常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病研究进展

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）是一种在成人时发病且以显性方式遗传的小动脉血管病变。它的临床特征主要为反复性的脑皮质下梗死及痴呆症,在少数的患者身上同时可见先兆性偏头痛及精神疾病方面的症状。它的致病基因是NOTCH3。CADASIL是最常见的因为单基因变异所造成的遗传性脑血管病变。该文简单介绍CADASIL的临床症状、分子遗传致病机制、诊断方法、在台湾的现况以及治疗与预防建议。     

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一例

1病例简介先证者,男性,57岁,因“行走不稳、记忆力减退8年,加重伴尿失禁6个月”,收入北京天坛医院神经内科。患者8年前无明显诱因突发走路向一侧偏,即就诊于当地医院,诊断为“脑梗死”,给予活血化淤等治疗,当日恢复正常。     

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1例

正1病例介绍患者女性,57岁。主因"突发右侧肢体活动不灵、言语不利13 h"于2019年1月21日至潍坊医学院附属医院门诊就诊。患者于13 h前无明显诱因出现右侧肢体活动不灵、言语不利,右上肢抬举费力、持物欠稳,不能自行站立行走,言语含糊不清,可理解他人语言,表达尚可,症状持续不缓解。急诊行头颅CT检查示:右侧基底节区、脑桥腔隙性脑梗死,脑白质疏松改变。为进一步诊治收入神经内科。既往史:否认高血压、糖尿病、冠心病史;     

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：附一个家系临床

目的 探讨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 ａｕｔｏｓｏｍｅ ｄｏｍｉｎａｎｔ ａｒｔｅｒｉｏｐａｔｈｙ ｗｉｔｈ ｓｕｂｃｏｒｔｉｃａｌ ｉｎｆａｒｃｔｓ ａｎｄ ｌｅｕｋｏｅｎｃｅｐｈａｌｏｐａｔｈｙ,ＣＡＤＡＳＩＬ）患者的临床特点和诊断方法。方法 对１例ＣＡＤＡＳＩＬ患者及其亲属的临床表现、影像学（ＭＲＩ、ＣＴ）特点及基因改变等方面进行了系统研究,并针对性地进行了肌肉及神经活检。结果 患者的临床表现为记忆力减退,有脑卒中发作;ＭＲＩ、ＣＴ检查可见多发性梗死、脑白质变性、脑组织活检示小血管玻璃样变、嗜锇颗粒;ＮＯＴＣＨ３第４外显子错义突变以及明确的家族史,没有高血压、动脉硬化,故符合ＣＡＤＡＳＩＬ的诊断标准。结论 本病通过临床特点、影像学改变、基因检测及皮肤活检,可在生     

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的研究进展

<正>CADASIL是一种合并有皮质下梗死和脑白质变性的常染色体显性遗传性脑动脉病。本病最早记录在1955年,法国学者Van Bogaert将其命名为Binswanger样脑病~([1])。1977年,Sourander等~([2])通过对一家族三代5例患者的研究将其命名为"遗传性多梗死性痴呆"。随后各个学者相继报导了相似家系的临床疾病,但命名各异,直到1993年,Tournier Lasserve等~([3])用基因连锁分析的方法定位此病的致病基因在     

伴皮质下梗死和脑白质病的常染色体显性遗传性脑动脉病

伴皮质下梗死和脑白质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)是指一种非动脉硬化性、 非淀粉样血管病性的常染色体显性遗传性脑血管病.     

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1例报告

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)是一种中年发病的、非动脉硬化性、非淀粉样变性、遗传性脑小血管病.其发病与19号染色体上的Notch3基因突变有关.临床上以反复皮质下缺血性卒中发作、痴呆、假性球麻痹和偏头痛为特征.现将我院收治的1例CADASIL患者的诊治情况报告如下.     

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（附l例报道）

目的 探讨伴有皮层下梗死和白质脑病(Cerebral autonomic dominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)的常染色体显性遗传性脑动脉病的临床特点和诊断方法。方法 对1例CADASIL患者的临床表现、影像学(MRI、CT )特点及皮肤活检等方面进行了探讨。结果 患者临床表现为反复发作的缺血性脑卒中、记忆力减退、假性球麻痹、MRI、CT见皮质下梗死和白质脑病的改变，皮肤活检显示小动脉含糖原颗粒，管腔狭窄，血管内皮下黑色嗜锇颗粒。结论 通过本病的临床特点、影像学和皮肤活检，可在生前进行诊断。     

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机制研究进展

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）是一种中年发病的遗传性脑小动脉病,典型临床表现是偏头痛发作、频发性皮质下短暂性脑缺血发作或缺血性脑卒中、认知功能下降和精神症状。该病由NOTCH3基因突变所致,但具体发病机制不清,可能与电子致密嗜锇颗粒沉积、NOTCH3蛋白信号通路异常、胶质细胞损伤及自噬功能异常、配体介导的内吞障碍和NOTCH3蛋白胞外区清除障碍有关。该文就近年CADASIL的致病机制研究进展进行了综述。国际神经病学神经外科学杂志, 2023, 50(6): 63-67]     

