View source for CADASIL

{{Infobox medical condition (new)
| name            = CADASIL
| image           = CADASIL.jpg
| caption         = Brain [[Magnetic resonance imaging|MRI]] from patients with CADASIL showing multiple lesions.
| synonyms        = CADASIL syndrome
| symptoms        =Migraine headaches
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'''CADASIL''' or '''CADASIL syndrome''', involving '''cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy''', is the most common form of hereditary [[stroke]] disorder, and is thought to be caused by [[mutation]]s of the ''[[NOTCH3]]'' gene on [[chromosome 19]].<ref>{{cite journal |vauthors=Joutel A, Corpechot C, Ducros A |title=Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia |journal=Nature |volume=383 |issue=6602 |pages=707–10 |date=October 1996 |pmid=8878478 |doi=10.1038/383707a0 |display-authors=etal|bibcode=1996Natur.383..707J |s2cid=4351873 }}</ref> The disease belongs to a family of disorders called the [[leukodystrophies]]. The most common clinical manifestations are [[migraine]] headaches and [[transient ischemic attack]]s or strokes, which usually occur between 40 and 50 years of age, although [[Magnetic resonance imaging|MRI]] is able to detect signs of the disease years prior to clinical manifestation of disease.<ref name="Chabriat1995">{{cite journal |vauthors=Chabriat H, Vahedi K, Iba-Zizen MT |title=Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy |journal=Lancet |volume=346 |issue=8980 |pages=934–9 |date=October 1995 |pmid=7564728 |display-authors=etal| doi = 10.1016/s0140-6736(95)91557-5 |s2cid=44289660 }}</ref><ref>{{cite book |author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology |url=https://archive.org/details/andrewsdiseasess00mdwi_659 |url-access=limited |publisher=Saunders Elsevier |year=2006 |page=[https://archive.org/details/andrewsdiseasess00mdwi_659/page/n555 545] |isbn=978-0-7216-2921-6 |display-authors=etal}}</ref>
The condition was identified and named by French researchers [[Marie-Germaine Bousser]] and [[Elisabeth Tournier-Lasserve]] in the 1990s.<ref>{{Cite web|url=https://www.cadasilfoundation.org/bousser.html|title=CADASIL History|website=www.cadasilfoundation.org|access-date=2018-03-03|archive-date=2021-05-15|archive-url=https://web.archive.org/web/20210515112410/https://www.cadasilfoundation.org/bousser.html|url-status=dead}}</ref><ref>{{cite journal|pmid=9026542|title=[CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)] - Abstract|journal=Journal des Maladies Vasculaires|volume=21|issue=5|pages=277–82|year=1996|last1=Chabriat|first1=H.|last2=Joutel|first2=A.|last3=Vahedi|first3=K.|last4=Iba-Zizen|first4=M. T.|last5=Tournier-Lasserve|first5=E.|last6=Bousser|first6=M. G.}}</ref> Together with two other researchers, [[Hugues Chabriat]] and [[Anne Joutel]], they received the 2019 [[The Brain Prize|Brain Prize]] for their research into the condition.<ref>{{Cite web|last=Office|first=FENS|title=The Brain Prize 2019: French neuroscientists honoured for outstanding research into small vessel strokes in the brain|url=https://www.fens.org/News-Activities/News/20191/031/The-Brain-Prize-2019-awarded/|access-date=2021-03-04|website=FENS.org|language=English|archive-date=2021-05-15|archive-url=https://web.archive.org/web/20210515112411/https://www.fens.org/News-Activities/News/20191/031/The-Brain-Prize-2019-awarded/|url-status=dead}}</ref>
==Signs and symptoms==
CADASIL may start with attacks of [[migraine]] with [[Aura (symptom)|aura]] or subcortical transient ischemic attacks or strokes, or mood disorders between 35 and 55 years of age. The disease progresses to [[subcortical dementia]] associated with [[pseudobulbar palsy]] and [[urinary incontinence]].{{citation needed|date=September 2019}}
[[Ischemic stroke]]s are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developing [[transient ischemic attack]]s or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30–70). A classic [[lacunar syndrome]] occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. It is worthy of note that ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. Recurrent silent strokes, with or without clinical strokes, often lead to cognitive decline and overt subcortical dementia. A case of CADASIL presenting as schizophreniform organic psychosis has been reported.<ref>{{cite journal | doi = 10.1016/j.genhosppsych.2015.02.006 | pmid=25824603 | title=CADASIL presenting as schizophreniform organic psychosis | journal=General Hospital Psychiatry| volume=37 | issue=3 | pages=273.e11–273.e13 | year=2015 | last1=Ho | first1=Cyrus S.H. | last2=Mondry | first2=Adrian }}</ref>
