CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)

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CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral angiopathy (see image below). As the name implies, it is dominantly inherited. The condition was first described more than 30 years ago in a Swedish family [1] , although the acronym CADASIL did not emerge until the early 1990s [2] . Clinically, CADASIL is associated with progressive dementia, mood disorders, migraine, and recurrent subcortical cerebral infarctions.

CADASIL is caused by a mutation in the NOTCH3 gene on chromosome 19q12. The gene mutation was first identified in 1996. [3] NOTCH3 codes for a transmembrane receptor protein whose function is not precisely known. The NOTCH3 receptor is located on the surface of smooth muscle cells surrounding arteries. Mutations are typically located within epidermal growth factor–like repeat domains in the extracellular part of the NOTCH3 receptor. [4] Accumulation of the pathologic NOTCH3 receptor protein in small and medium-sized cerebral arteries is responsible for the pathogenesis and phenotypic presentation of CADASIL. [5] Cerebral infarctions result from thickening and fibrosis of the walls of small and medium-sized arteries.

United States

The incidenceand prevalence of CADASIL in the United States are not known.

International

The incidence and prevalence of CADASIL worldwide are not known.

The exact mortality rate in patients with CADASIL is unknown. The age at onset for stroke is 45-50 years. The mean age at death has been reported to be 61 years after a mean disease duration of approximately 23 years. [6] Men tend to die earlier than women. [7] Fewer than half of patients older than age 60 could walk without assistance. [5] Close to 80% of patients are completely dependent immediately before death. [7]

Although CADASIL was first reported in European families, it has been observed in American, Middle Eastern, African, and Asiatic pedigrees. [8]

CADASIL appears to be equally distributed between men and women.

The onset of clinical symptoms usually occurs in the fourth decade of life [9] , with a mean age at presentation of 46.1 years [6] . Symptomatic onset as early as age 8 years has been reported. [10]

Sourander P, Walinder J. Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol. 1977 Aug 31. 39(3):247-54. [Medline].

Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet. 1993 Mar. 3(3):256-9. [Medline].

Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996 Oct 24. 383(6602):707-10. [Medline].

Peters N, Freilinger T, Opherk C, Pfefferkorn T, Dichgans M. Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL. J Neurol Sci. 2007 Sep 15. 260(1-2):100-5. [Medline].

Meschia JF, Brott TG, Brown RD Jr. Genetics of cerebrovascular disorders. Mayo Clin Proc. 2005 Jan. 80(1):122-32. [Medline].

Dichgans M, Mayer M, Uttner I, Bruning R, Müller-Hocker J, Rungger G, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998 Nov. 44(5):731-9. [Medline].

Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov. 127:2533-9. [Medline].

Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. 1997 Sep. 56(9):947-64. [Medline].

Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D, Gutierrez JE, et al. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. 2002 Jul 23. 59(2):277-9. [Medline].

Hartley J, Westmacott R, Decker J, Shroff M, Yoon G. Childhood-onset CADASIL: clinical, imaging, and neurocognitive features. J Child Neurol. 2010 May. 25(5):623-7. [Medline].

Davous P. CADASIL: a review with proposed diagnostic criteria. Eur J Neurol. 1998 May. 5(3):219-233. [Medline].

Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP. The natural history of CADASIL: a pooled analysis of previously published cases. Stroke. 1999 Jun. 30(6):1230-3. [Medline].

Harris JG, Filley CM. CADASIL: neuropsychological findings in three generations of an affected family. J Int Neuropsychol Soc. 2001 Sep. 7(6):768-74. [Medline].

Gunda B, Hervé D, Godin O, Bruno M, Reyes S, Alili N, et al. Effects of Gender on the Phenotype of CADASIL. Stroke. 2012 Jan. 43(1):137-41. [Medline].

Chabriat H, Bousser MG. Neuropsychiatric manifestations in CADASIL. Dialogues Clin Neurosci. 2007. 9(2):199-208. [Medline].

Choi JC, Kang SY, Kang JH, Park JK. Intracerebral hemorrhages in CADASIL. Neurology. 2006 Dec 12. 67(11):2042-4. [Medline].

Bentley P, Wang T, Malik O, Nicholas R, Ban M, Sawcer S. CADASIL with cord involvement associated with a novel and atypical NOTCH3 mutation. J Neurol Neurosurg Psychiatry. 2011 Jan 8. [Medline].

Ito D, Tanahashi N, Murata M, Sato H, Saito I, Watanabe K, et al. Notch3 gene polymorphism and ischaemic cerebrovascular disease. J Neurol Neurosurg Psychiatry. 2002 Mar. 72(3):382-4. [Medline].

Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005 Jul. 62(7):1091-4. [Medline].

