Migraine and Neurogenetic Disorders

Secondary Headache (K Henry, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Secondary Headache


In the current classification of headache disorders, headache attributable to genetic disorders is not classified separately, rather as headache attributed to cranial or cervical vascular disorder. The classification thus implies that a vascular pathology causes headache in these genetic disorders. Unquestionably, migraine is one of the prominent presenting features of several genetic cerebral small vessel diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty. Shared genetic features, increased susceptibility, and/or vascular endothelial dysfunction may play a role in pathogenesis of migraine. Common or overlapping pathways involving the responsible genes may provide insight regarding the pathophysiological mechanisms that can explain their comorbidity with migraine. This review focuses on clinical features of genetic vasculopathies. An independent category—migraine related to genetic disorders—should be considered to classify these disorders.


CADASIL COL4A1 Headache HIHRTL MELAS Migraine NOTCH3 RVCL Small vessel disease TREX1 


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Goadsby PJ. The vascular theory of migraine – a great story wrecked by the facts. Brain. 2009;132:6–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Schoonman GG, van der Grond J, Kortmann C, et al. Migraine headache is not associated with cerebral or meningeal vasodilatation – a 3T magnetic resonance angiography study. Brain. 2008;131:2192–200.PubMedCrossRefGoogle Scholar
  3. 3.
    Maassenvandenbrink A, Duncker DJ, Saxena PR. Migraine headache is not associated with cerebral or meningeal vasodilatation – a 3T magnetic resonance angiography study. Brain. 2009;132:e112.CrossRefGoogle Scholar
  4. 4.
    Dreier JP, Kleeberg J, Alam M, et al. Endothelin-1-induced spreading depression in rats is associated with a microarea of selective neuronal necrosis. Exp Biol Med (Maywood). 2007;232:204–13.Google Scholar
  5. 5.
    Brennan KC, Beltran-Parrazal L, López-Valdés HE, et al. Distinct vascular conduction with cortical spreading depression. J Neurophysiol. 2007;97:4143–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Porter A, Gladstone JP, Dodick DW. Migraine and white matter hyperintensities. Curr Pain Headache Rep. 2005;9:289–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Tzourio C, Benslamia L, Guillon B, Aïdi S, et al. Migraine and the risk of cervical artery dissection: a case–control study. Neurology. 2002;59:435–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Goadsby PJ. Neurovascular headache and a midbrain vascular malformation: evidence for a role of the brainstem in chronic migraine. Cephalalgia. 2002;22:107–11.PubMedCrossRefGoogle Scholar
  9. 9.
    Kupersmith MJ, Vargas ME, Yashar A, et al. Occipital arteriovenous malformations: visual disturbances and presentation. Neurology. 1996;46:953–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Kurita H, Ueki K, Shin M, et al. Headaches in patients with radiosurgically treated occipital arteriovenous malformations. J Neurosurg. 2000;93:224–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Calabrese LH, Dodick DW, Schwedt TJ. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med. 2007;146:34–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.PubMedCrossRefGoogle Scholar
  13. 13.
    Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731–9.PubMedCrossRefGoogle Scholar
  14. 14.
    • Chabriat H, Joutel A, Dichgans M, et al. Cadasil. Lancet Neurol. 2009;8:643–53. Summarizes current understanding of CADASIL and how it serves as a model for the more common forms of subcortical ischemic strokes and pure vascular dementia.PubMedCrossRefGoogle Scholar
  15. 15.
    Razvi SS, Davidson R, Bone I, Muir KW. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J Neurol Neurosurg Psychiatry. 2005;76:739–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Desmond D, Moroney J, Lynch T, et al. The natural history of CADASIL a pooled analysis of previously published cases. Stroke. 1999;30:1230–3.PubMedCrossRefGoogle Scholar
  17. 17.
    Vahedi K, Chabriat H, Levy C, et al. Migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL. Arch Neurol. 2004;61:1237–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Markus HS, Martin RJ, Simpson MA, et al. Diagnostic strategies in CADASIL. Neurology. 2002;59:1134–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Singhal S, Bevan S, Barrick T, et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004;127:2031–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Verin M, Rolland Y, Landgraf F, et al. New phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19: Migraine as the prominent clinical feature. J Neurol Neurosurg Psychiatry. 1995;59:579–85.Google Scholar
  21. 21.
