NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL

Wang, Zhaoxia; Yuan, Yun; Zhang, Wei; Lv, He; Hong, Daojun; Chen, Bin; Liu, Yang; Luan, Xinghua; Xie, Shusen; Wu, Shiwen

doi:10.1136/jnnp.2010.209247

Cited by 69 publications

(72 citation statements)

References 27 publications

(29 reference statements)

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“…Despite complete penetrance of the gene mutations, clinical presentation of the disorder can be highly variable even between siblings with the same mutation [1]. The variability seems to be by and large independent of the type of mutation [22,23,24,25,26,27]. This variability in genetic, clinic and radiological features were also reported in a few studies from Turkey [28,29,30].…”

Section: Discussionmentioning

confidence: 85%

Clinical and Radiological Features in CADASIL and NOTCH3-Negative Patients: A Multicenter Study from Turkey

İnce

Benbir²,

Síva³

et al. 2014

Eur Neurol

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Background: The diversity of clinical presentation and neuroimaging findings of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) from different regions of the world has not yet been studied in depth. Here we investigated the variability of clinical, radiological and genetic data of 48 patients analyzed for NOTCH3 mutation in Turkey. Methods: Clinical evaluation was made according to a preformed questionnaire. Cranial neuroimaging findings were determined on the basis of T1, T2, FLAIR and proton-density magnetic resonance scans. For genetic analysis, polymerase chain reaction was performed with primers flanking exons 2-6 and 11 of NOTCH3 gene. Results: Twenty-five patients (52.1%) were diagnosed as CADASIL with NOTCH3 mutation, while 23 patients (47.9%) had no mutation (NOTCH3-negative patients). The mean age and age at stroke onset were lower in male CADASIL patients (p < 0.03). A family history of migraine (p = 0.012), stroke (p < 0.001), recurrent strokes (p = 0.020) and dementia (p = 0.012) was more common in CADASIL patients. Temporal pole involvement was more common in CADASIL patients (p = 0.004). Conclusion: It is of clinical importance to identify the heterogeneity of CADASIL from different countries due to a low correlation of clinical and radiological data with respect to NOTCH3 mutation.

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Section: Discussionmentioning

confidence: 85%

Clinical and Radiological Features in CADASIL and NOTCH3-Negative Patients: A Multicenter Study from Turkey

İnce

Benbir²,

Síva³

et al. 2014

Eur Neurol

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“…Table 2 summarizes the detailed results of genetic analysis. [16][17][18][19][20][21][22][23] Clinical and demographic characteristics were compared between individuals positive and negative on genetic testing ( Table 3). The only significant difference was a family history of stroke (92% versus 47%; P=0.002).…”

Section: Resultsmentioning

confidence: 99%

Clinical Pregenetic Screening for Stroke Monogenic Diseases

Bersano

Markus

Quaglini

et al. 2016

Stroke

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Background and Purpose— Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease Methods— We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. Results— In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. Conclusions— In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.

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“…On one hand, R75P and ∆88-91 showed significantly enhanced aggregation behavior within the range of cysteine mutations. R75P was described in multiple Asian families 11,16,17 and can be considered the best characterized cysteine-sparing NOTCH3 mutation to date. ∆88-91, although identified so far only in a single Italian family, can be considered as sufficiently documented based on the available genetic, clinical, and histological data.…”

Section: March 2015mentioning

confidence: 99%

Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro

Wollenweber

Hanecker

Bayer-Karpinska

et al. 2015

Stroke

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Background and Purpose-Mutations in NOTCH3 cause cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic cause of stroke and vascular dementia. Misfolding and aggregation of NOTCH3 proteins triggered by cysteine-affecting mutations are considered to be the key disease mechanisms. However, the significance of cysteine-sparing mutations is still debated. Methods-We studied a family with inherited small vessel disease by standardized medical history, clinical examination, MRI, ultrastructural analysis of skin biopsies, and Sanger sequencing of all NOTCH3 exons. In addition, we performed in vitro characterization of NOTCH3 variants using recombinant protein fragments and a single-particle aggregation assay. Results-We identified a novel cysteine-sparing NOTCH3 mutation (D80G) in 4 family members, which was absent in a healthy sibling. All mutation carriers exhibited a CADASIL typical brain imaging and clinical phenotype, whereas skin biopsy showed inconsistent results. In vitro aggregation behavior of the D80G mutant was similar compared with cysteine-affecting mutations. This was reproduced with cysteine-sparing mutations from previously reported families having a phenotype consistent with CADASIL. Conclusions-Our

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NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL

Cited by 69 publications

References 27 publications

Clinical and Radiological Features in CADASIL and <b><i>NOTCH3</i></b>-Negative Patients: A Multicenter Study from Turkey

Clinical and Radiological Features in CADASIL and <b><i>NOTCH3</i></b>-Negative Patients: A Multicenter Study from Turkey

Clinical Pregenetic Screening for Stroke Monogenic Diseases

Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro

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