常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病的周围神经改变

目的报道常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（CADASIL）患者的周围神经电生理和病理改变特点。方法7例经病理和基因检查确诊的CADASIL患者，女性5例，男性2例。年龄在33～46岁之间，病程从4个月到3年不等。其中1例出现手套袜套样痛觉减退及四肢腱反射减弱。除1例有长期饮酒史外，所有被检者均无其他导致周围神经损害的危险因素。其中3例进行了周围神经电生理检查。7例患者均进行了腓肠神经活体组织的光镜和电镜检查。结果电生理检查显示1例患者的感觉和运动神经以及另1例患者的运动神经传导速度减慢。腓肠神经病理检查显示7例患者均出现轻到中度的有髓神经纤维脱失，6例出现薄髓鞘有髓神经纤维，4例出现个别小有髓神经纤维变性改变，3例伴随小有髓神经纤维的再生簇结构。1例可见血管周围少量炎细胞浸润，5例患者神经滋养动脉的血管平滑肌细胞出现脱失，2例出现增生改变，5例毛细血管基底膜肥厚。结论CADASIL周围神经病多存在亚临床的神经纤维脱失，髓鞘损害比较突出。周围神经的病理改变可能主要与组织缺血有关，不同Notch3基因突变者周围神经损害程度存在差异。     

CADASIL syndrome - cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited neurodegenerative disease associated with mutations in the Notch 3 receptor on vascular smooth muscle cells. Clinically the syndrome is manifested as migraine, recurrent subcortical ischaemic events, dementia and mood disorders. CADASIL, considered one of the important causes of "subcortical vascular dementia", is relatively easy to overlook or misdiagnose if it is not taken into consideration in differential diagnosis. Diagnosis of CADASIL is established on the basis of results of skin biopsy and genetic examination. In this article we present a short review of the literature concerning pathogenesis and clinical presentation of the syndrome and provide recommendations for detection, diagnosis and management strategies.     

Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by a cerebral non-atherosclerotic, non-amyloid angiopathy mainly affecting the small arteries penetrating the white matter. In the brain vessels of two patients with CADASIL, abnormal patches of granular osmiophilic material have recently been described. Here we report the observation of similar granular osmiophilic material within the vessel walls of muscle and skin biopsies from a 54-year-old woman belonging to a CADASIL family, who suffered from subcortical dementia with leukoencephalopathy demonstrated on neuroimaging. Postmortem examination disclosed changes of the vessel walls in all the organs chiefly leading to cerebral lesions. Ultrastructural study showed destruction of the vascular smooth muscle cells (VSMC) and the granular osmiophilic material already found in muscle and skin biopsies in this patient. Both changes were found all along the arterial tree. The findings of this study indicate that CADASIL is a systemic vascular disease involving arterial VSMC and that the lesions are different in each organ and vessel wall, depending on their fine structure. Moreover, it emphasizes that skin and muscle biopsies might be useful for diagnosis of and research into CADASIL.Presented in part at the Société Belge de Neurologie et Neuropathologie, 7 May 1994, Antwerp, Belgium and the Société Française de Neuropathologie, 27–28 May 1994, Caen, France     

Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Background and purpose: Although sudden death (SD) accounts for numerous cases of premature mortality in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the risk factors responsible for this dramatic event remain unclear. We sought possible differences in the QT variability index (QTVI) – a well‐known index of temporal dispersion in myocardial repolarization strongly associated with the risk of SD – between a group of patients with CADASIL and healthy controls. Methods: A total of 13 patients with CADASIL and 13 healthy volunteers underwent a 5‐min electrocardiogram recording to calculate the QTVI. All the patients also underwent a clinical assessment, including functional status by Rankin score, and a magnetic resonance imaging (MRI) brain scan for quantitative analysis of T2‐weighted (T2‐W) and T1‐weighted (T1‐W) lesion volume (LV). Results: Short‐term QT‐interval analysis showed significantly higher QTVI (P = 0.029) in patients than in controls. In patients, notwithstanding the limitations of the small sample size, QTVI also well correlated with T1‐W LV (r = 0.747, P = 0.003) and T2‐W LV (r = 0.731, P = 0.005). Conclusion: Because patients with CADASIL have increased temporal cardiac repolarization variability as assessed by QTVI, this mechanism could underlie these patients’ risk of SD. Whether this easily assessed, non‐invasive marker could be used to stratify the risk of malignant ventricular arrhythmias in patients with CADASIL and, possibly, to guide their therapeutic management warrants confirmation from larger prospective studies.     