    Schon F, Martin RJ, Prevett M, et al. “CADASIL coma”: An underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry. 2003;74:249–52.PubMedCrossRefGoogle Scholar
  22. 22.
    Sathe S, DePeralta E, Pastores G, Kolodny EH. Acute confusional migraine may be a presenting feature of CADASIL. Headache. 2009;49:590–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Le Ber I, Carluer L, Derache N, et al. Unusual presentation of CADASIL with reversible coma and confusion. Neurology. 2002;59:1115–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Ducray F, Ritzenthaler T, Cho TH, et al. Acute headache followed by focal neuropsychological impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Stroke Cerebrovasc Dis. 2010;19:75–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Jouvent E, Mangin JF, Hervé D, et al. Cortical folding influences migraine aura symptoms in CADASIL. J Neurol Neurosurg Psychiatry. 2012;83:213–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Campolo J, De Maria R, Frontali M, et al. Impaired vasoreactivity in mildly disabled CADASIL patients. J Neurol Neurosurg Psychiatry. 2012;83:268–74.PubMedCrossRefGoogle Scholar
  27. 27.
    Fujiwara Y, Mizuno T, Okuyama C, et al. Simultaneous impairment of intracranial and peripheral artery vasoreactivity in CADASIL patients. Cerebrovasc Dis. 2012;33:128–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Forteza AM, Brozman B, Rabinstein AA, Romano JG, Bradley WG. Acetazolamide for the treatment of migraine with aura in CADASIL. Neurology. 2010;57:2144–5.CrossRefGoogle Scholar
  29. 29.
    Vahedi K, Taupin P, Djomby R, et al. Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomized placebo-controlled trial. J Neurol. 2002;249:206–11.PubMedCrossRefGoogle Scholar
  30. 30.
    Donnini I, Nannucci S, Valenti R, et al. Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary experience. J Headache Pain. 2012;13:299–302.PubMedCrossRefGoogle Scholar
  31. 31.
    Yonas H, Darby JM, Marks EC, Durham SR, Maxwell C. CBF measured by Xe-CT: approach to analysis and normal values. J Cereb Blood Flow Metab. 1991;11:716–25.PubMedCrossRefGoogle Scholar
  32. 32.
    Eskey CJ, Sanelli PC. Perfusion imaging of cerebrovascular reserve. Neuroimaging Clin N Am. 1991;15:367–81.CrossRefGoogle Scholar
  33. 33.
    Huang L, Yang Q, Zhang L, et al. Acetazolamide improves cerebral hemodynamics in CADASIL. J Neurol Sci. 2010;292:77–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Chabriat H, Pappata S, Ostergaard L, et al. Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke. 2000;31:1904–12.PubMedCrossRefGoogle Scholar
  35. 35.
    Park SA, Yang CY, Choi SS, Kim WH. Assessment of cerebral hemodynamics to acetazolamide using brain perfusion SPECT in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Clin Nucl Med. 2011;36:158–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages – 3rd–6th decades. Radiology. 2003;229:683–90.PubMedCrossRefGoogle Scholar
  37. 37.
    Lesnik Oberstein SA, van den Boom R, van Buchem MA, et al. Cerebral microbleeds in CADASIL. Neurology. 2001;57:1066–70.PubMedCrossRefGoogle Scholar
  38. 38.
    • Joutel A. Pathogenesis of CADASIL Transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature. Bioessays. 2011;33:73–80. Critical overview of mouse models of CADASIL, future directions, and further work that needs to be done to understand small vessel diseases.PubMedCrossRefGoogle Scholar
  39. 39.
    Joutel A, Andreux F, Gaulis S, et al. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest. 2000;105:597–605.PubMedCrossRefGoogle Scholar
  40. 40.
    Opherk C, Duering M, Peters N, et al. CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet. 2009;18:2761–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383:707–10.PubMedCrossRefGoogle Scholar
  42. 42.
    Peters N, Opherk C, Bergmann T, Castro M, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005;62:1091–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Morrow D, Guha S, Sweeney C, et al. Notch and vascular smooth muscle cell phenotype. Circ Res. 2008;103:1370–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Grand MG, Kaine J, Fulling K, et al. Cerebroretinal vasculopathy. A new hereditary syndrome. Ophthalmology. 1988;95:649–59.PubMedGoogle Scholar
  45. 45.
