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Cardiology64 papers

CLCN2-related leukoencephalopathy

Last edited: 4/22/2026

Overview

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to progressive neurological decline characterized by recurrent strokes, cognitive impairment, and dementia 2823.

Diagnosis

  • Genetic Testing: Mutation analysis of the NOTCH3 gene is definitive 6726.
  • MRI Findings: Early white matter changes, lacunes, and microbleeds are characteristic 1925.
  • Clinical Features: Migraine with aura, recurrent strokes, cognitive decline, and psychiatric symptoms are common 210.
  • Histopathology: Presence of granular osmiophilic material in vascular smooth muscle cells supports diagnosis 2430.

    • Management

  • Supportive Care: Management of symptoms including migraine prophylaxis, anticoagulation for secondary stroke prevention, and cognitive support 210.
  • Blood Pressure Control: Tight control of hypertension to reduce vascular risk 27.
  • Lifestyle Modifications: Smoking cessation, healthy diet, and regular exercise to mitigate vascular risk factors 210.

    • Special Populations

  • Pediatrics: Early MRI detection of white matter changes in asymptomatic children of affected parents 19.
  • Pregnancy: Limited data; careful monitoring of vascular complications and neurological status 18.
  • Comorbidities: Consider impact on cardiovascular health; manage comorbidities to reduce overall vascular risk 210.

    • Key Recommendations

  • Genetic Testing for Diagnosis: Confirm CADASIL through NOTCH3 gene mutation analysis (Evidence: Strong 67).
  • Regular MRI Monitoring: Use MRI to detect early white matter changes and monitor disease progression (Evidence: Moderate 1925).
  • Aggressive Blood Pressure Management: Implement tight blood pressure control to mitigate vascular risks (Evidence: Moderate 27).
  • Symptomatic Treatment: Provide migraine prophylaxis and cognitive support tailored to individual needs (Evidence: Expert opinion).