Nerve conduction studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral microangiopathy linked to mutations in the Notch3 gene. The cerebral impairments of CADASIL are well-known, but peripheral nervous impairments such as polyneuropathy are less clear. Recently, peripheral neuropathy was proposed as one of the CADASIL phenotypes. We investigated peripheral nerve involvement in CADASIL patients. Forty-three CADASIL patients with confirmed Notch3 gene mutations underwent a nerve conduction studies using a conventional surface technique in 86 upper and lower extremities. Nerve conduction abnormalities were apparent in seven of the 43 patients. Of the seven patients, four displayed nerve entrapment syndromes (carpal tunnel syndrome, n = 3; ulnar neuropathy, n = 1), and three displayed sensorimotor polyneuropathy. Of the latter three, two patients had diabetes mellitus. We suggest that peripheral neuropathy may not be part of the CASASIL phenotype. However, genotype–phenotype heterogeneity can not be excluded.     

常染色体显性遗传性脑动脉病伴皮质下脑梗死和白质脑病患者的临床和MRI表现

目的探讨常染色体显性遗传性脑动脉病伴皮质下脑梗死和白质脑病(CADASIL)患者临床表现与MRI改变之间的关系。方法对一家系同代4例患者施行常规MRI和MRA检查,并对其脑部病变的信号特征、分布范围、分布规律、脑萎缩程度及相关临床表现进行分析。其中3例(先证者及其姐妹)经Notch3基因检查和皮肤组织活检明确诊断,余1例(先证者弟)经MRI和临床检查拟诊为常染色体显性遗传性脑动脉病。结果先证者经皮肤组织活检证实血管平滑肌细胞表面存在嗜锇颗粒沉积;Notch3基因突变;临床表现为渐进性记忆力减退,伴轻度偏瘫。家系中连续2代5例于43～48岁发病,均以痴呆伴轻度偏瘫为主要表现。MRI显示多发小灶性脑梗死,脑深部白质广泛稀疏和O'Sullivan征、双侧额叶和顶叶大致对称性广泛皮质下与侧脑室旁的白质病灶、脑萎缩、皮质下腔隙性脑梗死、"人字征"、基底节和脑干形态不一的陈旧性腔隙性脑梗死、"黑洞征(black holes sign)"和"胡椒壶征(pepperpot sign)"等。简易智能状态检查量表评分先证者和其姐分别为21分和23分,其妹和弟分别为22分和29分;Coulthard评分先证者和其姐分别为32分和29分,其妹和弟分别为25分和27分。结论Coulthard评分提示CADASIL伴痴呆患者的MRI改变更为广泛,但该评分难以反映疾病早期的临床表现。     

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的外周血管改变规律

目的　报道 4例伴皮层下梗死和白质脑病的常染逑孕砸糯阅远霾(CADASIL)患者的外周血管病理改变规律。方法　4例患者分别来自 4个不同的CADASIL家族,其发病年龄分别在 41、38、44和 39岁,病程在 8个月至 3年不等,均以发作性头晕、轻度偏瘫和痴呆为主要表现。基因检查证实Notch3基因存在突变。4例患者均做腓肠神经活检, 6例同龄的非CADASIL患者作为对照,观察血管的结构改变。结果　4例患者的外周小动脉血管表现: (1)血管各层结构大致正常(例 1和 4); (2)血管中层萎缩性改变(例 3),小动脉壁平滑肌细胞萎缩和脱失伴随血管内膜肥厚,个别血管周围少量炎细胞浸润,毛细血管基底膜以及小直径微小动脉外膜出现肥厚;(3)血管中层增生性改变(例 2),不同直径小动脉中层平滑肌细胞肥大变圆和细胞数增多,伴大直径微小动脉的内膜肥厚以及小直径微小动脉的外膜肥厚。静脉结构光镜下均正常。电镜下颗粒嗜锇性物质主要出现在小动脉平滑肌细胞表面,偶尔累及毛细血管周细胞和小静脉平滑肌。6例对照中仅 2例出现轻度的内膜肥厚。结论　CADASIL主要累及小动脉壁中层平滑肌细胞,提示此病为小动脉肌病,任何部位的组织活检实质上是在检查微小动脉。不同患者外周微小动脉的病理改变存在不同的差别,这些改变和临床表现以及Notch     