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的磁共振表现与早期特征

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）是人类19p13上的Notch3基因突变引起的遗传性脑小动脉病。自从该病被首届国际CADASIL专题研讨会（1993）共识并统一使名以来，国外尤其是欧洲各国对该病进行了多层次的研究。     

伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(附一例报告及文献复习)

目的 提高对伴有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)临床特点和诊断方法的认识。方法 对2003年4月7日收治的1例CADASIKL患的临床表现、影像学特点及皮肤活检结果等临床资料进行回顾性分析。结果 主要临床表现为偏头痛、记忆力下降，头部MRI检查可见皮质下梗死、脑白质变性；皮肤活检电子显微镜显示小血管内皮下出现嗜锇酸颗粒。结论 对出现反复发作性偏头痛的中年人，MRI检查示皮质下白质或基底节区长T1、长T2异常信号，应高度怀疑为CADASIL，需进一步行皮肤活检及基因检测，以明确诊断。     

伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病的临床和影像学特征分析

目的 报道1例影像学上表现为双侧小脑和胼胝体膝部梗死的伴有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CADASIL的临床及影像学表现。方法 对1例疑诊为CADASIL的78岁女性患者进行临床表现、影像学检查及实验室检查,神经心理测评的收集,取得患者知情同意后对其进行NOTCH3基因检测和皮肤活检,并对家系成员进行验证分析。结果 患者首发症状为记忆力减退,起病年龄较大,伴有情感淡漠、步态不稳、小便功能障碍,无偏头痛,头颅磁共振见广泛的脑白质脱髓鞘,丘脑、胼胝体膝部、双侧基底节、双侧小脑半球多发陈旧性腔隙性脑梗死,NOTCH3基因检测发现11号外显子存在c.1630C>T错义突变,即p.R544C。结论 本例CADASIL患者的起病年龄75岁,首发症状为记忆力减退,腔隙性脑梗死不仅累及丘脑、基底节,同样也可以累及小脑。胼胝体全层梗死为CADASIL的特征性影像表现之一。     

以椎-基底动脉系统短暂性脑缺血发作为主要临床表现的CADASIL家族

目的 报道一个以椎-基底动脉系统短暂性脑缺血发作为主要临床表现的常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病(CADASIL)家族，探讨其临床、影像学以及基因和病理特点。方法 先证者为中年女性，出现反复发作的头晕和智能减退。对其进行l临床、电生理、影像学分析和腓肠神经病理检查，并调查其家族中其他成员的发病情况。家族中连续3代有7例发病，两性均累及，发病年龄在40～50岁之间，均反复出现头晕、卒中和痴呆，症状呈阶梯性加重。结果 MR1检查显示基底节、丘脑、脑桥、胼胝体及脑室旁白质出现多发腔隙性低密度灶，白质疏松，累及双侧颞极。腓肠神经活检发现小动脉壁平滑肌细胞变性，其表面出现大量的颗粒样嗜锇性物质沉积。Notch3基因检查显示R607C突变。结论 CADASIL可以主要表现为椎一基底动脉系统的缺血性卒中和痴呆，其病理改变主要累及小动脉壁平滑肌细胞。含有小动脉的腓肠神经超微病理检查可能更有利于此病的诊断。基因检查可以进一步证实该病的诊断和筛查其他家族成员。     

以急性可逆性意识模糊或浅昏迷为主要临床表现的CADASIL（附1例报道）

目的报道1例以急性可逆性意识模糊或浅昏迷为主要临床表现的伴皮质下梗死和白质脑病的常染色显性遗传性脑动脉病（Cerebral autonomic dominant arteriopathy with subcortical infarcts and leucoencephalopathy，CADASIL），探讨其临床特点和可能的发病机制。方法对1例临床表现为反复发作的发热、头痛、呕吐、意识模糊或浅昏迷的患者，进行临床、影像学、皮肤活检检查。结果患者临床表现为反复发作的发热、头痛、呕吐、意识模糊或浅昏迷，MRI见广泛的脑白质病变，皮肤活检光镜下见小动脉含糖原颗粒，管腔狭窄，电镜下见血管内皮下黑色嗜锇颗粒沉积。结论CADASIL可以表现为急性可逆性意识障碍或浅昏迷，当临床上出现用其它原因不能解释的急性可逆性意识障碍时，需考虑CADASIL的可能。     

Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and depression, but not migraine. A skin biopsy in the proband patient showed characteristic pathological findings of CADASIL on electron microscopy. Afterward, genetic analysis found an Arg332Cys mutation at exon 6 of NOTCH3. Neuropsychological evaluation showed vascular dementia in two of four affected people. Head MRI showed multiple infarcts in bilateral basal ganglia, thalami, periventricular white matter, external capsules, and brainstem, but involvement of the anterior temporal pole was found only in two people with milder symptoms. To our knowledge, the Arg332Cys NOTCH3 mutation at exon 6, which was identified in the studied family, has not been reported in Asian populations. Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL.     

