The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China

He, Dan; Chen, Daiqi; Li, Xuefei; Hu, Zheng; Yu, Zhiyuan; Wang, Wei; Luo, Xiang

doi:10.1186/s10194-016-0646-5

Cited by 14 publications

(16 citation statements)

References 31 publications

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“…There have been some previous attempts of identifying specific clinical and neuroradiological features distinguishing NOTCH3 positive from negative patients. These studies, showed that several MRI characteristics, such as temporal lobe lesions, external capsule lacunes, severe WMHs as well as the family history, were more frequent in positive patients [9,[18][19][20][21][22]. Some specific algorithms supporting the identification of clinically suspected CADASIL have been proposed so far but the reliability is still debated since in most cases they were elaborated from heterogeneous and retrospectively collected populations [12][13][14][15][16][17][18][19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

The role of clinical and neuroimaging features in the diagnosis of CADASIL

Bersano¹,

Bedini²,

Markus³

et al. 2018

J Neurol

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Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. Methods: Patients with lacunar stroke or TIA, were included in the present study. For each patient demographic and clinical data were collected.MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. Results: 128 patients (mean age 56.3±12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of all these factors together with familial history for stroke result in a higher positive predictive value and specificity. Conclusions: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

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Section: Discussionmentioning

confidence: 99%

The role of clinical and neuroimaging features in the diagnosis of CADASIL

Bersano¹,

Bedini²,

Markus³

et al. 2018

J Neurol

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“…To our knowledge, the homozygous NOTCH3 c.1759C > T (p.R587C) mutation has not been reported before, though the heterozygous cases were discussed in previous studies [15,18,19]. Whether homozygous NOTCH3 mutations are associated with much more severe phenotypes in patients with CADASIL remains to be controversial.…”

Section: Discussionmentioning

confidence: 92%

Homozygous NOTCH3 p.R587C mutation in Chinese patients with CADASIL: a case report

Sun

et al. 2020

BMC Neurol

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Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations. Case presentation: We recruited two affected individuals with CADASIL from a mainland Chinese family. The proband (Patient 1), a 60-year-old male, presented with slow progressive gait instability, severe cognitive impairment, and emotional disorder for more than 2 years with a history of ischemic stroke and hypertension. His younger brother (Patient 2) presented with apparent gait difficulties, dysarthria as well as cognitive decline at 59 years old. Brain magnetic resonance imaging (MRI) showed diffused white matter lesions involving bilateral periventricular white matter, semioval center region, and anterior temporal lobes. Molecular genetic testing identified a homozygous variant, c.1759C > T (p.R587C), in NOTCH3 gene in both patients. Pathological analysis revealed granular osmiophilic material (GOM) deposits in small arterial walls of skin from the proband. The diagnosis of CADASIL was confirmed. Conclusions: Our cases of CADASIL with homozygous mutation c.1759C > T (p.R587C) in NOTCH3 share similar manifestation to the patients with heterozygous same mutation reported previously. Other than genetic factors, vascular risk factors or environmental factors might contribute to the phenotypic variation of CADASIL.

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“…In addition, previous work by Markus et al tested the sensitivity of single strand conformation polymorphism (SSCP) analysis for detecting NOTCH3 mutations, with an effective success rate of 80 to 85 % [14]. More recently, He et al reported that varying and population-dependant results in the effectiveness of using the pre-genetic “CADASIL scale” screening tool which evaluates clinical presentations and neuroimaging data in an effort to minimise NOTCH3 gene testing [15, 16]. As such, current diagnosis relies on the screening of all exons by sequencing to identify mutations in NOTCH3 .…”

Section: Discussionmentioning

confidence: 99%

“…However, in this study, patient C-3 was found to carry non-cysteine NOTCH3 gene variants (p.S496L and p.A1020P). As yet, a comparison of the effect of these two non-cysteine variants on the pathogenic mechanisms of CADASIL or CADASIL-like phenotype [16] to a single non-cysteine variant on disease pathogenesis has not been functionally tested.…”

Section: Discussionmentioning

confidence: 99%

Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients

et al. 2016

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BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic, hereditary, small vessel disease of the brain causing stroke and vascular dementia in adults. CADASIL has previously been shown to be caused by varying mutations in the NOTCH3 gene. The disorder is often misdiagnosed due to its significant clinical heterogeneic manifestation with familial hemiplegic migraine and several ataxia disorders as well as the location of the currently identified causative mutations. The aim of this study was to develop a new, comprehensive and efficient single assay strategy for complete molecular diagnosis of NOTCH3 mutations through the use of a custom next-generation sequencing (NGS) panel for improved routine clinical molecular diagnostic testing.ResultsOur custom NGS panel identified nine genetic variants in NOTCH3 (p.D139V, p.C183R, p.R332C, p.Y465C, p.C597W, p.R607H, p.E813E, p.C977G and p.Y1106C). Six mutations were stereotypical CADASIL mutations leading to an odd number of cysteine residues in one of the 34 NOTCH3 gene epidermal growth factor (EGF)-like repeats, including three new typical cysteine mutations identified in exon 11 (p.C597W; c.1791C>G); exon 18 (p.C977G; c.2929T>G) and exon 20 (p.Y1106C; c.3317A>G). Interestingly, a novel missense mutation in the CACNA1A gene was also identified in one CADASIL patient. All variants identified (novel and known) were further investigated using in silico bioinformatic analyses and confirmed through Sanger sequencing.ConclusionsNGS provides an improved and effective methodology for the diagnosis of CADASIL. The NGS approach reduced time and cost for comprehensive genetic diagnosis, placing genetic diagnostic testing within reach of more patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0093-z) contains supplementary material, which is available to authorized users.

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The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China

Cited by 14 publications

References 31 publications

The role of clinical and neuroimaging features in the diagnosis of CADASIL

The role of clinical and neuroimaging features in the diagnosis of CADASIL

Homozygous NOTCH3 p.R587C mutation in Chinese patients with CADASIL: a case report

Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients

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