为深入分析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(CADASIL)的研究现状和趋势,利用Web of Science数据库检索2013-2023年与CADASIL相关的文献,并通过VOSviewer和CiteSpace等工具进行可视化分析。结果显示,近10年来,CADASI...为深入分析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(CADASIL)的研究现状和趋势,利用Web of Science数据库检索2013-2023年与CADASIL相关的文献,并通过VOSviewer和CiteSpace等工具进行可视化分析。结果显示,近10年来,CADASIL相关文章的数量呈现出稳步增长的趋势,主要集中在美国、中国、德国和法国等国家;在这一领域,Chabriat、Jouvent和Duering等学者被认为是最具影响力的核心作者,他们合作频繁,并涉及临床表现及影响等多个方面;法国巴黎狄德罗大学是该领域出版物数量最多的机构,通过与其他研究机构的合作,推动了CADASIL的研究进展;Brain期刊在学术影响力方面表现突出,成为该领域的重要发表平台。当前,CADASIL的研究重点主要集中在病理变化、基因突变和影像学表现等方面。然而,尽管取得了一定的研究成果,CADASIL领域仍面临治疗方法不足、预后评估不完善等诸多挑战,亟需进一步研究以解决这些问题。展开更多
目的:对一例临床诊断为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, OMIM#125310)的学龄期男童及其家系成员的临床...目的:对一例临床诊断为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, OMIM#125310)的学龄期男童及其家系成员的临床资料进行整理、分析,以期丰富该病临床资料。方法:收集2023年青岛大学附属医院儿童神经内科临床诊断为CADASIL的一例患者及其家系成员的临床及影像学资料,并采用二代高通量测序(NGS)对先证者进行检测。结果:先证者为8岁学龄期男童,有头痛病史、颅脑MRI显示白质异常信号,其姐姐、父亲均有头痛病史及脑白质异常信号且其父亲有脑萎缩表现。先证者全外显子检测未发现NOCH3及HTRIA基因变异。结论:对有明确家族史的偏头痛样发作患儿,且颅脑MRI显示颞极或外囊白质异常信号,要警惕CADASIL,需进行基因检测和(或)皮肤活检,如二者均未发现异常,可诊断为类CADASIL (CACASIL-Like)病,应定期进行随访、追踪,寻找潜在的病因。Objective: We organized and analyzed the clinical data of a school-age boy and his family members who were clinically diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL, OMIM#125310), to provide a scientific basis for the diagnosis of CADASIL. Methods: The clinical and brain MRI data of patient and his family members who were clinically diagnosed as CADASIL by the Pediatric Neurology of the Affiliated Hospital of Qingdao University in 2023 were collected, and the proband was detected by next-generation sequencing (NGS). Results: The proband was an 8-year-old schoolboy with a history of migraine, and brain MRI revealed T2 white matter hyperintensity (WMHs). His sister and father had a history of migraine and significant white matter hyperintensities on brain MRI, and his father had brain atrophy. No variants were found in NOCH3 and HTRIA genes in the proband by whole exon sequencing. Conclusion: For children with a clear family history of migraine like attacks and abnormal white matter signals on cranial MRI, CADASIL should be alerted and genetic testing and/or skin biopsy should be performed. If no abnormalities are found in both, it can be diagnosed as CACASIL-like disease, and regular follow-up and tracking should be conducted to search for potential causes.展开更多
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADASIL rem...Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADASIL remains unclear, and patients have limited treatment options. Here, we use human induced pluripotent stem cells (hiPSCs) generated from the peripheral blood mononuclear cells of a patient with CADASIL carrying a heterozygous NOTCH3 mutation (c.1261C>T, p.R421C) to develop a disease model. The correction efficiency of different adenine base editors (ABEs) is tested using the HEK293T-NOTCH3 reporter cell line. ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects. Vascular smooth muscle cells (VSMCs) differentiated from CADASIL hiPSCs show NOTCH3 deposition and abnormal actin cytoskeleton structure, and the abnormalities are recovered in corrected hiPSC-derived VSMCs. Furthermore, CADASIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes, including the downregulation of cell adhesion, extracellular matrix organization, and vessel development. The dual adeno-associated virus (AAV) split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82%. Collectively, we present potential genetic therapeutic strategies for patients with CADASIL using blood vessel organoids and the dual AAV split-ABEmax system.展开更多