==Pathophysiology==
The underlying pathology of CADASIL is progressive hypertrophy of the [[smooth muscle tissue|smooth muscle cells]] in [[blood vessel]]s. [[Dominance (genetics)|Autosomal dominant]] mutations in the ''[[NOTCH3]]'' gene (on the long arm of chromosome 19) cause an abnormal accumulation of Notch 3 protein at the [[cytoplasmic]] membrane of vascular smooth muscle cells both in [[cerebrum|cerebral]] and extracerebral vessels,<ref>{{cite journal|vauthors=Joutel A, Andreux F, Gaulis S |title=The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients |journal=J. Clin. Invest. |volume=105 |issue=5 |pages=597–605 |date=March 2000 |pmid=10712431 |pmc=289174 |doi=10.1172/JCI8047 |display-authors=etal}}</ref> seen as granular [[osmiophilic]] deposits on [[electron microscopy]].<ref>{{cite journal |vauthors=Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D |title=Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy |journal=Acta Neuropathol. |volume=89 |issue=6 |pages=500–12 |year=1995 |pmid=7676806|doi=10.1007/BF00571504|s2cid=24884723 }}</ref> [[Leukoencephalopathy]] follows. Depending on the nature and position of each mutation, a consensus significant loss of [[beta sheet]] structure of the Notch3 protein has been predicted using [[in silico]] analysis.<ref>{{cite journal|vauthors=Vlachakis D, Champeris Tsaniras S, Ioannidou K, Papageorgiou L, Baumann M, Kossida S |title=A series of Notch3 mutations in CADASIL; insights from 3D molecular modelling and evolutionary analyses |journal=Journal of Molecular Biochemistry |volume=3 |issue=3 |pages=97–105 |date=October 2014}}</ref>
==Diagnosis==
[[Image:CADASIL - very high mag.jpg|thumb|A [[micrograph]] showing punctate [[immunostaining]] (brown) with a Notch 3 [[antibody]], as is characteristic in CADASIL.]]
MRIs show hypointensities on [[Magnetic resonance imaging|T1-weighted images]] and [[hyperintensities]] on [[Magnetic resonance imaging|T2-weighted images]], usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the [[basal ganglia]], peri-[[Ventricular system|ventricular]] [[white matter]], and the [[pons]], and are similar to those seen in [[Binswanger disease]].<ref name="Chabriat1995"/><ref>{{cite book |veditors=Ropper AH, Brown RH |chapter=Cerebrovascular Diseases |title=Adams and Victor's Principles of Neurology |publisher=McGraw-Hill |location=New York |year=2005 |isbn=978-0-07-141620-7}}</ref> These white matter lesions are also seen in asymptomatic individuals with the mutated gene.<ref>{{cite journal |vauthors=Tournier-Lasserve E, Joutel A, Melki J |title=Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12 |journal=Nat. Genet. |volume=3 |issue=3 |pages=256–9 |date=March 1993 |pmid=8485581 |doi=10.1038/ng0393-256 |s2cid=13031278 |display-authors=etal}}</ref>  While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms.{{citation needed|date=December 2020}}
The definitive test is sequencing the whole ''NOTCH3'' gene, which can be done from a sample of blood. However, as this is quite expensive and CADASIL is a systemic [[arterial disease]], evidence of the mutation can be found in small and medium-size arteries. Therefore, skin biopsies are often used for the diagnosis.<ref>{{cite journal |vauthors=Joutel A, Favrole P, Labauge P |title=Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis |journal=Lancet |volume=358 |issue=9298 |pages=2049–51 |date=December 2001 |pmid=11755616 |doi=10.1016/S0140-6736(01)07142-2 |s2cid=31459077 |display-authors=etal}}</ref><ref>{{cite journal |vauthors=Ueda M, Nakaguma R, Ando Y |title=[Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)] |language=Japanese |journal=Rinsho Byori |volume=57 |issue=3 |pages=242–51 |date=March 2009 |pmid=19363995 }}</ref>
==Treatment==
