CADASIL

皮質下梗塞および白質脳症を伴う常染色体優性脳動脈症、カダシル、cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/08/02 15:49:10」(JST)

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CADASIL
Synonyms	CADASIL syndrome
Brain MRI from patients with CADASIL showing multiple lesions.
Classification and external resources
OMIM	125310
DiseasesDB	2161
Patient UK	CADASIL
MeSH	D046589
GeneReviews	CADASIL
Orphanet	136

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. 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.

Signs and symptoms

CADASIL 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.

Pathophysiology

The underlying pathology of CADASIL is progressive degeneration of the smooth muscle cells in blood vessels. autosomal dominant mutations in the Notch 3 gene (on the short 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, seen as granular osmiophilic deposits on electron microscopy. Leukoencephalopathy follows.

Diagnosis

A micrograph showing punctate immunostaining (brown) with a Notch 3 antibody, as is characteristic in CADASIL.

MRIs 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. These white matter lesions are also seen in asymptomatic individuals with the mutated gene. 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.

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 is limited. Antiplatelet agents such as aspirin, dipyridamole, or clopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages. Control of high blood pressure is particularly important in CADASIL patients. Short-term use of atorvastatin, a statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters, although treatment of comorbidities such as high cholesterol is recommended. Stopping oral contraceptive pills may be recommended. Some authors advise against the use of triptan medications for migraine treatment, their vasoconstrictive effects, although this sentiment is not universal. As with other individuals, people with CADASIL should be encouraged to quit smoking.

Administering tPA following onset of stroke is not advised for CADASIL patients, due to increased risk of microhemorrhages.

L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL, but as of 2017 there is no clinical data to support its use. Aricept, normally used for Alzheimer's Disease, was not shown not to improve executive functioning in CADASIL patients.

In popular culture

John Ruskin has been suggested to have suffered from CADASIL. 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.

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. 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.

The character Julia, in the 2004 Spanish film The Sea Inside, has the condition.

See also

• Proteopathy
• CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy)

External links

• CADASIL Family Registry
• Datagenno - CADASIL Syndrome
• cureCADASIL Association
• CADASIL Support Website - St George's Hospital, London
• The CADASIL Foundation
• United Leukodystrophy Foundation: CADASIL
• Lesnik Oberstein SA, Boon EM, Terwindt GM (June 28, 2012). CADASIL. PMID 20301673. NBK1500.  In Pagon RA, Bird TD, Dolan CR, et al., eds. (1993–). GeneReviews™ [Internet]. Seattle WA: University of Washington, Seattle. 

UpToDate Contents

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• 1. 皮質下梗塞および白質脳症を伴う常染色体優性脳動脈症（CADASIL） cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy cadasil
• 2. 片麻痺性片頭痛 hemiplegic migraine
• 3. 脳血管性認知症の病因、臨床症状、および診断 etiology clinical manifestations and diagnosis of vascular dementia
• 4. 小児および若年成人における虚血性脳卒中：病因と臨床的特徴 ischemic stroke in children and young adults etiology and clinical features
• 5. Primary angiitis of the central nervous system in adults

English Journal

• Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

• Testi S, Malerba G, Ferrarini M, Ragno M, Pradotto L, Mauro A, Fabrizi GM.SourceDepartment of Neurological, Neuropsychological, Morphological and Movement Sciences; Section of Neuropathology, University of Verona, Italy.
• Journal of the neurological sciences.J Neurol Sci.2012 Aug 15;319(1-2):37-41. Epub 2012 Jun 3.
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11
• PMID 22664156

• Endocytosis and control of Notch signaling.

• Kandachar V, Roegiers F.SourceProgram in Cancer Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, United States.
• Current opinion in cell biology.Curr Opin Cell Biol.2012 Jul 18. [Epub ahead of print]
• The Notch signaling pathway controls patterning and cell fate decisions during development in metazoans, and is associated with human diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and certain cancers. Studies over the last sever
• PMID 22818956

Japanese Journal

• 皮膚生検で早期に診断しえた側頭極病変に乏しいCADASILの1例

• 今野 卓哉,梅田 麻衣子,梅田 能生 [他]
• 臨床神経学 51(10), 770-773, 2011-10
• NAID 40019031126

• 非動脈硬化性脳網膜小血管病の1例

• 荒川 奈央子,柏井 聡,鷲田 和夫,金田 大太,正井 宏和,廣井 佳野,田口 朗,藤原 一哉
• 日本眼科學会雜誌 115(4), 391-397, 2011-04-10
• NAID 10029367759

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「カダシル」

　　[★] 皮質下梗塞および白質脳症を伴う常染色体優性脳動脈症、CADASIL、cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

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cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy、CADASIL

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「cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy」

　　[★] 皮質下梗塞および白質脳症を伴う常染色体優性脳動脈症、カダシル、CADASIL