目的探讨NOTCH3基因第5外显子C260S位点突变导致的伴有皮层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)家系的临床和影像学...目的探讨NOTCH3基因第5外显子C260S位点突变导致的伴有皮层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)家系的临床和影像学特征。方法选取2021年12月首都医科大学附属北京同仁医院来自同一家庭的CADASIL患者,对所有患者进行NOTCH3基因测序,回顾性分析患者的临床表现和头颅影像学特征。复习既往文献报道的导致同一位置氨基酸改变的其他突变类型的临床及影像学特征。结果4名家庭成员中,包括先证者(46岁,女)及其两个姐姐(分别为48岁和50岁)和女儿(18岁)。先证者及其父亲、两个姐姐都有偏头痛病史,其中大姐有记忆力减退;先证者患有脑梗死及伴有视觉先兆的偏头痛;先证者女儿体健;先证者父亲因脑梗死去世。4名家庭成员均存在C260S位点的NOTCH3基因突变。既往文献无此位点突变的报道,先证者头颅MRI示右侧脑桥亚急性梗死,颞叶、脑室周围及脑干异常高信号改变,其大姐脑桥可见腔隙性梗死灶。结论NOTCH3基因第5外显子c.778T>A(p.C260S)的罕见突变导致的CADASIL发病时间早,早期会出现认知障碍。合并偏头痛的脑干梗死患者,需警惕CADASIL的可能。展开更多
应用透射电镜观察研究16例伴有皮层下梗死及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)患者血管的超微病理特点,探讨其发病机制,为...应用透射电镜观察研究16例伴有皮层下梗死及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)患者血管的超微病理特点,探讨其发病机制,为临床诊断提供超微病理诊断依据。收集从2000年至2014年16例北京天坛医院神经内科CADASIL患者的皮肤活检组织标本,在透射电镜下仔细观察血管组织的超微病理特点,并对CADASIL患者的超微病理学、影像学及临床表现的关系进行讨论。电镜检查可见血管平滑肌细胞基膜凹陷处出现特征性颗粒状电子致密嗜锇物质(granular electron dense osmiophilic material,GEOM),并在该物质附近伴有许多胞吐小泡。CADASIL病患者临床特点为中年发病、反复发作的脑卒中及进行性智力下降。该病是与Notch3基因突变相关以显性遗传方式表达的脑动脉病,头颅核磁共振检查呈现多发腔隙性梗死及脑白质病变。CADASIL病的电镜超微病理特点为血管平滑肌细胞基膜凹陷处聚积特征的GEOM是诊断该病的重要手段,该物质可能与所伴随的胞吐小泡的分泌有关。展开更多
目的分析1例以先兆型偏头痛为主要临床表现的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 autonomic dominant arteriopathy with subcortical infarcts and leucoencephalopathy,CADASIL),探讨该病早期的临床特点。...目的分析1例以先兆型偏头痛为主要临床表现的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 autonomic dominant arteriopathy with subcortical infarcts and leucoencephalopathy,CADASIL),探讨该病早期的临床特点。方法对1例临床表现为先兆型偏头痛患者,进行临床、影像学分析、Notch3基因外显子测序。结果该患主要表现为有家族史的先兆型偏头痛,头颅MRI见T2加权像和FLAIR像特征性颞极白质异常高信号,与放射冠、半卵圆中心区腔隙性脑梗死灶并存,Notch3基因外显子测序提示杂合突变c.353C→G(p.Ser118Cys)。结论重视先兆型偏头痛患者的头颅MRI表现,颞极异常信号提示CADASIL可能,进一步行Notch3基因外显子测序可提高CADASIL确诊率。展开更多
常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病(cerebral autosomal dominantarteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)是一种较为少见的遗传性小动脉病,致病基因为Notch3。我国患者主要表现为皮...常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病(cerebral autosomal dominantarteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)是一种较为少见的遗传性小动脉病,致病基因为Notch3。我国患者主要表现为皮层下缺血及认知障碍,伴有先兆的偏头痛极少见。影像学特点为多发皮质下梗死灶,侧脑室旁白质多发斑点状异常信号,外囊、前颞区和胼胝体为特征性受累部位。Notch3基因突变热区分布在第11、4和3号外显子,可能存在热点突变。展开更多
目的通过一个新发现的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)致病基因,说明基因测序对于CADASIL诊断的必要性及C...目的通过一个新发现的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)致病基因,说明基因测序对于CADASIL诊断的必要性及CADASIL诊断的复杂性。方法对1例疑似CADASIL患者的临床表现、实验室检查、影像学检查、家系及基因测序进行分析。临床上主要表现为反复缺血性卒中及进行性记忆力下降;实验室检查排除一些高凝疾病及血管炎;头部MRI提示皮质下白质广泛对侧性信号异常及多部位的新旧梗死病灶;家系分析患者家族成员存在偏头痛、反复卒中及记忆力下降;基因测序提示NOTCH3基因3号外显子存在一个基因突变(c.331G>T p.Gly111Cys),而这个突变位点截止到目前并未报道过。结果结合患者临床表现、影像学、家系及基因测序分析确诊该患者为CADASIL,通过分析CADASIL突变基因的致病机制确认该患者存在的突变基因为CADASIL一个新发现的致病突变。结论新的CADASIL致病基因突变的发现强调了基因测序及提高对突变基因致病机制认识的重要性。展开更多