    Terwindt GM, Haan J, Ophoff RA, et al. Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud’s phenomenon. Brain. 1998;121:303–16.PubMedCrossRefGoogle Scholar
  46. 46.
    Jen J, Cohen AH, Yue Q, et al. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology. 1997;49:1322–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Richard A, Van den Maagdenberg AM, et al. Truncations in the carboxyl-terminus of human 3'-5' DNA exonuclease TREX1 cause retinal vasculopathy with cerebral leukodystrophy. Nat Genet. 2007;39:1068–70.CrossRefGoogle Scholar
  48. 48.
    Ophoff RA, DeYoung J, Service SK, et al. Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3. Am J Hum Genet. 2001;69:447–53.PubMedCrossRefGoogle Scholar
  49. 49.
    Weil S, Reifenberger G, Dudel C, et al. Cerebroretinal vasculopathy mimicking a brain tumor: a case of a rare hereditary syndrome. Neurology. 1999;53:629–31.PubMedCrossRefGoogle Scholar
  50. 50.
    Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet. 2006;38:917–20.PubMedCrossRefGoogle Scholar
  51. 51.
    Rice G, Newman WG, Dean J, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;80:811–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Lee-Kirsch MA, Chowdhury D, Harvey S, et al. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med. 2007;85:531–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Lee-Kirsch MA, Gong M, Chowdhury D, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39:1065–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Mazur DJ, Perrino FW. Excision of 3' termini by the Trex1 and TREX2 3' – >5' exonucleases. Characterization of the recombinant proteins. J Biol Chem. 2001;276:17022–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Morita M, Stamp G, Robins P, et al. Gene-targeted mice lacking the Trex1 (DNase III) 3' – >5' DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol. 2004;24:6719–27.PubMedCrossRefGoogle Scholar
  56. 56.
    Martinvalet D, Zhu P, Lieberman J. Granzyme A: induces caspase independent mitochondrial damage, a required first step for apoptosis. Immunity. 2005;22:355–70.PubMedCrossRefGoogle Scholar
  57. 57.
    Chowdhury D, Beresford PJ, Zhu P, et al. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell. 2006;23:133–42.PubMedCrossRefGoogle Scholar
  58. 58.
    Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell. 2007;131:873–86.PubMedCrossRefGoogle Scholar
  59. 59.
    Vahedi K, Massin P, Guichard J-P, et al. Hereditary infantilehemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy. Neurology. 2003;60:57–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Vahedi K, Boukobza M, Massin P, et al. Clinical and brain MRI follow-up study of a family with COL4A1 mutation. Neurology. 2007;69:1564–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Sibon I, Coupry I, Menegon P, et al. COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Ann Neurol. 2007;62:177–84.PubMedCrossRefGoogle Scholar
  62. 62.
    Van Agtmael T, Schlotzer-Schrehardy U, McKie L, et al. Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy. Hum Mol Genet. 2005;14:3161–8.PubMedCrossRefGoogle Scholar
  63. 63.
    van der Knaap MS, Smit LM, et al. Neonatal porencephaly and adult stroke related to mutations in collagen IV A1. Ann Neurol. 2006;59:504–11.PubMedCrossRefGoogle Scholar
  64. 64.
    de Vries LS, Koopman C, Groenendaal F, et al. COL4A1 mutation in two preterm siblings with antenatal onset of parenchymal hemorrhage. Ann Neurol. 2009;65:12–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science. 2005;308:1167–71.PubMedCrossRefGoogle Scholar
  66. 66.
    Gould DB, Phalan FC, van Mil SE, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. 2006;354:1489–96.PubMedCrossRefGoogle Scholar
  67. 67.
    Mine M, Tournier-Lasserve E. Intracerebral hemorrhage and COL4A1 mutations, from preterm infants to adult patients. Ann Neurol. 2009;65:1–2.PubMedCrossRefGoogle Scholar
  68. 68.
    • Stam AH, Haan J, van den Maagdenberg AM, et al. Migraine and genetic and acquired vasculopathies. Cephalalgia. 2009;29:1006–17. Review on genetic and acquired vasculopathies associated with migraine, as well as how genetic and acquired vascular mechanisms might be involved in migraine.PubMedCrossRefGoogle Scholar
  69. 69.
