Exploration and challenge of CADASIL genetics research / 中华神经科杂志

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common single gene hereditary cerebral small vessel disease in adults. With the development of gene sequencing technology and imaging, the disease is more and more recognized by people. In this paper, according to the research progress in recent years, the mutation types of NOTCH3 gene in CADASIL patients, the hot spot regions and sites of mutation in different populations, and the relationship between genotype and phenotype were summarized from the perspective of genetics. The future gene therapy of the disease was prospected.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy / 中华神经科杂志

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3 gene mutation. The main manifestations of the disease are migraine,cerebral ischemic stroke, progressive cognitive impairment, psychological abnormality which developed at different stage of disease. Multiple cerebral lacunar infarctions, white matter T 2 hyperintensities and cerebral microbleeds can be seen on brain magnetic resonance imaging. The definite diagnosis evidence of CADASIL is the presence of granularosmiophilic material on the surface of arteriolar smooth muscle cells and (or) the identification of pathogenic variants of NOTCH3 gene. With the wide application of second-generation sequencing, more and more patients with CADASIL have been diagnosed. This article will give a summary on the pathogenesis mechanism, clinical manifestations, diagnostic workup, and management of CADASIL.

Relationship between clinical phenotype and NOTCH3 genotype in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy / 第二军医大学学报

Objective To explore the relationship between exon mutations of NOTCH3 gene and clinical phenotype in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods We consecutively included 30 CADASIL patients with clinical symptoms in 15 pedigrees, who visited Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine from May 2015 to Dec. 2017, and collected the clinical data and genetic analysis results. Furthermore, we analyzed the relationship between the exon mutations of NOTCH3 gene and clinical phenotypes, including age at onset, first clinical symptoms and frequency of symptomatic ischemic stroke. Results Twelve mutation sites of NOTCH3 gene were detected in the 15 pedigrees. Seven of them were located in exon 4, 3 in exon 11, 1 in exon 19, and 1 in exon 20. The onset age of the patients carrying exon 11 mutations was the latest ([53.6±13.3] years, n＝7), followed by the patients carrying exon 4 mutations ([42.7±5.7] years, n＝15). The onset age of 8 patients with mutations in other exons (exon 19 and 20) was (33.5±7.5) years, which was significantly earlier compared with the patients with exon 4 and 11 mutation (P0.01 and P0.05). Most of the patients with mutations of exon 4 had motor and speech disorders (11/15, 73.3%), while ones with mutations of exon 19 and 20 had cognitive impairment (7/8, 87.5%). Most of the patients (11/15, 73.3%) carrying mutations in exon 4 had motor and speech disorders at onset, while 7 of 8 patients (87.5%) with mutations in exon 19 and exon 20 had impaired cognition at onset. The times of symptomatic ischemic stroke in patients with mutations in exon 4 was 3 (median) and in patients with mutations in exon 11 was 2 (median), and no symptomatic ischemic stroke occurred in the patients with mutations in exon 19 and 20. Conclusion Exon 4 and exon 11 of NOTCH3 gene are hotspots of mutations in the cohort of CADASIL cases, and the mutations in different exons are associated with onset age, first symptoms and symptomatic ischemic stroke.

The correlation between NOTCH3 gene polymorphism and white matter lesions / 中华急诊医学杂志

Objective To investigate the correlation between NOTCH3 polymorphic locus rs1043994 and white matter lesions (WML). Methods The enrolled subjects were elderly in the outpatient clinic for health check-up from January 2015 to January 2017. According to the results of cranial MR examination, 337 elderly people were divided into the WML group (n=172) and normal control group (n=165). The inclusion criteria were: (1) age ≥ 50 years old; (2) those who can cooperate with head MRI examination; (3) those who understand the study and agree to retain blood samples for SNP testing. Exclusion criteria were: (1) previous neurological diseases such as cerebrovascular disease, intracranial infection, dementia, and trauma; (2) having a history of mental illness; (3) suffering from serious diseases such as liver and kidney dysfunction, heart disease, tumors. The clinical data of the subjects were collected and the peripheral venous blood was extracted for DNA extraction. The cognitive function was evaluated by the Mini-mental State Examination. The genotyping of the subjects was carried out by restriction endonuclease. The correlation between rs1043994 polymorphism and WML was analyzed by Logistic regression. Results There was no significant difference in gender, education level, diabetes, hyperlipidemia, smoking, uric acid and Hcy between the two groups (P>0.05). Compared with the control group, the WML group had a higher average age and a higher proportion of hypertension (P<0.05), and the Mini-mental State Examination scores between the two groups were statistically significant different (P<0.01). The genotypes (AA, AG, GG) frequency and allele (A, G) frequency distribution of rs1043994 were statistically different between the two groups (P<0.05). Multivariate Logistic regression analysis showed that age (P=0.001), hypertension (P=0.012) and AA genotype (P=0.019) were independent risk factors of WML (P<0.05). The risk of WML in AA genotype is 2.512 times higher than that in AG/GG genotype. Conclusions The rs1043994 polymorphism of NOTCH3 gene is associated with WML in the elderly population, and the A allele is a susceptibility gene for WML. The rs1043994 polymorphism of the NOTCH3 gene may be a genetic risk factor for WML in the Chinese elderly population.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with spinal cord lesion: A case report and literature review