    • References

    1 Aygun FB, Özkorkmaz C, Kadayıfcılar S. Branch retinal vein occlusion as a manifestation of systemic vasculopathy in CADASIL: a multimodal imaging case report. Ophthalmic genetics 2026. link 2 Argirò A, Sciagrà R, Marchi A, Beltrami M, Spinelli E, Salvadori E et al.. Coronary microvascular function is impaired in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. European journal of neurology 2021. link 3 Langer C, Adukauskaite A, Plank F, Feuchtner G, Cartes-Zumelzu F. Cerebral Autosomal Dominant Arteriopathy (CADASIL) with cardiac involvement (ANOCA) and subcortical leukencephalopathy. Journal of cardiovascular computed tomography 2020. link 4 Moreton FC, Cullen B, Delles C, Santosh C, Gonzalez RL, Dani K et al.. Vasoreactivity in CADASIL: Comparison to structural MRI and neuropsychology. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2018. link 5 De Guio F, Vignaud A, Chabriat H, Jouvent E. Different types of white matter hyperintensities in CADASIL: Insights from 7-Tesla MRI. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2018. link 6 You J, Liao S, Zhang F, Ma Z, Li G. First Report of Arg587Cys Mutation of Notch3 Gene in Two Chinese Families with CADASIL. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2017. link 7 Kim YE, Yoon CW, Seo SW, Ki CS, Kim YB, Kim JW et al.. Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiology of aging 2014. link 8 Kobayashi J, Sato S, Okumura K, Miyashita F, Ueda A, Ando Y et al.. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy without anterior temporal pole involvement: a case report. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2014. link 9 Viitanen M, Sundström E, Baumann M, Poyhonen M, Tikka S, Behbahani H. Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells. Experimental cell research 2013. link 10 Gunda B, Hervé D, Godin O, Bruno M, Reyes S, Alili N et al.. Effects of gender on the phenotype of CADASIL. Stroke 2012. link 11 Campolo J, De Maria R, Frontali M, Taroni F, Inzitari D, Federico A et al.. Impaired vasoreactivity in mildly disabled CADASIL patients. Journal of neurology, neurosurgery, and psychiatry 2012. link 12 Pradotto L, Orsi L, Daniele D, Caroppo P, Lauro D, Milesi A et al.. A new NOTCH3 mutation presenting as primary intracerebral haemorrhage. Journal of the neurological sciences 2012. link 13 O'Sullivan M, Ngo E, Viswanathan A, Jouvent E, Gschwendtner A, Saemann PG et al.. Hippocampal volume is an independent predictor of cognitive performance in CADASIL. Neurobiology of aging 2009. link 14 Hervé D, Godin O, Dufouil C, Viswanathan A, Jouvent E, Pachaï C et al.. Three-dimensional MRI analysis of individual volume of Lacunes in CADASIL. Stroke 2009. link 15 Manganelli F, Ragno M, Cacchiò G, Iodice V, Trojano L, Silvaggio F et al.. Motor cortex cholinergic dysfunction in CADASIL: a transcranial magnetic demonstration. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 2008. link 16 Bohlega S, Al Shubili A, Edris A, Alreshaid A, Alkhairallah T, AlSous MW et al.. CADASIL in Arabs: clinical and genetic findings. BMC medical genetics 2007. link 17 Schröder JM, Züchner S, Dichgans M, Nagy Z, Molnar MJ. Peripheral nerve and skeletal muscle involvement in CADASIL. Acta neuropathologica 2005. link 18 Milunsky A, Konialis C, Shim SH, Maher TA, Spengos K, Ito M et al.. The prenatal diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by mutation analysis. Prenatal diagnosis 2005. link 19 Fattapposta F, Restuccia R, Pirro C, Malandrini A, Locuratolo N, Amabile G et al.. Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI. Functional neurology 2004. link 20 Peters N, Opherk C, Zacherle S, Capell A, Gempel P, Dichgans M. CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Experimental cell research 2004. link 21 Rafalowska J, Fidziańska A, Dziewulska D, Podlecka A, Szpak GM, Kwieciński H. CADASIL: new cases and new questions. Acta neuropathologica 2003. link 22 Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH et al.. Diagnostic strategies in CADASIL. Neurology 2002. link 23 Dichgans M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: phenotypic and mutational spectrum. Journal of the neurological sciences 2002. link00270-8) 24 Ruchoux MM, Brulin P, Brillault J, Dehouck MP, Cecchelli R, Bataillard M. Lessons from CADASIL. Annals of the New York Academy of Sciences 2002. link 25 Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E et al.. Cerebral microbleeds in CADASIL. Neurology 2001. link 26 Oliveri RL, Muglia M, De Stefano N, Mazzei R, Labate A, Conforti FL et al.. A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings. Archives of neurology 2001. link 27 Manabe Y, Murakami T, Iwatsuki K, Narai H, Warita H, Hayashi T et al.. Nocturnal blood pressure dip in CADASIL. Journal of the neurological sciences 2001. link00636-0) 28 LaPoint SF, Patel U, Rubio A. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Advances in anatomic pathology 2000. link 29 Escary JL, Cécillon M, Maciazek J, Lathrop M, Tournier-Lasserve E, Joutel A. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Human mutation 2000. link16:6<518::AID-HUMU9>3.0.CO;2-Q) 30 Caronti B, Calandriello L, Francia A, Scorretti L, Manfredi M, Sansolini T et al.. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Neuropathological and in vitro studies of abnormal elastogenesis. Acta neurologica Scandinavica 1998. link 31 Rubio A, Rifkin D, Powers JM, Patel U, Stewart J, Faust P et al.. Phenotypic variability of CADASIL and novel morphologic findings. Acta neuropathologica 1997. link