No specific treatment for CADASIL is available. While most treatments for CADASIL patients' symptoms – including migraine and stroke – are similar to those without CADASIL, these treatments are almost exclusively empiric, as data regarding their benefit to CADASIL patients are limited.<ref name="Andre">{{cite journal|last1=André|first1=Charles|title=CADASIL: pathogenesis, clinical and radiological findings and treatment|journal=Arq. Neuro-Psiquiatr.|date=April 2010|volume=68|issue=2|pages=287–99|pmid=20464302|doi=10.1590/S0004-282X2010000200026|doi-access=free}}</ref> Antiplatelet agents such as [[aspirin]], [[dipyridamole]], or [[clopidogrel]] might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages.<ref name="auto">{{Cite journal|title = Cerebral microbleeds in CADASIL|journal = Neurology|date = 2001-09-25|issn = 0028-3878|pmid = 11571335|pages = 1066–1070|volume = 57|issue = 6|first1 = S. A.|last1 = Lesnik Oberstein|first2 = R.|last2 = van den Boom|first3 = M. A.|last3 = van Buchem|first4 = H. C.|last4 = van Houwelingen|first5 = E.|last5 = Bakker|first6 = E.|last6 = Vollebregt|first7 = M. D.|last7 = Ferrari|first8 = M. H.|last8 = Breuning|first9 = J.|last9 = Haan|doi=10.1212/wnl.57.6.1066|s2cid = 22934154}}</ref> Control of high blood pressure is particularly important in CADASIL patients.<ref name="Andre" /> Short-term use of atorvastatin, a [[statin]]-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters,<ref name="Peters">{{cite journal|last1=Peters|first1=N|title=Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL|journal=J Neurol Sci|date=15 September 2007|volume=260|issue=1–2|pages=100–105|doi=10.1016/j.jns.2007.04.015|pmid=17531269|s2cid=6502194}}</ref> although treatment of comorbidities such as high cholesterol is recommended.<ref name="auto1">{{cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1500/|title=GeneReviews|first1=Julie|last1=Rutten|first2=Saskia A.J.|last2=Lesnik Oberstein|editor-first1=Roberta A.|editor-last1=Pagon|editor-first2=Margaret P.|editor-last2=Adam|editor-first3=Holly H.|editor-last3=Ardinger|editor-first4=Stephanie E.|editor-last4=Wallace|editor-first5=Anne|editor-last5=Amemiya|editor-first6=Lora J.H.|editor-last6=Bean|editor-first7=Thomas D.|editor-last7=Bird|editor-first8=Nikki|editor-last8=Ledbetter|editor-first9=Heather C.|editor-last9=Mefford|editor-first10=Richard J.H.|editor-last10=Smith|editor-first11=Karen|editor-last11=Stephens|date=1 January 1993|publisher=University of Washington, Seattle|via=PubMed|pmid=20301673|chapter=Cadasil}}</ref> Stopping oral contraceptive pills may be recommended.<ref name="Cambridge">{{Cite web|url=https://www.cambridgestroke.com/faqs.php|title=Questions about cadasil|website=www.cambridgestroke.com}}</ref> Some authors advise against the use of [[triptan]] medications for migraine treatment, given their vasoconstrictive effects,<ref>{{Cite web|url=https://rarediseases.org/rare-diseases/cadasil/|title=CADASIL|first=Lisa|last=Sencen}}</ref> although this sentiment is not universal.<ref name="auto1"/> In this regard, the advent of the "Ditans" such as Lasmiditan, lacking vasoconstrictive effect, and the "Gepants" such as Ubrogepant and Rimegepant, are attractive alternatives, albeit not yet field-tested in this condition.   As with other individuals, people with CADASIL should be encouraged to quit smoking.<ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/1049/cadasil#diseaseTreatmentSection|title=CADASIL - About the Disease - Genetic and Rare Diseases Information Center|website=rarediseases.info.nih.gov|access-date=2017-04-01|archive-date=2021-10-27|archive-url=https://web.archive.org/web/20211027232618/https://rarediseases.info.nih.gov/diseases/1049/cadasil#diseaseTreatmentSection|url-status=dead}}</ref>
In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) on [[MRI]].<ref name="auto"/>
L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL,<ref>{{cite journal|last1=Peters|first1=N|title=Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL|journal=Journal of Neurology|date=August 2008|volume=255|issue=8|pages=1203–1208|doi=10.1007/s00415-008-0876-9|pmid=18537053|s2cid=42107389}}</ref> but as of 2017 there are no clinical studies supporting its use.<ref name="Cambridge" /> [[Donepezil]], normally used for Alzheimer's Disease, was shown not to improve executive functioning in CADASIL patients.<ref>{{cite journal|title=Donepezil Fails to Improve Cognition in Patients with CADASI... : Neurology Today|journal=Neurology Today|volume=8|issue=7|pages=25|doi=10.1097/01.NT.0000316148.27827.bc|date=2008-04-03|last1=Susman|first1=Ed|s2cid=72564626}}</ref>
== Society and culture ==