    Schwaag S, Evers S, Schirmacher A, et al. Genetic variants of the NOTCH3 gene in migraine– a mutation analysis and association study. Cephalalgia. 2006;26:158–61.PubMedCrossRefGoogle Scholar
  70. 70.
    Borroni B, Brambilla C, Liberini P, et al. Investigating the association between Notch3 polymorphism and migraine. Headache. 2006;46:317–21.PubMedCrossRefGoogle Scholar
  71. 71.
    Peters N, Freilinger T, Opherk C, Pfefferkorn T, Dichgans M. Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL. J Neurol. 2008;255:1203–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Liem MK, Lesnik Oberstein SA, Haan J, et al. Reactivity C is a main determinant of white matter hyperintensity progression in CADASIL. AJNR Am J Neuroradiol. 2009;30:1244–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Ruchoux MM, Guerouaou D, Vandenhaute B, et al. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropathol. 1995;89:500–12.PubMedCrossRefGoogle Scholar
  74. 74.
    Dreier JP, Kleeberg J, Petzold G, et al. Endothelin-1 potently induces Leao’s cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain. 2002;125:102–12.PubMedCrossRefGoogle Scholar
  75. 75.
    Goto Y, Horai S, Matsuoka T, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42:545–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, De Vivo DC, et al. MELAS: an original case and clinical criteria for diagnosis. Neuromusc Disord. 1992;2:125–35.PubMedCrossRefGoogle Scholar
  77. 77.
    • Sparaco M, Feleppa M, Lipton RB, et al. Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia. 2006;26:361–72. Review of morphological, biochemical, imaging, and genetic studies which bear on the hypothesis that migraine may be related to mitochondrial dysfunction.PubMedCrossRefGoogle Scholar
  78. 78.
    Koo B, Becker LE, Chuang S, Merante F, Robinson BH, MacGregor D, et al. Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations. Ann Neurol. 1993;34:25–32.PubMedCrossRefGoogle Scholar
  79. 79.
    Montagna P, Galassi R, Medori R, Govoni E, Zeviani M, Di Mauro S, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology. 1988;38:751–4.PubMedCrossRefGoogle Scholar
  80. 80.
    Ciafaloni E, Ricci E, Shanske S, Moraes CT, Silvestri G, Hirano M, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 1992;31:391–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Silvestri G, Ciafaloni E, Santorelli FM, Shanske S, Servidei S, Graf WD, et al. Clinical features associated with the A–>G transition at nucleotide 8344 of mtDNA (‘MERRF mutation’). Neurology. 1993;43:1200–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Hammans SR, Sweeney MG, Brockington M, Lennox GG, Lawton NF, Kennedy CR, et al. The mitochondrial DNA transfer RNA (Lys) A–>G (8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain. 1993;116:617–32.PubMedCrossRefGoogle Scholar
  83. 83.
    Huoponen K. Leber hereditary optic neuropathy: clinical and molecular genetic findings. Neurogenetics. 2001;3:119–25.PubMedCrossRefGoogle Scholar
  84. 84.
    Haan J, Terwindt GM, Maassen JA, Hart LM, Frants RR, Ferrari MD. Search for mitochondrial DNA mutations in migraine subgroups. Cephalalgia. 1999;19:20–2.PubMedCrossRefGoogle Scholar
  85. 85.
    Schoenen J. Deficient habituation of evoked cortical potentials in migraine: a link between brain biology, behavior and trigeminovascular activation? Biomed Pharmacother. 1996;50:71–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Phelps ME, Kuhl DE. Metabolic mapping of the brain’s response to visual stimulation: studies in humans. Science. 1981;211:1445–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Fox PT, Raichle ME, Mintum MA, Dence C. Nonoxidative glucose consumption during focal physiological neural activity. Science. 1988;241:462–4.PubMedCrossRefGoogle Scholar
  88. 88.
    Prichard JW, Rothmann DL, Novotny E, Petroff OAC, Kuwabara T, Avison M, et al. Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci USA. 1991;88:5829–31.PubMedCrossRefGoogle Scholar
  89. 89.
    Sacco S, Carolei A. Migraine attributed to genetic disorder. Funct Neurol. 2007;22:117–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Saint Joseph’s Regional Medical CenterPatersonUSA

Personalised recommendations