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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Martin Dichgans, MD
Section Editor
Scott E Kasner, MD
Deputy Editor
John F Dashe, MD, PhD


Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited angiopathy caused by mutations in the NOTCH3 gene on chromosome 19 [1]. CADASIL is now recognized as an important cause of stroke in the young [2,3].

Stroke and vascular cognitive impairment remain the main causes of morbidity and mortality in patients with CADASIL. Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of the same condition.


CADASIL is caused by pathogenic mutations in the NOTCH3 gene, which lead to vasculopathic changes predominantly involving small penetrating arteries, arterioles, and brain capillaries. The underlying vascular lesion is a specific non-atherosclerotic, amyloid-negative angiopathy involving small arteries (100 to 400 microns in diameter) and capillaries, primarily in the brain but also in other organs [4].

Molecular mechanisms — The NOTCH3 gene on chromosome 19p13.2-p13.1 is one of four mammalian homologs of the Drosophila NOTCH gene [5]. NOTCH genes code for large transmembrane receptors involved in cell fate decisions during embryonic development [6]. The protein product Notch3 is critical for vascular smooth muscle cell (VSMC) differentiation and vascular development [7]. In adults, expression of NOTCH3 is largely restricted to VSMCs and capillary pericytes.

Like all Notch receptors, the Notch3 receptor is proteolytically processed in the trans-Golgi network as it traffics from the endoplasmic reticulum to the plasma membrane. Proteolytic cleavage results in a large extracellular fragment and a small intracellular fragment that contains the transmembrane region.


