NOTCH3 Gene Mutation in a Chilean Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Family

IntroductionCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke disorder caused by mutations in the NOTCH3 gene. We report the first Chilean CADASIL family with complete radiological and histological studies.MethodsThe family tree was constructed from an autopsy-confirmed confirmed patient, and includes 3 generations. We performed clinical, pathologic, genetic, and radiologic examinations on members of a family with CADASIL.ResultsIn the second generation, findings compatible with CADASIL were identified in 6 individuals, all of whom had a missense mutation in exon 3 (c.268C>T) resulting in an arginine to cysteine amino acid substitution at position 90 (R90C). In the third generation, a missense mutation was detected in one of the 4 asymptomatic individuals.ConclusionsThere are similarities in clinical presentation between this family and previously described Asian and European series with R90C mutations. Detecting genotypes with a gain or loss of cysteine residues opens the door to future gene transfection-based therapies.     

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。     

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Associated With a Novel In-Frame Mutation in the NOTCH3 Gene in a Japanese Patient

Here, we report a case involving a 67-year-old Japanese woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) associated with a novel in-frame complex rearrangement in the NOTCH3 gene. The patient had gradually developed cognitive impairment since the occurrence of an ischemic stroke at the age of 53 years. Her mother had a history of stroke and dementia. Fluid-attenuated inversion recovery magnetic resonance imaging of the brain showed hyperintense lesions in the bilateral temporal poles, external capsules, and periventricular white matter accompanied by multiple cerebral microbleeds on T2*-weighted gradient-echo imaging. A novel in-frame mutation (c.598_610delinsAGAACCC) resulting in the loss of Cys201 in the fifth epidermal growth factor-like repeat of NOTCH3 was identified; this led to a diagnosis of CADASIL. In summary, we report a novel pathogenic mutation (NOTCH3 c.598_610delinsAGAACCC; p.Pro200_Ser204delinsArgThrPro) associated with CADASIL. Further investigations should elucidate the genotype-phenotype correlations in patients with this in-frame complex rearrangement.     

CADASIL的磁共振影像学、临床表现及Notch3基因的研究

【摘要】
目的 探讨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）的临床、影像学特点和基因突变类型。
方法 收集非家系CADASIL患者,对其颅脑磁共振成像（magnetic resonance imaging,MRI）特点、临床表现和基因检测结果进行回顾性分析。
结果 本研究共收录11例患者,其中患有头痛者5例（45.45%）、记忆力下降者5例（45.45%）。11例患者均进行了MRI检查,有脑干损害的患者7例（63.63%）,其中脑干损害患者全部存在脑桥病变。进行心理评测的7例患者中存在焦虑和（或）抑郁的患者有4例（57.14%）。5例患者进行了基因检测,其中4例（80%）为Notch3基因外显子4位点突变,1例（20%）为Notch3基因外显子3位点突变。
结论 头痛是CADASIL患者的重要临床特点;脑桥是CADASIL患者常见的脑干受累部位。     

显性遗传性脑动脉病伴随皮层下梗死和白质脑病一例

1 病例简介 患者,女性,51岁,主诉“反复发作头昏、右侧肢体无力8年,伴随记忆力减退5年”于2008年3月入院。     

伴有皮质下梗死及白质脑病的常染色体隐性遗传性脑动脉病

1985年福武敏夫报告一个家族性青年起病,临床以秃头、腰痛、白质脑病为特征的新的综合征(伴有皮质下梗死及白质脑病的常染色体隐性遗传性脑动脉病,CARASIL)。CARASIL,具有与Binswanger病十分相似的血管性白质脑病的临床影像及病理学改变。但CARASIL有几点有别于典型的Binswanger病:①家族史;②青少年起病;③缺乏脑血管病的危险因子(尤其是高血压);④弥漫性秃头;⑤骨骼系统疾病。MRI T2加权及FLARI序列可见皮质深部白质高信号和基底节、丘脑腔隙梗死灶。CARASIL病因迄今不明,但文献资料已经证明不仅归属动脉硬化性脑病,而且为遗传性脑病的小血管病。     

伴有皮质下梗死及白质脑病的常染色体隐性遗传性脑动脉病1例报告及文献复习

目的：报告1例中国十分罕见的疾病——伴有皮质下梗死及白质脑病的常染色体隐性遗传性脑动脉病（CARASIL）。方法：结合国外文献复习对本CARASIL病例进行分析。结果：患者青年期发病,以突然左下肢无力、跛行、行走缓慢起病,同时出现记忆力减退和性格改变。结合其早年秃发,有反复急性腰痛史（腰椎CT证实L3～4、L4～5椎间盘突出）,头颅MRI示双侧大脑白质广泛、斑片状融合的长T1长T2异常信号,双侧基底节区、侧脑室旁多个腔隙性梗死灶,可确诊为CARASIL。结论：CARASIL是青年期发病,以弥漫性大脑白质病变为主,同时基底节区散在腔隙性梗死灶并伴有秃发、腰痛为临床特征的罕见遗传性脑血管病。CARASIL除日本报道外,也见于中国。临床症状和神经影像学是诊断CARASIL的主要依据,抗血小板聚集药可能预防脑卒中复发。     