Pescini F, Nannucci S, Bertaccini B, Salvadori E, Bianchi S, Ragno M, 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 Nov. 43(11):2871-6. [Medline].

Chabriat H, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A, et al. Patterns of MRI lesions in CADASIL. Neurology. 1998 Aug. 51(2):452-7. [Medline].

Lesnik Oberstein SA, van den Boom R, Middelkoop HA, Ferrari MD, Knaap YM, van Houwelingen HC, et al. Incipient CADASIL. Arch Neurol. 2003 May. 60(5):707-12. [Medline].

Dichgans M, Filippi M, Bruning R, Iannucci G, Berchtenbreiter C, Minicucci L, et al. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. 1999 Apr 22. 52(7):1361-7. [Medline].

O’Sullivan M, Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology. 2001 Mar 13. 56(5):628-34. [Medline].

Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, et al. Diagnostic strategies in CADASIL. Neurology. 2002 Oct 22. 59(8):1134-8. [Medline].

Jouvent E, Viswanathan A, Mangin JF, O’Sullivan M, Guichard JP, Gschwendtner A, et al. Brain atrophy is related to lacunar lesions and tissue microstructural changes in CADASIL. Stroke. 2007 Jun. 38(6):1786-90. [Medline].

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 Sep 25. 57(6):1066-70. [Medline].

Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001 Dec 15. 358(9298):2049-51. [Medline].

LaPoint SF, Patel U, Rubio A. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Adv Anat Pathol. 2000 Sep. 7(5):307-21. [Medline].

Malandrini A, Gaudiano C, Gambelli S, Berti G, Serni G, Bianchi S, et al. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology. 2007 Apr 24. 68(17):1430-2. [Medline].

Kusaba T, Hatta T, Kimura T, Sonomura K, Tanda S, Kishimoto N, et al. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Clin Nephrol. 2007 Mar. 67(3):182-7. [Medline].

Oh JH, Lee JS, Kang SY, Kang JH, Choi JC. Aspirin-associated intracerebral hemorrhage in a patient with CADASIL. Clin Neurol Neurosurg. 2008 Apr. 110(4):384-6. [Medline].

Dichgans M, Markus HS, Salloway S, Verkkoniemi A, Moline M, Wang Q. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol. 2008 Apr. 7(4):310-8. [Medline].

Forteza AM, Brozman B, Rabinstein AA, Romano JG, Bradley WG. Acetazolamide for the treatment of migraine with aura in CADASIL. Neurology. 2001 Dec 11. 57(11):2144-5. [Medline].

Weller M, Dichgans J, Klockgether T. Acetazolamide-responsive migraine in CADASIL. Neurology. 1998 May. 50(5):1505. [Medline].

Huang L, Yang Q, Zhang L, Chen X, Huang Q, Wang H. Acetazolamide improves cerebral hemodynamics in CADASIL. J Neurol Sci. 2010 May 15. 292(1-2):77-80. [Medline].

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 Feb. 36(2):158-9. [Medline].

Reza Behrouz, DO, FACP Assistant Professor, Division of Cerebrovascular Diseases and Neurological Critical Care, Department of Neurology, The Ohio State University College of Medicine

Reza Behrouz, DO, FACP is a member of the following medical societies: American Academy of Neurology, American College of Physicians, Society of Critical Care Medicine, Society for Vascular Medicine, Neurocritical Care Society

Disclosure: Nothing to disclose.

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acorda, Livanova, Eisai, Greenwich, Lundbeck, Neuropace, Sunovion, Upsher-Smith.<br/>Serve(d) as a speaker or a member of a speakers bureau for: Livanova, Eisai, Greenwich, Lundbeck, Neuropace, Sunovion.<br/>Received research grant from: Acorda, Livanova, Greenwich, Lundbeck, Sepracor, Sunovion, UCB, Upsher-Smith.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alnylam Pharmaceuticals<br/>Received income in an amount equal to or greater than $250 from: Alnylam Pharmaceuticals; GLG.

Helmi L Lutsep, MD Professor and Vice Chair, Department of Neurology, Oregon Health and Science University School of Medicine; Associate Director, OHSU Stroke Center

Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology, American Stroke Association

Disclosure: Medscape Neurology Editorial Advisory Board for: Stroke Adjudication Committee, CREST2; Executive Committee for the NINDS-funded DEFUSE3 Trial; Physician Advisory Board for Coherex Medical.

Paul E Barkhaus, MD, FAAN, FAANEM Professor of Neurology and Physical Medicine and Rehabilitation, Chief, Neuromuscular and Autonomic Disorders Program, Director, ALS Program, Department of Neurology, Medical College of Wisconsin

Paul E Barkhaus, MD, FAAN, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Neurological Association

Disclosure: Nothing to disclose.

CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)

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