文摘为深入分析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(CADASIL)的研究现状和趋势,利用Web of Science数据库检索2013-2023年与CADASIL相关的文献,并通过VOSviewer和CiteSpace等工具进行可视化分析。结果显示,近10年来,CADASIL相关文章的数量呈现出稳步增长的趋势,主要集中在美国、中国、德国和法国等国家;在这一领域,Chabriat、Jouvent和Duering等学者被认为是最具影响力的核心作者,他们合作频繁,并涉及临床表现及影响等多个方面;法国巴黎狄德罗大学是该领域出版物数量最多的机构,通过与其他研究机构的合作,推动了CADASIL的研究进展;Brain期刊在学术影响力方面表现突出,成为该领域的重要发表平台。当前,CADASIL的研究重点主要集中在病理变化、基因突变和影像学表现等方面。然而,尽管取得了一定的研究成果,CADASIL领域仍面临治疗方法不足、预后评估不完善等诸多挑战,亟需进一步研究以解决这些问题。
文摘目的:对一例临床诊断为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, OMIM#125310)的学龄期男童及其家系成员的临床资料进行整理、分析,以期丰富该病临床资料。方法:收集2023年青岛大学附属医院儿童神经内科临床诊断为CADASIL的一例患者及其家系成员的临床及影像学资料,并采用二代高通量测序(NGS)对先证者进行检测。结果:先证者为8岁学龄期男童,有头痛病史、颅脑MRI显示白质异常信号,其姐姐、父亲均有头痛病史及脑白质异常信号且其父亲有脑萎缩表现。先证者全外显子检测未发现NOCH3及HTRIA基因变异。结论:对有明确家族史的偏头痛样发作患儿,且颅脑MRI显示颞极或外囊白质异常信号,要警惕CADASIL,需进行基因检测和(或)皮肤活检,如二者均未发现异常,可诊断为类CADASIL (CACASIL-Like)病,应定期进行随访、追踪,寻找潜在的病因。Objective: We organized and analyzed the clinical data of a school-age boy and his family members who were clinically diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL, OMIM#125310), to provide a scientific basis for the diagnosis of CADASIL. Methods: The clinical and brain MRI data of patient and his family members who were clinically diagnosed as CADASIL by the Pediatric Neurology of the Affiliated Hospital of Qingdao University in 2023 were collected, and the proband was detected by next-generation sequencing (NGS). Results: The proband was an 8-year-old schoolboy with a history of migraine, and brain MRI revealed T2 white matter hyperintensity (WMHs). His sister and father had a history of migraine and significant white matter hyperintensities on brain MRI, and his father had brain atrophy. No variants were found in NOCH3 and HTRIA genes in the proband by whole exon sequencing. Conclusion: For children with a clear family history of migraine like attacks and abnormal white matter signals on cranial MRI, CADASIL should be alerted and genetic testing and/or skin biopsy should be performed. If no abnormalities are found in both, it can be diagnosed as CACASIL-like disease, and regular follow-up and tracking should be conducted to search for potential causes.
基金funded by the National Natural Science Foundation of China(31971365)the Guangdong Basic and Applied Basic Research Foundation(2020B1515120090)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2019BT02Y276).
文摘Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADASIL remains unclear, and patients have limited treatment options. Here, we use human induced pluripotent stem cells (hiPSCs) generated from the peripheral blood mononuclear cells of a patient with CADASIL carrying a heterozygous NOTCH3 mutation (c.1261C>T, p.R421C) to develop a disease model. The correction efficiency of different adenine base editors (ABEs) is tested using the HEK293T-NOTCH3 reporter cell line. ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects. Vascular smooth muscle cells (VSMCs) differentiated from CADASIL hiPSCs show NOTCH3 deposition and abnormal actin cytoskeleton structure, and the abnormalities are recovered in corrected hiPSC-derived VSMCs. Furthermore, CADASIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes, including the downregulation of cell adhesion, extracellular matrix organization, and vessel development. The dual adeno-associated virus (AAV) split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82%. Collectively, we present potential genetic therapeutic strategies for patients with CADASIL using blood vessel organoids and the dual AAV split-ABEmax system.