Denaturing high-performance liquid chromatography to diagnose cerebral autosomal dominant arteriopathy in Chinese patients with subcortical infarcts and leukoencephalopathy*★

BACKGROUND： Notch3 mutations are the molecular genetic foundation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy （CADASIL）. Of all currently available detection methods, direct sequencing or restriction enzymes are frequently used, but the cost is relatively high, because the Notch3 gene is composed of many exons and mutational sites are widely distributed. Denaturing high-performance liquid chromatography （DHPLC） exhibits high efficiency and specificity and has been applied to gene detection. To date, there has no report regarding DHPLC in gene detection of large-scale CADASIL families in China. OBJECTIVE： To explore the application and value of DHPLC in the diagnosis of CADASIL by a mutation screening for Notch3 gene in CADASIL probands and their family members. DESIGN, TIME AND SETTING： A comparative observation was performed at the Genetic Diagnosis Laboratory of Institute of Geriatrics, Xuanwu Hospital of Capital Medical University and the Key Laboratory for Neurodegenerative Disease of the Ministry of Education between August 2003 and May 2004. PARTICIPANTS： Fourteen CADASIL patients and their family members, comprising eight males and six females, aged 38-62 years, were included. Their key features included recurrent sub-cortical ischemic events and vascular dementia. In addition, 100 healthy physical examinees were selected as controls, including 52 males and 48 females, aged 56-72 years, who had no neurodegenerative disease or psychosis, and no history or high risk for cerebrovascular disease. METHODS： DNA was extracted from white blood cells. Ten hotspots of the Notch3 gene for sequence variation were first amplified by PCR, and the products were detected using DHPLC, Exons exhibiting a variant in the DHPLC profile underwent another PCR amplification, followed by DNA sequencing to identify the mutation type, In addition, patients with normal DHPLC peak profiles underwent PCR amplification for the remaining 13 exons, DNA sequencing was per     

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Greek family

Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset inherited disease, characterised by recurrent strokes, migraine and cognitive impairment. We present the first Greek family with CADASIL, caused by the R153C mutation at exon 4 of the Notch3 gene. A member of this family carrying this mutation was also found to be heterozygotic for the MTHFR mutation, factor V Leiden mutation and had low serum levels of antithrombin III, thus resulting in the appearance of recurrent strokes and thrombotic episodes since his early adulthood. The co-existence of these thrombophilic disorders with CADASIL in a single person poses serious therapeutic dilemmas, as the administration of anticoagulant agents may correlate with increased risk of potentially fatal intracerebral haemorrhage.     

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): A patient from Sri Lanka

We report the first patient from Sri Lanka (the third patient from the Indian subcontinent) with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The patient experienced a young onset familial stroke with an 856T>G missense mutation in exon 5 of the NOTCH3 gene resulting in a C260G mutation in the sixth epidermal growth factor-like repeat. We believe this is the first reported Sri Lankan patient. CADASIL is probably underdiagnosed in the region.     

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

This study was performed on a family of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) subjects. Neuropathological alterations of small arteries consisting in thickening, reduplication and fragmentation of the internal elastic lamella, and granular periodic acid-Schiff-positive material deposited in the arterial media were demonstrated in 1 autopsy case by histochemistry and electron microscopy. This material reacted with a monoclonal antibody anti-elastin (aE), as demonstrated by immunohistochemistry and immunoelectron microscopy. Significant increases of aE-immunoreactivity and elastin mRNA expression were found in cultured skin fibroblasts from 5 family members genetically affected by CADASIL, but not genetically and clinically healthy members. These results suggest that alterations of the elastic apparatus are associated with CADASIL genotype and related to the clinical expression of the disease.     

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a morphological study of a German family

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized clinically by recurrent cerebral infarcts, subcortical dementia and pseudobulbar palsy, and morphologically by a granular degeneration of cerebral and, to a lesser degree, extracerebral blood vessels. We present morphological findings in a further German family affected by CADASIL. The index case showed the typical periodic acid-Schiff-positive granular degeneration of vascular smooth muscle cells (VSMC) in cerebral vessels, which did not react with antibodies against various immunoglobulins or complement factors. Ultrastructurally, granular osmiophilic material (GOM) covered the VSMC in different cerebral regions as well as in extracerebral organs (muscle, nerve, skin, small and large intestine, liver, kidney and heart). Skin biopsy samples from other family members of the last two generations also revealed GOM irrespective of the clinical symptomatology (CADASIL, migraine only or asymptomatic). Patients in the third generation had higher amounts of GOM in skin vessels than did asymptomatic or migraine patients in the fourth generation. We conclude that skin biopsy is a useful and less-invasive screening method for the differential diagnosis of CADASIL. Received: 9 February 1996 / Revised, accepted: 24 April 1996