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy(CADASIL)is a common hereditary disease caused by NOTCH3 gene. The major clinical manifestations includerecurrent small-vessel ischaemic events, migraine, dementia and mood disturbance. Herein, wereport a 32-years-old male presented with right leg weakness and persistent migraine. We carried outneurological exams, genetic testing, blood and cerebrospinal fluid analysis (CSF) as well as magneticresonance imaging (MRI) for the brain and spinal cord. There were no anti-aquaporin-4 antibodiesand oligoclonal bands in the CSF and blood investigations were within the normal range. MRI scansrevealed multiple hyperintense regions in the brain and longitudinally hyperintense signal in spinal cord.Further, we identified a c.383G>A(p.Cys128Tyr) mutation in NOTCH3 gene. Therefore, the patientwas diagnosed with CADASIL concurrent with spinal cord lesion. The patient’s condition slightlyimproved after two weeks treatment with daily dosage of 0.5 g citicoline and 75 mg clopidogrel.

Amyotrophic Lateral Sclerosis Associated With CADASIL

No abstract available.

Amyotrophic Lateral Sclerosis Associated With CADASIL

No abstract available.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and lecukoencephalopathy / 医学研究生学报

Cerebral autosomal dominant arteriopathy with subcortical infarcts and lecukoencephalopathy (CADASIL) is a recently described neurovascular disease affecting young to middle aged individuals. The disease is caused by mutations in the Notch3 gene located in the long arm of chromosome 19. The disease clinically is characterized by migrainous headaches ,mood disturbances, focal neurologic deficits, transient ischemic attaches, strokes and dementia. Pathologically, the disease is characterized by a stereotypic degeneration of the arterial walls with deposition in the media of a nonatheromatous,(nonamyloidotic) substance that under the electron microscope (EM) appears as a granular osmiophilic material (GOM). A review of current literature is presented concerning the clinical, radiological, pathologic and genetic feature of CADASIL.

A Novel Mutation (C67Y) in the NOTCH3 Gene in a Korean CADASIL Patient

We report a 52-yr-old Korean woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose diagnosis was confirmed by skin biopsy and the presence of a novel mutation in the NOTCH3 gene. The patient's clinical features were rather unusual in that 1) clinical presentations were only two episodes of stroke and mild dementia unaccompanied by mood disturbances or migraine, and 2) there was no family history. Brain MRI showed T2 hyperintensities in both temporal pole areas in line with the recent suggestion by O'Sullivan et al. that the abnormality could be a radiologic marker of CADASIL. FDG-PET also showed a hypometabolism in the temporal pole areas with an abnormal finding on MRI in addition to the hypometabolism in cortical and subcortical regions. We could learn from this case that CADASIL may be included in the differential diagnoses in patients with vascular dementia associated with a small vessel disease, even in the absence of a family history, especially when there are no known stroke risk factors and when the MRI shows T2 hyperintensity in the temporal pole regions.

NOTCH3 gene diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy / 临床神经病学杂志

Objective To analyse the mutation types of the NOTCH3 gene with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL). Methods Including 4 probands of CADASIL,10 cases of CADASIL and 4 normal members from 3 CADASIL families and 100 healthy controls were recruited. Genomic DNA was extracted from white blood cell. The amplicons were analyzed by the denaturing high-performance liquid chromatography (DHPLC) technique. The positive samples which identified by the DHPLC were sequenced to determine the specific mutation or polymorphism, respectively. Results Three heterozygous missense mutations including Cys90Arg, Arg141Cys, Cys134Tyr located in the exon3 and exon4 were found in the 4 probands and 10 cases of CADASIL among the 3 families. 15 polymorphisms were also found. 2 members individual from family 1 and 2 were found to carry the same pathological mutations as in their proband but without clinical symptoms. They were identified as preclinical patients. Conclusions Mutation detection of NOTCH3 is the molecular genetic mechanical for CADASIL. The exon3 and exon4 are possible hot mutation spots in Chinese patients. The mutation of Cys134Tyr in exon4 is a novel mutation which has not been reported previously in China.