文摘目的探讨NOTCH3基因第5外显子C260S位点突变导致的伴有皮层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)家系的临床和影像学特征。方法选取2021年12月首都医科大学附属北京同仁医院来自同一家庭的CADASIL患者,对所有患者进行NOTCH3基因测序,回顾性分析患者的临床表现和头颅影像学特征。复习既往文献报道的导致同一位置氨基酸改变的其他突变类型的临床及影像学特征。结果4名家庭成员中,包括先证者(46岁,女)及其两个姐姐(分别为48岁和50岁)和女儿(18岁)。先证者及其父亲、两个姐姐都有偏头痛病史,其中大姐有记忆力减退;先证者患有脑梗死及伴有视觉先兆的偏头痛;先证者女儿体健;先证者父亲因脑梗死去世。4名家庭成员均存在C260S位点的NOTCH3基因突变。既往文献无此位点突变的报道,先证者头颅MRI示右侧脑桥亚急性梗死,颞叶、脑室周围及脑干异常高信号改变,其大姐脑桥可见腔隙性梗死灶。结论NOTCH3基因第5外显子c.778T>A(p.C260S)的罕见突变导致的CADASIL发病时间早,早期会出现认知障碍。合并偏头痛的脑干梗死患者,需警惕CADASIL的可能。
文摘应用透射电镜观察研究16例伴有皮层下梗死及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)患者血管的超微病理特点,探讨其发病机制,为临床诊断提供超微病理诊断依据。收集从2000年至2014年16例北京天坛医院神经内科CADASIL患者的皮肤活检组织标本,在透射电镜下仔细观察血管组织的超微病理特点,并对CADASIL患者的超微病理学、影像学及临床表现的关系进行讨论。电镜检查可见血管平滑肌细胞基膜凹陷处出现特征性颗粒状电子致密嗜锇物质(granular electron dense osmiophilic material,GEOM),并在该物质附近伴有许多胞吐小泡。CADASIL病患者临床特点为中年发病、反复发作的脑卒中及进行性智力下降。该病是与Notch3基因突变相关以显性遗传方式表达的脑动脉病,头颅核磁共振检查呈现多发腔隙性梗死及脑白质病变。CADASIL病的电镜超微病理特点为血管平滑肌细胞基膜凹陷处聚积特征的GEOM是诊断该病的重要手段,该物质可能与所伴随的胞吐小泡的分泌有关。
文摘目的分析1例以先兆型偏头痛为主要临床表现的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 autonomic dominant arteriopathy with subcortical infarcts and leucoencephalopathy,CADASIL),探讨该病早期的临床特点。方法对1例临床表现为先兆型偏头痛患者,进行临床、影像学分析、Notch3基因外显子测序。结果该患主要表现为有家族史的先兆型偏头痛,头颅MRI见T2加权像和FLAIR像特征性颞极白质异常高信号,与放射冠、半卵圆中心区腔隙性脑梗死灶并存,Notch3基因外显子测序提示杂合突变c.353C→G(p.Ser118Cys)。结论重视先兆型偏头痛患者的头颅MRI表现,颞极异常信号提示CADASIL可能,进一步行Notch3基因外显子测序可提高CADASIL确诊率。
文摘常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病(cerebral autosomal dominantarteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)是一种较为少见的遗传性小动脉病,致病基因为Notch3。我国患者主要表现为皮层下缺血及认知障碍,伴有先兆的偏头痛极少见。影像学特点为多发皮质下梗死灶,侧脑室旁白质多发斑点状异常信号,外囊、前颞区和胼胝体为特征性受累部位。Notch3基因突变热区分布在第11、4和3号外显子,可能存在热点突变。
文摘目的通过一个新发现的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)致病基因,说明基因测序对于CADASIL诊断的必要性及CADASIL诊断的复杂性。方法对1例疑似CADASIL患者的临床表现、实验室检查、影像学检查、家系及基因测序进行分析。临床上主要表现为反复缺血性卒中及进行性记忆力下降;实验室检查排除一些高凝疾病及血管炎;头部MRI提示皮质下白质广泛对侧性信号异常及多部位的新旧梗死病灶;家系分析患者家族成员存在偏头痛、反复卒中及记忆力下降;基因测序提示NOTCH3基因3号外显子存在一个基因突变(c.331G>T p.Gly111Cys),而这个突变位点截止到目前并未报道过。结果结合患者临床表现、影像学、家系及基因测序分析确诊该患者为CADASIL,通过分析CADASIL突变基因的致病机制确认该患者存在的突变基因为CADASIL一个新发现的致病突变。结论新的CADASIL致病基因突变的发现强调了基因测序及提高对突变基因致病机制认识的重要性。
