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Genetics of Cluster Headache and Other Trigeminal Autonomic Cephalalgias

  • Arn M. J. M. van den MaagdenbergEmail author
  • Anne DucrosEmail author
Chapter
Part of the Headache book series (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.

Keywords

Cluster headache Trigeminal autonomic cephalalgia Twins Family studies Genes Pathways 

References

  1. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet. 2005;366:843–55.PubMedCrossRefGoogle Scholar
  3. 3.
    Nesbitt AD, Goadsby PJ. Cluster headache. Br Med J. 2012;344:e2407.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 5.
    Goadsby PJ. Trigeminal autonomic cephalalgias. Pathophysiology and classification. Rev Neurol. 2005;161:692–5.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009;8:755–64.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Barloese MCJ. The pathophysiology of the trigeminal autonomic cephalalgias, with clinical implications. Clin Auton Res. 2018;28(3):315–24.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352:275–8.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Sjostrand C. Genetic aspects of cluster headache. Expert Rev Neurother. 2009;9:359–68.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 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. 13.
    Salvesen R. Cluster headache sine headache: case report. Neurology. 2000;55:451.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Leone M, Rigamonti A, Bussone G. Cluster headache sine headache: two new cases in one family. Cephalalgia. 2002;22:12–4.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Leroux E, Ducros A. Cluster headache. Orphanet J Rare Dis. 2008;3:20.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 19.
    Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol. 2004;3:279–83.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Goadsby PJ, Cittadini E, Cohen AS. Trigeminal autonomic cephalalgias: paroxysmal hemicrania, SUNCT/SUNA, and hemicrania continua. Semin Neurol. 2010;30:186–91.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Williams MH, Broadley SA. SUNCT and SUNA: clinical features and medical treatment. J Clin Neurosci. 2008;15:526–34.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Rapoport AM, Bigal ME. Hemicrania continua: clinical and nosographic update. Neurol Sci. 2003;24(Suppl 2):S118–21.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Silberstein SD, Peres MF. Hemicrania continua. Arch Neurol. 2002;59:1029–30.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Sjaastad O, Salvesen R. Cluster headache: are we only seeing the tip of the iceberg? Cephalalgia. 1986;6:127–9.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Sjaastad O, Shen JM, Stovner LJ, Elsas T. Cluster headache in identical twins. Headache. 1993;33:214–7.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Eadie MJ, Sutherland JM. Migrainous neuralgia. Med J Aust. 1966;1:1053–7.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Couturier EG, Hering R, Steiner TJ. The first report of cluster headache in identical twins. Neurology. 1991;41:761.PubMedCrossRefGoogle Scholar
  31. 31.
    Roberge C, Bouchard JP, Simard D, Gagne R. Cluster headache in twins. Neurology. 1992;42:1255–6.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 34.
    D’Amico D, Leone M, Moschiano F, Bussone G. Familial cluster headache: report of three families. Headache. 1996;36:41–3.PubMedCrossRefGoogle Scholar
  35. 35.
    Spierings EL, Vincent AJ. Familial cluster headache: occurrence in three generations. Neurology. 1992;42:1399–400.PubMedCrossRefGoogle Scholar
  36. 36.
    Kudrow L, Kudrow DB. Inheritance of cluster headache and its possible link to migraine. Headache. 1994;34:400–7.PubMedCrossRefGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 38.
    Russell MB, Andersson PG, Thomsen LL. Familial occurrence of cluster headache. J Neurol Neurosurg Psychiatry. 1995;58:341–3.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Torelli P, Manzoni GC. Clinical observations on familial cluster headache. Neurol Sci. 2003;24:61–4.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Cruz S, Lemos C, Monteiro JM. Familial aggregation of cluster headache. Arq Neuropsiquiatr. 2013;71:866–70.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Vliet JA, Ferrari MD, Haan J. Genetic factors in cluster headache. Expert Rev Neurother. 2003;3:301–6.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    De Simone R, Fiorillo C, Bonuso S, Castaldo G. A cluster headache family with possible autosomal recessive inheritance. Neurology. 2003;61:578–9.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Cohen AS, Matharu MS, Goadsby PJ. Paroxysmal hemicrania in a family. Cephalalgia. 2006;26:486–8.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Boes CJ, Dodick DW. Refining the clinical spectrum of chronic paroxysmal hemicrania: a review of 74 patients. Headache. 2002;42:699–708.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Weatherall MW, Bahra A. Familial hemicrania continua. Cephalalgia. 2011;31:245–9.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Gantenbein AR, Goadsby PJ. Familial SUNCT. Cephalalgia. 2005;25:457–9.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Martins IP, Viana P, Lobo PP. Familial SUNCT in mother and son. Cephalalgia. 2016;36:993–7.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Russell MB, Iselius L, Olesen J. Migraine without aura and migraine with aura are inherited disorders. Cephalalgia. 1996;16:305–9.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Manzoni GC. Cluster headache and lifestyle: remarks on a population of 374 male patients. Cephalalgia. 1999;19:88–94.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Schurks M, Diener HC. Cluster headache and lifestyle habits. Curr Pain Headache Rep. 2008;12:115–21.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Schurks M. Genetics of cluster headache. Curr Pain Headache Rep. 2010;14:132–9.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 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.PubMedPubMedCentralGoogle Scholar
  71. 71.
    de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM. Molecular genetics of migraine. Hum Genet. 2009;126:115–32.PubMedCrossRefGoogle Scholar
  72. 72.
    Sutherland HG, Griffiths LR. Genetics of migraine: insights into the molecular basis of migraine disorders. Headache. 2017;57:537–69.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 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.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Departments of Human Genetics and NeurologyLeiden University Medical CentreLeidenThe Netherlands
  2. 2.Department of Neurology, Gui de Chauliac Hospital, CHU de MontpellierUniversity of MontpellierMontpellierFrance

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