal hemicrania, SUNCT/SUNA, and hemicrania continua. Semin Neurol. 2010;30:186–91.

    Article  PubMed  Google Scholar 

  21. Prakash S, Belani P, Susvirkar A, Trivedi A, Ahuja S, Patel A. Paroxysmal hemicrania: a retrospective study of a consecutive series of 22 patients and a critical analysis of the diagnostic criteria. J Headache Pain. 2013;14:26.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Goadsby P, Lipton R. A review of paroxysmal hemicranias, SUNCT syndrome, and other short lasting headaches with autonomic features, including new cases. Brain. 1997;120:193–209.

    Article  PubMed  Google Scholar 

  23. Williams MH, Broadley SA. SUNCT and SUNA: clinical features and medical treatment. J Clin Neurosci. 2008;15:526–34.

    Article  PubMed  Google Scholar 

  24. Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA)—a prospective clinical study of SUNCT and SUNA. Brain. 2006;129:2746–60.

    Article  PubMed  Google Scholar 

  25. Rapoport AM, Bigal ME. Hemicrania continua: clinical and nosographic update. Neurol Sci. 2003;24(Suppl 2):S118–21.

    PubMed  Google Scholar 

  26. Silberstein SD, Peres MF. Hemicrania continua. Arch Neurol. 2002;59:1029–30.

    Article  PubMed  Google Scholar 

  27. Sjaastad O, Salvesen R. Cluster headache: are we only seeing the tip of the iceberg? Cephalalgia. 1986;6:127–9.

    CAS  PubMed  Google Scholar 

  28. Sjaastad O, Shen JM, Stovner LJ, Elsas T. Cluster headache in identical twins. Headache. 1993;33:214–7.

    Article  CAS  PubMed  Google Scholar 

  29. Eadie MJ, Sutherland JM. Migrainous neuralgia. Med J Aust. 1966;1:1053–7.

    CAS  PubMed  Google Scholar 

  30. Couturier EG, Hering R, Steiner TJ. The first report of cluster headache in identical twins. Neurology. 1991;41:761.

    Article  CAS  PubMed  Google Scholar 

  31. Roberge C, Bouchard JP, Simard D, Gagne R. Cluster headache in twins. Neurology. 1992;42:1255–6.

    Article  CAS  PubMed  Google Scholar 

  32. Svensson D, Ekbom K, Pedersen NL, Traff H, Waldenlind E. A note on cluster headache in a population-based twin register. Cephalalgia. 2003;23:376–80.

    Article  PubMed  Google Scholar 

  33. Ekbom K, Svensson DA, Pedersen NL, Waldenlind E. Lifetime prevalence and concordance risk of cluster headache in the Swedish twin population. Neurology. 2006;67:798–803.

    Article  PubMed  Google Scholar 

  34. D’Amico D, Leone M, Moschiano F, Bussone G. Familial cluster headache: report of three families. Headache. 1996;36:41–3.

    Article  PubMed  Google Scholar 

  35. Spierings EL, Vincent AJ. Familial cluster headache: occurrence in three generations. Neurology. 1992;42:1399–400.

    Article  CAS  PubMed  Google Scholar 

  36. Kudrow L, Kudrow DB. Inheritance of cluster headache and its possible link to migraine. Headache. 1994;34:400–7.

    Article  CAS  PubMed  Google Scholar 

  37. Montagna P, Mochi M, Prologo G, Sangiorgi S, Pierangeli G, Cevoli S, et al. Heritability of cluster headache. Eur J Neurol. 1998;5:343–5.

    Article  Google Scholar 

  38. Russell MB, Andersson PG, Thomsen LL. Familial occurrence of cluster headache. J Neurol Neurosurg Psychiatry. 1995;58:341–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Leone M, Russell MB, Rigamonti A, Attanasio A, Grazzi L, D’Amico D, et al. Increased familial risk of cluster headache. Neurology. 2001;56:1233–6.

    Article  CAS  PubMed  Google Scholar 

  40. El Amrani M, Ducros A, Boulan P, Aidi S, Crassard I, Visy JM, et al. Familial cluster headache: a series of 186 index patients. Headache. 2002;42:974–7.

    Article  PubMed  Google Scholar 

  41. Torelli P, Manzoni GC. Clinical observations on familial cluster headache. Neurol Sci. 2003;24:61–4.

    CAS  PubMed  Google Scholar 

  42. Cruz S, Lemos C, Monteiro JM. Familial aggregation of cluster headache. Arq Neuropsiquiatr. 2013;71:866–70.

    Article  PubMed  Google Scholar 

  43. Taga A, Russo M, Manzoni GC, Torelli P. Familial cluster headache in an Italian case series. Neurol Sci. 2015;36(Suppl 1):141–3.

