| 词条 | CADASIL |
| 释义 |
| name = CADASIL | image = CADASIL.jpg | caption = Brain MRI from patients with CADASIL showing multiple lesions. | synonyms = CADASIL syndrome | symptoms = | complications = | onset = | duration = | types = | cause s = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }}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 mutations of the Notch 3 gene on chromosome 19.[1] The disease belongs to a family of disorders called the leukodystrophies. The most common clinical manifestations are migraine headaches and transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease.[2][3] The condition was identified and named by French researchers Marie-Germaine Bousser and Elisabeth Tournier-Lasserve, in the 1990s.[4][5] Signs and symptomsCADASIL may start with attacks of migraine with 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. Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developing transient ischemic attacks 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.[6]PathophysiologyThe underlying pathology of CADASIL is progressive hypertrophy of the smooth muscle cells in blood vessels. Autosomal dominant mutations in the Notch 3 gene (on the long arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth muscle cells both in cerebral and extracerebral vessels,[7] seen as granular osmiophilic deposits on electron microscopy.[8] Leukoencephalopathy follows. Depending on the nature and position of each mutation, a consensus significant loss of betasheet structure of the Notch3 protein has been predicted using in silico analysis.[9] DiagnosisMRIs show hypointensities on T1-weighted images and hyperintensities on T2-weighted images, usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the basal ganglia, peri-ventricular white matter, and the pons, and are similar to those seen in Binswanger disease.[2][10] These white matter lesions are also seen in asymptomatic individuals with the mutated gene.[11] While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms. The definitive test is sequencing the whole Notch 3 gene, which can be done from a sample of blood. However, as this is quite expensive and CADASIL is a systemic arteriopathy, evidence of the mutation can be found in small and medium-size arteries. Therefore, skin biopsies are often used for the diagnosis.[12][13] TreatmentNo 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 is limited.[14] Antiplatelet agents such as aspirin, dipyridamole, or clopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages.[15] Control of high blood pressure is particularly important in CADASIL patients.[14] Short-term use of atorvastatin, a statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters,[16] although treatment of comorbidities such as high cholesterol is recommended.[17] Stopping oral contraceptive pills may be recommended.[18] Some authors advise against the use of triptan medications for migraine treatment, given their vasoconstrictive effects,[19] although this sentiment is not universal.[17] As with other individuals, people with CADASIL should be encouraged to quit smoking.[20] In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) on MRI.[15] L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL,[21] but as of 2017 there are no clinical studies supporting its use.[18] Donepezil, normally used for Alzheimer's Disease, was not shown not to improve executive functioning in CADASIL patients.[22] Though there are few clinical trials currently (2018) ongoing, there are natural history studies that patients can join. Studies can be found at www.clinicaltrials.gov. The [https://clinicaltrials.gov/ct2/show/NCT02821780 CADASIL Disease Discovery Study (NCT02821780)] was the first prospective study in the US, sponsored by the National Institute of Health National Heart, Lung, and Blood Institute (NHLBI) starting in 2016 and led by principal investigator Manfred Boehm. In popular cultureJohn Ruskin has been suggested to have suffered from CADASIL.[23] 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.[23]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.[24] 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.[25] The character Julia, in the 2004 Spanish film The Sea Inside, has the condition. Rock bassist and vocalist James Dewar was posthumously identified as having died of the condition.[26] See also
References1. ^{{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}} 2. ^1 {{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 }} 3. ^{{cite book |author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |year=2006 |page=545 |isbn=0-7216-2921-0 |display-authors=etal}} 4. ^{{cite web|url=https://www.cadasilfoundation.org/bousser.html |title=History of CADASIL}} 5. ^{{cite journal|pmid=9026542|title=[CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)] - Abstract}} 6. ^{{cite journal | doi = 10.1016/j.genhosppsych.2015.02.006 | title=CADASIL presenting as schizophreniform organic psychosis | journal=General Hospital Psychiatry}} 7. ^{{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}} 8. ^{{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}} 9. ^{{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}} 10. ^{{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}} 11. ^{{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 |display-authors=etal}} 12. ^{{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 |display-authors=etal}} 13. ^{{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 }} 14. ^1 {{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|url=http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2010000200026}} 15. ^1 {{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|first = S. A.|last = 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}} 16. ^{{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|url=https://www.sciencedirect.com/science/article/pii/S0022510X07002833|accessdate=1 April 2017}} 17. ^1 {{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK1500/|title=GeneReviews(®)|first1=Julie|last1=Rutten|first2=Saskia AJ|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 JH|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 JH|editor-last10=Smith|editor-first11=Karen|editor-last11=Stephens|date=1 January 1993|publisher=University of Washington, Seattle|via=PubMed|pmid=20301673|chapter=Cadasil}} 18. ^1 {{cite web|url=http://www.cambridgestroke.com/faqs.php|title=Questions about cadasil|publisher=}} 19. ^{{cite web|url=https://rarediseases.org/rare-diseases/cadasil/|title=CADASIL - NORD (National Organization for Rare Disorders)|publisher=}} 20. ^{{cite web|url=https://rarediseases.info.nih.gov/diseases/1049/cadasil#diseaseTreatmentSection|title=CADASIL - Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|publisher=}} 21. ^{{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}} 22. ^{{cite journal|url=http://journals.lww.com/neurotodayonline/Citation/2008/04030/Donepezil_Fails_to_Improve_Cognition_in_Patients.14.aspx|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}} 23. ^1 {{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 |url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18287121}} 24. ^{{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 }} 25. ^{{cite web|url=http://chambermusictoday.blogspot.com/2008/09/mendelssohns-premature-death.html|title=Blogger|publisher=}} 26. ^{{Cite news|url=http://www.jimmydewar.com/home/2014/5/15/the-mystery-comes-to-an-end.html|title=The mystery comes to an end.|work=Jimmy Dewar|access-date=2017-06-15|language=en-US}} Further reading{{commons category}}
External links{{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}} 4 : Deficiencies of intracellular signaling peptides and proteins|Cerebrovascular diseases|Skin conditions resulting from errors in metabolism|Syndromes |
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