Multiple Border-Zone Infarcts Triggered by Influenza A Virus Infection in a Patient With Cerebral Autosomal Dominant Arteriopathy Presenting With Subcortical Infarcts and Leukoencephalopathy

Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can develop multiple border-zone infarcts due to hypotension, hypovolemia, or surgery. We report the case of a 41-year-old woman with CADASIL who developed multiple border-zone infarcts due to influenza A virus infection. The patient had no apparent history or episode of stroke or altered consciousness following the onset of respiratory symptoms, which were due to the influenza A infection. Diffusion-weighted magnetic resonance images of the brain showed multiple acute-phase infarcts in border-zone areas of both cerebral hemispheres and the corpus callosum; fluid-attenuated inversion-recovery magnetic resonance images showed increased signal in the subcortical areas of both temporal poles. Gene analysis identified a heterozygous mutation c.160C>T in exon 2 of the NOTCH3 gene (p.Arg54Cys). A diagnosis of CADASIL was established. Our case demonstrates that infectious conditions such as influenza A can trigger multiple border-zone infarctions in patients with CADASIL.     

Occurrence of Intracranial Hemorrhage and Associated Risk Factors in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Systematic Review and Meta-Analysis

Background and PurposeIntracranial hemorrhage (ICH) is thought to be a rare but probably underestimated presentation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We conducted a systematic review and meta-analysis with the aim of comprehensively revealing the occurrence of ICH in patients with CADASIL.MethodsEnglish-language studies published up to September 30, 2021 were searched for in the MEDLINE (PubMed), Web of Science, and Cochrane Library databases. The design, patient characteristics, occurrence rate of ICH, and associated risk factors were retrieved for each identified relevant study.ResultsWe enrolled 13 studies in the final meta-analysis, which included 1,310 patients with CADASIL. The probability of ICH occurrence in patients with CADASIL was 10.1% (95% confidence interval [CI]=5.6%–18.0%, I²=85.1%). When stratified by geographic region, the occurrence rate of ICH was much higher in Asians (17.7%; 95% CI=11.0%–28.5%, I²=76.3%) than in Europeans (2.0%; 95% CI=0.4%–10.8%, I²=82.8%). A higher burden of cerebral microbleeds (CMBs) and a history of hypertension were the most commonly recorded risk factors for ICH, which were available for three and two of the included studies, respectively.ConclusionsOur study suggests that ICH is an important clinical manifestation of CADASIL, especially in Asians. A higher burden of CMBs and the existence of hypertension were found to be associated with a higher probability of ICH occurrence in patients with CADASIL.     

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy): an Australian perspective.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is a recently described cause of stroke or stroke-like episodes. It is caused by mutations in the Notch3 gene on chromosome 19p. We sought to demonstrate mutations of the Notch3 gene in Australian patients suspected of having CADASIL. Patients from several families were referred to the study. A diagnosis was determined clinically and by neuroimaging. Those suspected of having CADASIL had sequencing of exons 3 and 4 of the Notch3 gene. Eight patients, two of whom were siblings, were suspected of having CADASIL. Five patients (including the siblings) had mutations. Because of strong clustering of Notch3 mutations in CADASIL, this has potential as a reliable test for the disease in Australian patients.     

偏头痛伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病临床分析

目的探讨国人伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病合并偏头痛的可能性。方法对1例临床表现为偏头痛、记忆力减退和情感障碍的患者进行临床MRI、皮肤活检电镜检查。结果患者有家族性偏头痛史，记忆力减退、情感障碍IMRI显示多发性腔隙梗死、白质疏松；皮肤血管内皮细胞增厚，血管平滑肌嗜锇颗粒阳性。结论中国人伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病也有可能伴有偏头痛。皮肤活检的血管变化与脑动脉病的关系尚不明。     

伴皮质下梗死和白质脑病的脑部常染色体隐性动脉病1例

1病例介绍患者,女,25岁,蒙古族,以"突发右侧肢体无力1个月余"于2008年6月10日收入院。患者主诉于入院前1月余午睡后出现右腿麻木,无明显无力,未在意,次日晨起时发觉右侧肢体麻木加重,自觉没有知觉,伴有右侧肢体无力,易摔倒,需要人扶持方能行走,无头痛头晕、恶心呕吐、视物不清、言语