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Literature review current through: Apr 2017. | This topic last updated: May 15, 2017.
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  1. 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.
  2. Opherk C, Peters N, Herzog J, et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 2004; 127:2533.
  3. Chabriat H, Joutel A, Dichgans M, et al. Cadasil. Lancet Neurol 2009; 8:643.
  4. Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 1997; 56:947.
  5. Weinmaster G. The ins and outs of notch signaling. Mol Cell Neurosci 1997; 9:91.
  6. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999; 284:770.
  7. Domenga V, Fardoux P, Lacombe P, et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 2004; 18:2730.
  8. 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.
  9. Monet-Leprêtre M, Haddad I, Baron-Menguy C, et al. Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. Brain 2013; 136:1830.
  10. Ghosh M, Balbi M, Hellal F, et al. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann Neurol 2015; 78:887.
  11. Wang W, Prince CZ, Mou Y, Pollman MJ. Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis. J Biol Chem 2002; 277:21723.
  12. Morrow D, Sweeney C, Birney YA, et al. Cyclic strain inhibits Notch receptor signaling in vascular smooth muscle cells in vitro. Circ Res 2005; 96:567.
  13. Eikermann-Haerter K, Yuzawa I, Dilekoz E, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol 2011; 69:413.
  14. Miao Q, Paloneva T, Tuominen S, et al. Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white matter pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Brain Pathol 2004; 14:358.
  15. Dichgans M, Wick M, Gasser T. Cerebrospinal fluid findings in CADASIL. Neurology 1999; 53:233.
  16. Rutten J, Lesnik Oberstein SAJ. CADASIL. GeneReviews . https://www.ncbi.nlm.nih.gov/books/NBK1500/tifocal leukoencephalopathy (PML (Accessed on April 13, 2017).
  17. 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.
  18. Dichgans M. Klinische, bildgebende und genetische Untersuchungen bei CADASIL. Habilitationsschrift 2000.
  19. Narayan SK, Gorman G, Kalaria RN, et al. The minimum prevalence of CADASIL in northeast England. Neurology 2012; 78:1025.
  20. Moreton FC, Razvi SS, Davidson R, Muir KW. Changing clinical patterns and increasing prevalence in CADASIL. Acta Neurol Scand 2014; 130:197.
  21. Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998; 44:731.
  22. Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet 1995; 346:934.
  23. Schon F, Martin RJ, Prevett M, et al. "CADASIL coma": an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry 2003; 74:249.
  24. Feuerhake F, Volk B, Ostertag CB, et al. Reversible coma with raised intracranial pressure: an unusual clinical manifestation of CADASIL. Acta Neuropathol 2002; 103:188.
  25. Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals. Stroke 2010; 41:630.
  26. Hutchinson M, O'Riordan J, Javed M, et al. Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (CADASIL). Ann Neurol 1995; 38:817.
  27. Sourander P, Wålinder J. Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol 1977; 39:247.
  28. Gutiérrez-Molina M, Caminero Rodríguez A, Martínez García C, et al. Small arterial granular degeneration in familial Binswanger's syndrome. Acta Neuropathol 1994; 87:98.
  29. Hinze S, Goonasekera M, Nannucci S, et al. Longitudinally extensive spinal cord infarction in CADASIL. Pract Neurol 2015; 15:60.
  30. Maclean AV, Woods R, Alderson LM, et al. Spontaneous lobar haemorrhage in CADASIL. J Neurol Neurosurg Psychiatry 2005; 76:456.
  31. Choi JC, Kang SY, Kang JH, Park JK. Intracerebral hemorrhages in CADASIL. Neurology 2006; 67:2042.
  32. Lesnik Oberstein SA, Jukema JW, Van Duinen SG, et al. Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Medicine (Baltimore) 2003; 82:251.
  33. Cumurciuc R, Henry P, Gobron C, et al. Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study. Stroke 2006; 37:1100.
  34. Fattapposta F, Restuccia R, Pirro C, et al. Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI. Funct Neurol 2004; 19:239.
  35. Coulthard A, Blank SC, Bushby K, et al. Distribution of cranial MRI abnormalities in patients with symptomatic and subclinical CADASIL. Br J Radiol 2000; 73:256.
  36. Golomb MR, Sokol DK, Walsh LE, et al. Recurrent hemiplegia, normal MRI, and NOTCH3 mutation in a 14-year-old: is this early CADASIL? Neurology 2004; 62:2331.
  37. Granild-Jensen J, Jensen UB, Schwartz M, Hansen US. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy resulting in stroke in an 11-year-old male. Dev Med Child Neurol 2009; 51:754.
  38. Benabu Y, Beland M, Ferguson N, et al. Genetically proven cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a 3-year-old. Pediatr Radiol 2013; 43:1227.
  39. Liem MK, Oberstein SA, van der Grond J, et al. CADASIL and migraine: A narrative review. Cephalalgia 2010; 30:1284.
  40. Guey S, Mawet J, Hervé D, et al. Prevalence and characteristics of migraine in CADASIL. Cephalalgia 2015.
  41. 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.
  42. Chabriat H, Tournier-Lasserve E, Vahedi K, et al. Autosomal dominant migraine with MRI white-matter abnormalities mapping to the CADASIL locus. Neurology 1995; 45:1086.
  43. Gunda B, Hervé D, Godin O, et al. Effects of gender on the phenotype of CADASIL. Stroke 2012; 43:137.
  44. Ling Y, De Guio F, Duering M, et al. Predictors and Clinical Impact of Incident Lacunes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. Stroke 2017; 48:283.
  45. Rubio A, Rifkin D, Powers JM, et al. Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol 1997; 94:247.
  46. Choi EJ, Choi CG, Kim JS. Large cerebral artery involvement in CADASIL. Neurology 2005; 65:1322.
  47. Viswanathan A, Gschwendtner A, Guichard JP, et al. Lacunar lesions are independently associated with disability and cognitive impairment in CADASIL. Neurology 2007; 69:172.
  48. Peters N, Holtmannspötter M, Opherk C, et al. Brain volume changes in CADASIL: a serial MRI study in pure subcortical ischemic vascular disease. Neurology 2006; 66:1517.
  49. Duering M, Zieren N, Hervé D, et al. Strategic role of frontal white matter tracts in vascular cognitive impairment: a voxel-based lesion-symptom mapping study in CADASIL. Brain 2011; 134:2366.