    Article  PubMed  Google Scholar 

  44. Vliet JA, Ferrari MD, Haan J. Genetic factors in cluster headache. Expert Rev Neurother. 2003;3:301–6.

    Article  PubMed  Google Scholar 

  45. Russell MB, Andersson PG, Thomsen LL, Iselius L. Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. J Med Genet. 1995;32:954–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. De Simone R, Fiorillo C, Bonuso S, Castaldo G. A cluster headache family with possible autosomal recessive inheritance. Neurology. 2003;61:578–9.

    Article  PubMed  Google Scholar 

  47. Cohen AS, Matharu MS, Goadsby PJ. Paroxysmal hemicrania in a family. Cephalalgia. 2006;26:486–8.

    Article  CAS  PubMed  Google Scholar 

  48. Boes CJ, Dodick DW. Refining the clinical spectrum of chronic paroxysmal hemicrania: a review of 74 patients. Headache. 2002;42:699–708.

    Article  PubMed  Google Scholar 

  49. Weatherall MW, Bahra A. Familial hemicrania continua. Cephalalgia. 2011;31:245–9.

    Article  PubMed  Google Scholar 

  50. Gantenbein AR, Goadsby PJ. Familial SUNCT. Cephalalgia. 2005;25:457–9.

    Article  CAS  PubMed  Google Scholar 

  51. Martins IP, Viana P, Lobo PP. Familial SUNCT in mother and son. Cephalalgia. 2016;36:993–7.

    Article  PubMed  Google Scholar 

  52. Lambru G, Nesbitt A, Shanahan P, Matharu MS. Coexistence of hemiplegic migraine with SUNCT or SUNA: a case series. Cephalalgia. 2012;32:258–62.

    Article  PubMed  Google Scholar 

  53. Honkasalo ML, Kaprio J, Winter T, Heikkila K, Sillanpaa M, Koskenvuo M. Migraine and concomitant symptoms among 8167 adult twin pairs. Headache. 1995;35:70–8.

    Article  CAS  PubMed  Google Scholar 

  54. 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;45:242–6.

    Article  CAS  PubMed  Google Scholar 

  55. 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;42:332–6.

    Article  PubMed  Google Scholar 

  56. Russell MB, Iselius L, Olesen J. Migraine without aura and migraine with aura are inherited disorders. Cephalalgia. 1996;16:305–9.

    Article  CAS  PubMed  Google Scholar 

  57. Polderman TJ, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet. 2015;47:702–9.

    Article  CAS  PubMed  Google Scholar 

  58. Kuhlenbaumer G, Hullmann J, Appenzeller S. Novel genomic techniques open new avenues in the analysis of monogenic disorders. Hum Mutat. 2011;32:144–51.

    Article  PubMed  Google Scholar 

  59. Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maagdenberg AM. Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol. 2015;14:65–80.

    Article  CAS  PubMed  Google Scholar 

  60. Manzoni GC. Cluster headache and lifestyle: remarks on a population of 374 male patients. Cephalalgia. 1999;19:88–94.

    Article  CAS  PubMed  Google Scholar 

  61. Levi R, Edman GV, Ekbom K, Waldenlind E. Episodic cluster headache. II: high tobacco and alcohol consumption in males. Headache. 1992;32:184–7.

    Article  CAS  PubMed  Google Scholar 

  62. Schurks M, Diener HC. Cluster headache and lifestyle habits. Curr Pain Headache Rep. 2008;12:115–21.

    Article  PubMed  Google Scholar 

  63. Schurks M. Genetics of cluster headache. Curr Pain Headache Rep. 2010;14:132–9.

    Article  PubMed  Google Scholar 

  64. Rainero I, Gallone S, Valfre W, Ferrero M, Angilella G, Rivoiro C, et al. A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology. 2004;63:1286–8.

    Article  CAS  PubMed  Google Scholar 

  65. Schurks M, Kurth T, Geissler I, Tessmann G, Diener HC, Rosskopf D. Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology. 2006;66:1917–9.

    Article  CAS  PubMed  Google Scholar 

  66. Baumber L, Sjostrand C, Leone M, Harty H, Bussone G, Hillert J, et al. A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology. 2006;66:1888–93.