[[John Ruskin]] has been suggested to have had CADASIL.<ref name="Kempster">{{cite journal |vauthors=Kempster PA, Alty JE |title=John Ruskin's relapsing encephalopathy |journal=Brain |volume=131 |issue=Pt 9 |pages=2520–5 |date=September 2008 |pmid=18287121 |doi=10.1093/brain/awn019 |doi-access= }}</ref> Ruskin reported in his diaries having visual disturbances consistent with the disease, and it has also been suggested that it might have been a factor in causing him to describe [[James Whistler]]'s ''[[Nocturne in Black and Gold – The Falling Rocket]]'' as "ask[ing] two hundred guineas for throwing a pot of paint in the public's face". This resulted in the famous libel trial that resulted in a jury's awarding Whistler one farthing damages.<ref name="Kempster"/>
Recent research into the illness of philosopher [[Friedrich Nietzsche]] has suggested that his mental illness and death may have been caused by CADASIL rather than tertiary syphilis.<ref>{{cite journal |vauthors=Hemelsoet D, Hemelsoet K, Devreese D |title=The neurological illness of Friedrich Nietzsche |journal=Acta Neurol Belg |volume=108 |issue=1 |pages=9–16 |date=March 2008 |pmid=18575181 }}</ref>  Likewise, the early death of the composer [[Felix Mendelssohn]], at age 37, from a stroke has been potentially linked to CADASIL.  His sister, [[Fanny Mendelssohn]], was similarly affected.<ref>{{Cite web|url=https://accounts.google.com/v3/signin/identifier?dsh=S-1525686783%3A1658789663940002&continue=https%3A%2F%2Fwww.blogger.com%2Fblogin.g%3FblogspotURL%3Dhttp%3A%2F%2Fchambermusictoday.blogspot.com%2F2008%2F09%2Fmendelssohns-premature-death.html%26type%3Dblog%26zx%3D17zq5140evif8&hl=en-US&passive=true&service=blogger&flowName=WebLiteSignIn&flowEntry=ServiceLogin&ifkv=AQN2RmX5L8KsTIEzM1Pj-xbyDV30BvMW4IAPJXiUgDWWJGRPaPYIhBhJLk6SFadxRplVl5hCwqSvVA|title=Blogger|website=accounts.google.com}}</ref> And [[James Dewar (musician)|James Dewar]], best known as vocalist for [[Robin Trower]], died age 59 from complications of CADASIL.<ref>{{cite web |title=Jimmy Dewar, singer/bassist for Robin Trower's Rock Sensation |url=https://rockandrollparadise.com/jimmy-dewar-5-2002/ |website=Rock and Roll Paradise |access-date=2 July 2021 |date=23 March 2019}}</ref>
In the movie ''[[The Sea Inside]]'', one of the characters is stated to have CADASIL.<ref>{{cite web |last1=Fisher |first1=Christopher |title=CADASIL, A Vascular Brain Disorder, Is Often Misdiagnosed As Multiple Sclerosis |url=https://www.bmedreport.com/archives/24709 |website=BMED Report |access-date=28 July 2021 |date=14 March 2011}}</ref>
In the [[Netflix]] 2023 limited series ''[[The Fall of the House of Usher (miniseries)|The Fall of the House of Usher]]'', the main character [[Roderick Usher]] suffers from this disorder, and much of the series storyline surrounds his criminal and illicit attempts to find a cure. The limited series is based on the [[Edgar Allan Poe bibliography|life's work]] of [[Edgar Allan Poe]].
== See also ==
* [[Proteopathy]]
* CARASIL ([[cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy]])
== References ==
{{Reflist}}
==Further reading==
{{commons category}}
* {{cite book |vauthors=Lesnik Oberstein SA, Boon EM, Terwindt GM |title=CADASIL |url=https://www.ncbi.nlm.nih.gov/books/NBK1500/ |date=June 28, 2012 |id=NBK1500 |pmid=20301673|publisher=University of Washington, Seattle }} In {{cite book |veditors=Pagon RA, Bird TD, Dolan CR |title=GeneReviews [Internet] |publisher=University of Washington, Seattle |location=Seattle WA |url=https://www.ncbi.nlm.nih.gov/books/n/gene/TOC/ |display-editors=etal|year=1993 |pmid=20301295 |last1=Adam |first1=M. P. |last2=Everman |first2=D. B. |last3=Mirzaa |first3=G. M. |last4=Pagon |first4=R. A. |last5=Wallace |first5=S. E. |author6=Bean LJH |last7=Gripp |first7=K. W. |last8=Amemiya |first8=A. }}
== External links ==
* [https://www.nytimes.com/2019/05/01/magazine/symptoms-multiple-sclerosis-diagnosis.html A patient story] at ''The New York Times''
{{Medical resources
|   DiseasesDB     = 2161
|   ICD10          = {{ICD10|I|67|850|i|10}}
|   ICD9           =
|   ICDO           =
|   OMIM           = 125310
|   Orphanet       = 136
|   MedlinePlus    =
|   eMedicineSubj  =
|   eMedicineTopic =
|   MeshID         = D046589
|   GeneReviewsNBK  = NBK1500
|   GeneReviewsName = CADASIL
}}
{{Cerebrovascular diseases}}
{{Signal transduction disorder}}
{{DEFAULTSORT:Cadasil Syndrome}}
[[Category:Deficiencies of intracellular signaling peptides and proteins]]
[[Category:Cerebrovascular diseases]]
[[Category:Skin conditions resulting from errors in metabolism]]
[[Category:Syndromes]]