Yield of Screening for CADASIL Mutations in Lacunar Stroke and Leukoaraiosis
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Background and Purpose— Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in the Notch3 gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening for Notch3 mutations in lacunar stroke with or without leukoaraiosis. Methods— Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of the Notch3 gene for mutations and polymorphisms. Results— A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at ≤65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9). Conclusions— Notch3 mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening for Notch3 mutations has a low yield.Keywords:
CADASIL
Leukoaraiosis
Lacunar stroke
Stroke
CADASIL
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CADASIL
Vascular dementia
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Background and Purpose— Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in the Notch3 gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening for Notch3 mutations in lacunar stroke with or without leukoaraiosis. Methods— Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of the Notch3 gene for mutations and polymorphisms. Results— A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at ≤65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9). Conclusions— Notch3 mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening for Notch3 mutations has a low yield.
CADASIL
Leukoaraiosis
Lacunar stroke
Stroke
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Background and purpose: small vessel disease (SVD) is a major cause of vascular dementia. CADASIL is a monogenic variant of SVD caused by mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits. The current study determines the characteristics of cognitive abnormalities seen in CADASIL.
CADASIL
Vascular dementia
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Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease in adults. Many CADASIL cases were reported after NOTCH3 was identified as the causative gene of CADASIL. However, there is still no specific and effective therapies for CADASIL. In this review, we summarize recent research progress on disease models, symptomatic treatments and potential therapies for CADASIL, thereby providing a reference for follow-up CADASIL treatment research.伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy，CADASIL)是成人最常见的遗传性脑小血管病。自CADASIL的致病基因NOTCH3被鉴定以来，大量CADASIL病例被报道，但迄今仍缺乏有效的治疗药物。本文针对CADASIL的疾病模型和致病机制、对症药物治疗及潜在治疗方案研究进展进行综述，以期为后续CADASIL发病机制和治疗研究提供参考。.
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Pathogenesis
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small vessel diseases caused by a mutation in the NOTCH3 gene. The clinical manifestations of CADASIL range from single or multiple lacunar infarcts, transient ischemic attacks, dementia, migraine with aura to psychiatric disorders. The features of brain MRI of CADASIL include multiple lacunar infarcts and diffuse leukoencephalopathy, which frequently involves external capsules and anterior temporal regions. Almost all patients with CADASIL harbor cysteine-involving mutations in NOTCH3. In Taiwan, two thirds of CADASIL patients carry NOTCH3 p.R544C mutations, and only approximately 56% of patients with CADASIL have leukoencephalopathy with anterior temporal regions involvement.
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Vascular dementia
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Brain infarction due to cerebral small vessel disease (SVD) accounts for up to 25% of all ischemic strokes. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) are among the monogenic hereditary cerebral SVDs. Herein, we reported a case of sporadic CADASIL-like disease and provided information about CADASIL and CARASIL, two of the most common of inheredited SVDs that are usually overlooked
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Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small-vessel disease, but doctor’s knowledge in this sphere is still insufficient. We aimed to introduce the recommendations of the European Academy of Neurology to Russian clinicians because it can help them to discover CADASIL in time and to manage patients with this form of monogenic cerebral small-vessel disease. We present the own case report.
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BACKGROUND AND PURPOSE: Small vessel cerebrovascular disease is an important cause of vascular cognitive impairment. It is usually sporadic but also occurs secondary to the genetic disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recurrent lacunar stroke is a characteristic feature, although symptomatic events are relatively rare, making large numbers necessary for evaluation of potential therapies. Diffusion-weighted imaging is sensitive to acute ischemic lesions and differentiates them from chronic infarcts. Detection of asymptomatic lacunar infarcts with diffusion-weighted imaging is a potential surrogate marker for treatment trials. In this study, the frequency of asymptomatic new lesions in ischemic leukoaraiosis and CADASIL was determined as a step toward assessing the potential of this technique as a surrogate marker of disease activity. METHODS: Fifty patients with sporadic small vessel disease and 19 patients with CADASIL underwent diffusion-weighted imaging. All had been asymptomatic for 3 months before imaging. Diffusion-weighted images were screened by two raters for new lesions; lesions were confirmed as recent by a visible reduction of diffusivity on the corresponding apparent diffusion coefficient maps. RESULTS: Recent ischemic lesions were identified in four patients with sporadic small vessel disease (8.0%) and two patients with CADASIL (10.5%). CONCLUSION: Asymptomatic new lesions are found in cases of sporadic small vessel disease and CADASIL. The frequency of new lesions suggests that this approach has a potential role as a surrogate marker in therapeutic trials that warrants further investigation.
CADASIL
Leukoaraiosis
Surrogate endpoint
Subclinical infection
Lacunar stroke
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