    Article  CAS  PubMed  Google Scholar 

  67. Weller CM, Wilbrink LA, Houwing-Duistermaat JJ, Koelewijn SC, Vijfhuizen LS, Haan J, et al. Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis. Cephalalgia. 2015;35:741–7.

    Article  PubMed  Google Scholar 

  68. Nishizawa D, Kasai S, Hasegawa J, Sato N, Yamada H, Tanioka F, et al. Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies. Mol Brain. 2015;8:50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Shimomura T, Kitano A, Marukawa H, Mishima K, Isoe K, Adachi Y, et al. Point mutation in platelet mitochondrial tRNA(Leu(UUR)) in patient with cluster headache. Lancet. 1994;344:625.

    Article  CAS  PubMed  Google Scholar 

  70. Odawara M, Tamaoka A, Mizusawa H, Yamashita K. A case of cluster headache associated with mitochondrial DNA deletions. Muscle Nerve. 1997;20:394–5.

    CAS  PubMed  Google Scholar 

  71. de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM. Molecular genetics of migraine. Hum Genet. 2009;126:115–32.

    Article  CAS  PubMed  Google Scholar 

  72. Sutherland HG, Griffiths LR. Genetics of migraine: insights into the molecular basis of migraine disorders. Headache. 2017;57:537–69.

    Article  PubMed  Google Scholar 

  73. de Vries B, Anttila V, Freilinger T, Wessman M, Kaunisto MA, Kallela M, et al. Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set. Cephalalgia. 2016;36:604–14.

    Article  PubMed  Google Scholar 

  74. Schurks M, Neumann FA, Kessler C, Diener HC, Kroemer HK, Kurth T, et al. MTHFR 677C>T polymorphism and cluster headache. Headache. 2011;51:201–7.

    Article  PubMed  Google Scholar 

  75. Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14:365–76.

    Article  CAS  PubMed  Google Scholar 

  76. Bacchelli E, Cainazzo MM, Cameli C, Guerzoni S, Martinelli A, Zoli M, et al. A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants. J Headache Pain. 2016;17:114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, et al. 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101:5–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tuka B, Szabo N, Toth E, Kincses ZT, Pardutz A, Szok D, et al. Release of PACAP-38 in episodic cluster headache patients—an exploratory study. J Headache Pain. 2016;17:69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Ran C, Fourier C, Michalska JM, Steinberg A, Sjostrand C, Waldenlind E, et al. Screening of genetic variants in ADCYAP1R1, MME and 14q21 in a Swedish cluster headache cohort. J Headache Pain. 2017;18:88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Gormley P, Winsvold BS, Nyholt DR, Kallela M, Chasman DI, Palotie A. Migraine genetics: from genome-wide association studies to translational insights. Genome Med. 2016;8:86.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016;48:856–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C, Klarin D, et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell. 2017;170:522–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Franceschini R, Tenconi GL, Leandri M, Zoppoli F, Gonella A, Staltari S, et al. Endothelin-1 plasma levels in cluster headache. Headache. 2002;42:120–4.

    Article  CAS  PubMed  Google Scholar 

  84. Sjostrand C, Duvefelt K, Steinberg A, Remahl IN, Waldenlind E, Hillert J. Gene expression profiling in cluster headache: a pilot microarray study. Headache. 2006;46:1518–34.

    Article  PubMed  Google Scholar 

  85. Costa M, Squassina A, Piras IS, Pisanu C, Congiu D, Niola P, et al. Preliminary transcriptome analysis in lymphoblasts from cluster headache and bipolar disorder patients implicates dysregulation of circadian and serotonergic genes. J Mol Neurosci. 2015;56:688–95.

    Article  CAS  PubMed  Google Scholar 

  86. Eising E, Pelzer N, Vijfhuizen LS, Vries B, Ferrari MD, t Hoen PA, et al. Identifying a gene expression signature of cluster headache in blood. Sci Rep. 2017;7:40218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Arn M. J. M. van den Maagdenberg or Anne Ducros .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

van den Maagdenberg, A.M.J.M., Ducros, A. (2020). Genetics of Cluster Headache and Other Trigeminal Autonomic Cephalalgias. In: Leone, M., May, A. (eds) Cluster Headache and other Trigeminal Autonomic Cephalgias. Headache. Springer, Cham. https://doi.org/10.1007/978-3-030-12438-0_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-12438-0_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-12437-3

  • Online ISBN: 978-3-030-12438-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics