Clinical features and mutation spectrum in Chinese patients with <scp>CADASIL</scp>: A multicenter retrospective study

Chen, Sheng; Wang, Ni; Yin, Xinzhen; Liu, Hanqiu; Cong, Lu; Zheng, Quan; Zhao, Guodong; Xu, Yongfeng; Wu, Lei; Zhang, Liang; Wang, Ning; Li, Hongfu; Wu, Zhi‐Ying

doi:10.1111/cns.12719

Cited by 49 publications

(68 citation statements)

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“…In other cohorts that studied populations of similar ages, the suspicion based on the clinical‐radiological characterization was similar, with higher frequency of adult‐onset vanishing white matter disease, and other pathologies such as leukodystrophy with ovarian failure related to the mutation in the AARS2 gene, which we did not have in our series (Lynch et al., ). The sequence of the NOTCH3 gene confirmed the diagnosis in only four of the patients studied with suspected CADASIL, unlike other reports where the diagnostic yield was higher (Chen et al., ). In our particular case, we recognize the laxity in the selection criteria, as we studied those patients who met at least one clinical and one radiological criterion described by Davous () without being strict in the sum of 15 or more points on the diagnostic probability scale of CADASIL proposed by Pescini, Nannucci, & Pantoni (), there is a better performance in the molecular study of the NOTCH3 gene.…”

Section: Discussioncontrasting

confidence: 78%

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years

Cohen

Manín

Medina

et al. 2019

Annals of Human Genetics

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Introduction and objectives: Leukodystrophies and genetic leukoencephalopathiesconstitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. Materials and methods:A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones.Results: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. /journal/ahg 11 12 COHEN ET AL. Conclusions:Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase. K E Y W O R D Sdiagnostic procedure, genetic leukoencephalopathies, leukodystrophies, next-generation sequencing

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Section: Discussioncontrasting

confidence: 78%

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years

Cohen

Manín

Medina

et al. 2019

Annals of Human Genetics

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“…The confluent white matter hyperintensities as well as multiple lacunar infarcts shown on brain MRI scanning of our patients were in accordance with typical neuroimaging features of CADASIL. None of the patients in present study reported a history of migraine with or without aura, which is consistent with a relatively low frequency of migraine in patients of CADASIL from Asian countries [16,17]. The diagnosis of CADASIL was genetically confirmed by the detection of a homozygous mutation in exon 11 of NOTCH3 gene, which was predicted to cause a substitution of arginine with cysteine (p.R587C) in the encoded receptor.…”

Section: Discussionsupporting

confidence: 85%

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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“…Patients who exhibit agnogenic white matter abnormality, unexplained spastic paraparesis, or early‐onset dementia were suggestive of leukodystrophies . Firstly we screened causative genes for CADASIL, adrenoleukodystrophy, hereditary spastic paraplegia (HSP), and familial Alzheimer's disease (FAD) on these patients in our previous studies, and patients who carry pathogenic variants were excluded. Then, 28 unrelated patients (probands) were recruited consecutively between March 2015 and August 2018 from the Department of Neurology in Second Affiliated Hospital of Zhejiang University School of Medicine.…”

Section: Methodsmentioning

confidence: 99%

New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies

et al. 2019

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Aim Leukodystrophies are a group of inherited white matter disorders with clinical, genetic, and imaging heterogeneity, which usually pose a diagnostic challenge for physicians. We aimed to identify new clinical characteristics and novel pathogenic variants of hereditary leukodystrophies in this study. Methods Whole exome sequencing (WES) was performed in 28 unrelated patients clinically suspected with leukodystrophies. Leukocytes enzyme activity test, electroencephalogram (EEG), electromyography (EMG), and brain MRI were conducted. Functional analysis was performed, and the pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Results We made definite diagnosis in 8 probands with 12 pathogenic variants and reported new clinical characteristics and imaging features of these patients. Three novel pathogenic variants were identified, including a microdeletion variant c.2654_2654+3del within CSF1R, a nonsense variant c.1321C>T, and a missense variant c.166G>C within GALC. Conclusion Our results have deepened the understanding of clinical, genetic, and imaging heterogeneity of hereditary leukodystrophies, and expanded the spectrum of pathogenic variants and clinical features.

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Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study

Abstract: These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients.

Cited by 49 publications

References 34 publications

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years

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

New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies

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