  50. Dichgans M. Cognition in CADASIL. Stroke 2009; 40:S45.
  51. Amberla K, Wäljas M, Tuominen S, et al. Insidious cognitive decline in CADASIL. Stroke 2004; 35:1598.
  52. Buffon F, Porcher R, Hernandez K, et al. Cognitive profile in CADASIL. J Neurol Neurosurg Psychiatry 2006; 77:175.
  53. Peters N, Herzog J, Opherk C, Dichgans M. A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials. Stroke 2004; 35:1603.
  54. Peters N, Opherk C, Danek A, et al. The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia. Am J Psychiatry 2005; 162:2078.
  55. Valenti R, Poggesi A, Pescini F, et al. Psychiatric disturbances in CADASIL: a brief review. Acta Neurol Scand 2008; 118:291.
  56. Lågas PA, Juvonen V. Schizophrenia in a patient with cerebral autosomally dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL disease). Nord J Psychiatry 2001; 55:41.
  57. Reyes S, Viswanathan A, Godin O, et al. Apathy: a major symptom in CADASIL. Neurology 2009; 72:905.
  58. Chabriat H, Levy C, Taillia H, et al. Patterns of MRI lesions in CADASIL. Neurology 1998; 51:452.
  59. Auer DP, Pütz B, Gössl C, et al. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 2001; 218:443.
  60. Dichgans M, Filippi M, Brüning R, et al. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology 1999; 52:1361.
  61. Liem MK, Lesnik Oberstein SA, Haan J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: progression of MR abnormalities in prospective 7-year follow-up study. Radiology 2008; 249:964.
  62. O'Sullivan M, Jarosz JM, Martin RJ, et al. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 2001; 56:628.
  63. van den Boom R, Lesnik Oberstein SA, Ferrari MD, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages--3rd-6th decades. Radiology 2003; 229:683.
  64. van Den Boom R, Lesnik Oberstein SA, van Duinen SG, et al. Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology 2002; 224:791.
  65. Lesnik Oberstein SA, van den Boom R, van Buchem MA, et al. Cerebral microbleeds in CADASIL. Neurology 2001; 57:1066.
  66. Dichgans M, Holtmannspötter M, Herzog J, et al. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke 2002; 33:67.
  67. Viswanathan A, Guichard JP, Gschwendtner A, et al. Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study. Brain 2006; 129:2375.
  68. Duering M, Righart R, Csanadi E, et al. Incident subcortical infarcts induce focal thinning in connected cortical regions. Neurology 2012; 79:2025.
  69. Holtmannspötter M, Peters N, Opherk C, et al. Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study. Stroke 2005; 36:2559.
  70. 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.
  71. Tatsch K, Koch W, Linke R, et al. Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18F-FDG PET study. J Nucl Med 2003; 44:862.
  72. Tuominen S, Miao Q, Kurki T, et al. Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients. Stroke 2004; 35:1063.
  73. Jouvent E, Poupon C, Gray F, et al. Intracortical infarcts in small vessel disease: a combined 7-T postmortem MRI and neuropathological case study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2011; 42:e27.
  74. Dichgans M, Petersen D. Angiographic complications in CADASIL. Lancet 1997; 349:776.
  75. Roine S, Pöyhönen M, Timonen S, et al. Neurologic symptoms are common during gestation and puerperium in CADASIL. Neurology 2005; 64:1441.
  76. Joutel A, Chabriat H, Vahedi K, et al. Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL. Neurology 2000; 54:1874.
  77. Arboleda-Velasquez JF, Lopera F, Lopez E, et al. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology 2002; 59:277.
  78. Monet-Leprêtre M, Bardot B, Lemaire B, et al. Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. Brain 2009; 132:1601.
  79. Viswanathan A, Gray F, Bousser MG, et al. Cortical neuronal apoptosis in CADASIL. Stroke 2006; 37:2690.
  80. Pescini F, Nannucci S, Bertaccini B, et al. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke 2012; 43:2871.
  81. Tikka S, Baumann M, Siitonen M, et al. CADASIL and CARASIL. Brain Pathol 2014; 24:525.
  82. www.hgmd.cf.ac.uk/ac/gene.php?gene=NOTCH3 (Accessed on August 29, 2016).
  83. Peters N, Opherk C, Bergmann T, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol 2005; 62:1091.
  84. Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997; 350:1511.
  85. Mazzei R, Conforti FL, Lanza PL, et al. A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL. Neurology 2004; 63:561.
  86. Wollenweber FA, Hanecker P, Bayer-Karpinska A, et al. Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro. Stroke 2015; 46:786.
  87. Ruchoux MM, Chabriat H, Bousser MG, et al. Presence of ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL. Stroke 1994; 25:2291.
  88. Mayer M, Straube A, Bruening R, et al. Muscle and skin biopsies are a sensitive diagnostic tool in the diagnosis of CADASIL. J Neurol 1999; 246:526.
  89. Ebke M, Dichgans M, Bergmann M, et al. CADASIL: skin biopsy allows diagnosis in early stages. Acta Neurol Scand 1997; 95:351.
  90. Joutel A, Favrole P, Labauge P, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 2001; 358:2049.
  91. Lesnik Oberstein SA, van Duinen SG, van den Boom R, et al. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol 2003; 106:107.
  92. Onodera O, Nozaki H, Fukutake T. CARASIL. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK32533/ (Accessed on June 30, 2016).
  93. Verdura E, Hervé D, Scharrer E, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 2015; 138:2347.
  94. Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009; 360:1729.
  95. Chabriat H, Hervé D, Duering M, et al. Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prospective Cohort Study. Stroke 2016; 47:4.
  96. Wang Q, Yan J, Chen X, et al. Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol 2011; 230:27.
  97. Iannaccone S, Ferini-Strambi L. Pharmacologic treatment of emotional lability. Clin Neuropharmacol 1996; 19:532.
  98. Weller M, Dichgans J, Klockgether T. Acetazolamide-responsive migraine in CADASIL. Neurology 1998; 50:1505.
  99. Forteza AM, Brozman B, Rabinstein AA, et al. Acetazolamide for the treatment of migraine with aura in CADASIL. Neurology 2001; 57:2144.