    Original source

    1. [1]
      Branch retinal vein occlusion as a manifestation of systemic vasculopathy in CADASIL: a multimodal imaging case report. — Aygun FB, Özkorkmaz C, Kadayıfcılar S Ophthalmic genetics (2026)
    2. [2]
      Coronary microvascular function is impaired in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. — Argirò A, Sciagrà R, Marchi A, Beltrami M, Spinelli E, Salvadori E et al. European journal of neurology (2021)
    3. [3]
      Cerebral Autosomal Dominant Arteriopathy (CADASIL) with cardiac involvement (ANOCA) and subcortical leukencephalopathy. — Langer C, Adukauskaite A, Plank F, Feuchtner G, Cartes-Zumelzu F Journal of cardiovascular computed tomography (2020)
    4. [4]
      Vasoreactivity in CADASIL: Comparison to structural MRI and neuropsychology. — Moreton FC, Cullen B, Delles C, Santosh C, Gonzalez RL, Dani K et al. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (2018)
    5. [5]
      Different types of white matter hyperintensities in CADASIL: Insights from 7-Tesla MRI. — De Guio F, Vignaud A, Chabriat H, Jouvent E Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (2018)
    6. [6]
      First Report of Arg587Cys Mutation of Notch3 Gene in Two Chinese Families with CADASIL. — You J, Liao S, Zhang F, Ma Z, Li G Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association (2017)
    7. [7]
      Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. — Kim YE, Yoon CW, Seo SW, Ki CS, Kim YB, Kim JW et al. Neurobiology of aging (2014)
    8. [8]
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy without anterior temporal pole involvement: a case report. — Kobayashi J, Sato S, Okumura K, Miyashita F, Ueda A, Ando Y et al. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association (2014)
    9. [9]
      Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells. — Viitanen M, Sundström E, Baumann M, Poyhonen M, Tikka S, Behbahani H Experimental cell research (2013)
    10. [10]
      Effects of gender on the phenotype of CADASIL. — Gunda B, Hervé D, Godin O, Bruno M, Reyes S, Alili N et al. Stroke (2012)
    11. [11]
      Impaired vasoreactivity in mildly disabled CADASIL patients. — Campolo J, De Maria R, Frontali M, Taroni F, Inzitari D, Federico A et al. Journal of neurology, neurosurgery, and psychiatry (2012)
    12. [12]
      A new NOTCH3 mutation presenting as primary intracerebral haemorrhage. — Pradotto L, Orsi L, Daniele D, Caroppo P, Lauro D, Milesi A et al. Journal of the neurological sciences (2012)
    13. [13]
      Hippocampal volume is an independent predictor of cognitive performance in CADASIL. — O'Sullivan M, Ngo E, Viswanathan A, Jouvent E, Gschwendtner A, Saemann PG et al. Neurobiology of aging (2009)
    14. [14]
      Three-dimensional MRI analysis of individual volume of Lacunes in CADASIL. — Hervé D, Godin O, Dufouil C, Viswanathan A, Jouvent E, Pachaï C et al. Stroke (2009)
    15. [15]
      Motor cortex cholinergic dysfunction in CADASIL: a transcranial magnetic demonstration. — Manganelli F, Ragno M, Cacchiò G, Iodice V, Trojano L, Silvaggio F et al. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology (2008)
    16. [16]
      CADASIL in Arabs: clinical and genetic findings. — Bohlega S, Al Shubili A, Edris A, Alreshaid A, Alkhairallah T, AlSous MW et al. BMC medical genetics (2007)
    17. [17]
      Peripheral nerve and skeletal muscle involvement in CADASIL. — Schröder JM, Züchner S, Dichgans M, Nagy Z, Molnar MJ Acta neuropathologica (2005)
    18. [18]
      The prenatal diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by mutation analysis. — Milunsky A, Konialis C, Shim SH, Maher TA, Spengos K, Ito M et al. Prenatal diagnosis (2005)
    19. [19]
      Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI. — Fattapposta F, Restuccia R, Pirro C, Malandrini A, Locuratolo N, Amabile G et al. Functional neurology (2004)
    20. [20]
      CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. — Peters N, Opherk C, Zacherle S, Capell A, Gempel P, Dichgans M Experimental cell research (2004)
    21. [21]
      CADASIL: new cases and new questions. — Rafalowska J, Fidziańska A, Dziewulska D, Podlecka A, Szpak GM, Kwieciński H Acta neuropathologica (2003)
    22. [22]
      Diagnostic strategies in CADASIL. — Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH et al. Neurology (2002)
    23. [23]
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: phenotypic and mutational spectrum. — Dichgans M Journal of the neurological sciences (2002)
    24. [24]
      Lessons from CADASIL. — Ruchoux MM, Brulin P, Brillault J, Dehouck MP, Cecchelli R, Bataillard M Annals of the New York Academy of Sciences (2002)
    25. [25]
      Cerebral microbleeds in CADASIL. — Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E et al. Neurology (2001)
    26. [26]
      A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings. — Oliveri RL, Muglia M, De Stefano N, Mazzei R, Labate A, Conforti FL et al. Archives of neurology (2001)
    27. [27]
      Nocturnal blood pressure dip in CADASIL. — Manabe Y, Murakami T, Iwatsuki K, Narai H, Warita H, Hayashi T et al. Journal of the neurological sciences (2001)
    28. [28]
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). — LaPoint SF, Patel U, Rubio A Advances in anatomic pathology (2000)
    29. [29]
      Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. — Escary JL, Cécillon M, Maciazek J, Lathrop M, Tournier-Lasserve E, Joutel A Human mutation (2000)
    30. [30]
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Neuropathological and in vitro studies of abnormal elastogenesis. — Caronti B, Calandriello L, Francia A, Scorretti L, Manfredi M, Sansolini T et al. Acta neurologica Scandinavica (1998)
    31. [31]
      Phenotypic variability of CADASIL and novel morphologic findings. — Rubio A, Rifkin D, Powers JM, Patel U, Stewart J, Faust P et al. Acta neuropathologica (1997)
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