| CADASIL | |
|---|---|
| Other names | CADASIL syndrome |
 | |
| BrainMRI from patients with CADASIL showing multiple lesions. | |
| Specialty | Neurology,cardiology,medical genetics  |
| Symptoms | Migraine headaches |
CADASIL orCADASIL syndrome, involvingcerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditarystroke disorder and is thought to be caused bymutations of theNOTCH3 gene onchromosome 19.[1] The disease belongs to a family of disorders called theleukodystrophies. The most common clinical manifestations aremigraine headaches andtransient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, althoughMRI 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 researchersMarie-Germaine Bousser andElisabeth Tournier-Lasserve in the 1990s.[4][5] Together with two other researchers,Hugues Chabriat andAnne Joutel, they received the 2019Brain Prize for their research into the condition.[6]
CADASIL may start with attacks ofmigraine withaura or subcortical transient ischemic attacks or strokes, or mood disorders between 35 and 55 years of age. The disease progresses tosubcortical dementia associated withpseudobulbar palsy andurinary incontinence.[citation needed]
Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developingtransient ischemic attacks or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30–70). A classiclacunar 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.[7]
The underlying pathology of CADASIL is progressive hypertrophy of thesmooth muscle cells inblood vessels.Autosomal dominant mutations in theNOTCH3 gene (on the long arm of chromosome 19) cause an abnormal accumulation of Notch 3 protein at thecytoplasmic membrane of vascular smooth muscle cells both incerebral and extracerebral vessels,[8] seen as granularosmiophilic deposits onelectron microscopy.[9]Leukoencephalopathy follows. Depending on the nature and position of each mutation, a consensus significant loss ofbeta sheet structure of the Notch3 protein has been predicted usingin silico analysis.[10]
MRIs show hypointensities onT1-weighted images andhyperintensities onT2-weighted images, usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around thebasal ganglia, peri-ventricularwhite matter and thepons and are similar to those seen inBinswanger disease.[2][11] These white matter lesions are also seen in asymptomatic individuals with the mutated gene.[12] 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]
The definitive test is sequencing the wholeNOTCH3 gene, which can be done from a sample of blood. However, as this is quite expensive and CADASIL is a systemicarterial disease, evidence of the mutation can be found in small and medium-size arteries. Therefore, skin biopsies are often used for the diagnosis.[13][14]
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.[15] Antiplatelet agents such asaspirin,dipyridamole, orclopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages.[16] Control of high blood pressure is particularly important in CADASIL patients.[15] Short-term use of atorvastatin, astatin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters,[17] although treatment of comorbidities such as high cholesterol is recommended.[18] Stopping oral contraceptive pills may be recommended.[19] Some authors advise against the use oftriptan medications for migraine treatment, given their vasoconstrictive effects,[20] although this sentiment is not universal.[18] 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.[21]
In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) onMRI.[16]
L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL,[22] but as of 2017 there are no clinical studies supporting its use.[19]Donepezil, normally used for Alzheimer's Disease, was shown not to improve executive functioning in CADASIL patients.[23]
John Ruskin has been suggested to have had CADASIL.[24] 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 describeJames Whistler'sNocturne 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.[24]
Recent research into the illness of philosopherFriedrich Nietzsche has suggested that his mental illness and death may have been caused by CADASIL rather than tertiary syphilis.[25] Likewise, the early death of the composerFelix Mendelssohn, at age 37, from a stroke has been potentially linked to CADASIL. His sister,Fanny Mendelssohn, was similarly affected.[26] AndJames Dewar, best known as vocalist forRobin Trower, died age 59 from complications of CADASIL.[27]
In the movieThe Sea Inside, one of the characters is stated to have CADASIL.[28]
In theNetflix 2023 limited seriesThe Fall of the House of Usher, the main characterRoderick 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 thelife's work ofEdgar Allan Poe.