伴皮质下梗死及白质脑病常染色体显性遗传性脑动脉病的NOTCH3基因诊断

目的 分析伴皮质下梗死及白质脑病常染色体显性遗传性脑动脉病((CADASIL)的NOTCH3基因突变类型.方法 对临床诊断为CADASIL的4例先证者、来自3个家系10例患者及4例无类似临床表现成员、以及100名健康对照者进行NOTCH3基因PCR扩增及变性高压液相色谱分析(DHPLC)检测;对DHPLC阳性结果进行DNA双向测序,明确致病性突变或多态类型.结果 在CADASIL先证者及其家系患者中共发现134半胱氨酸→酪氨酸(Cys134Tyr)、141精氨酸→半胱氨酸(Arg141Cys)、90精氨酸→半胱氨酸(Arg90Cys)3种突变类型,存在于第3、第4外显子,为杂合错义突变.同时发现15种多态类型.其中家系1和家系2中分别发现1名成员与先证者存在相同位点的NOTCH3基因致病性突变,尚未出现与先证者相应的临床表现,被确定为临床前期患者.结论 NOTCH3单基因突变是CADASIL的分子遗传学基础,第3、4外显子可能是中国CADASIL家系的热点突变区.第4外显子Cys134Tyr突变类型为国内首次报告.     

皮肤活检对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诊断价值探讨

目的研究皮肤活检在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)中的诊断价值。方法 12例患者分别来自4个不同的CADASIL家族,均以发作性头晕、头痛、卒中和痴呆为主要表现。基因检查证实均存在Notch3基因突变。12例患者均做皮肤活检,16例同龄的非CADASIL患者作为对照,评估超微结构GOM沉积方法和Notch3N-末端多克隆抗体免疫组化方法的敏感性和特异性。结果 12例患者超微结构GOM沉积的敏感性为58.3%,特异性为93.8%;而用Notch3N-末端多克隆抗体的免疫组化方法的敏感性66.6%,特异性96.9%;将两种方法结合其敏感性为91.7%,特异性为95.4%。结论将皮肤活检中超微结构GOM检查和Notch3N-末端多克隆抗体的免疫组化方法结合起来能有效提高CADASIL确诊率,可运用于CADASIL的诊断。     

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]     

常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病的临床特征及其与头颅磁共振改变的关系

目的 总结常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病(CADASIL)的眼底动脉改变规律,探讨其与临床表现以及头颅MRI改变的关系.方法 7个家系的16例患者(男4例,女12例)经过我院病理和基因检查证实为CADASIL,平均年龄(43.4±8.1)岁,平均病程(4.7±3.4)年.对所有患者进行简易精神状态量表(MMSE)评分、改良Rankin评分、眼底动脉检查和头颅MRI检查,把眼底动脉狭窄程度分为0～Ⅲ级,对头颅MRI改变进行Coulthard评分.计算患者眼底动脉狭窄分级与头颅MRI评分、MMSE、改良Rankin评分以及年龄的相关系数.选择16名健康人(在性别、年龄、视力等方面匹配)作为对照进行眼底血管检查.结果 16例患者中15例出现眼底动脉狭窄,其中4例存在轻度动脉-静脉交叉压迫.出现0级、Ⅰ级、Ⅱ级和Ⅲ级眼底动脉狭窄的患者分别为1例、4例、7例和4例,相应头颅MRI的Coulthard评分平均分按眼底动脉狭窄程度从0到Ⅲ级分别为6.0、19.0、25.1和29.8分.眼底动脉狭窄分级和头颅MRI的Coulthard评分、MMSE、改良Rankin评分、年龄的相关系数分别为0.743(P＜0.001)、-0.429(P＜0.05)、0.437(P＞0.05)和0.299(P＞0.05).对照组有2例出现Ⅰ级眼底动脉狭窄.结论 眼底动脉狭窄是CADASIL常见的视网膜改变;眼底动脉狭窄和头颅MRI改变以及痴呆可能有一定的统计学相关性.     

A kindred affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

We report a 2-year prospective neuropsychological study of five asymptomatic subjects with magnetic resonance imaging (MRI) abnormalities from an Italian kindred affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These subjects completed tests for attention capacities, processing speed, abstract thinking, short-term memory, learning and constructional praxis. Seven normal subjects matched for age and education, belonging to the same pedigree and not having MRI hyperintensities were examined as controls. The results did not show significant differences between asymptomatic subjects and normal controls. Cognitive performance of asymptomatic subjects did not deteriorate during a 2-year follow-up. Our findings suggest that, at this stage of the disease process, the presence of diffuse leukoencephalopathy does not imply subtle cognitive defects. Received: 1 April 1997 Received in revised form: 10 November 1997 Accepted: 18 November 1997     

伴有皮质下梗死和白质病变的常染色体隐性遗传性脑动脉病一家系

目的报道中国第一个伴有皮质下梗死和白质病变的常染色体隐性遗传性脑动脉病（CARASIL）家系，探讨其临床病理特征。方法对2例患者的临床、影像及病理特征进行分析，并对第19号染色体Notch3的2～6外显子全段测序。结果2例患者系同胞姐弟，父母系近亲结婚，发病年龄分别为25、20岁，临床均表现为秃顶、急性腰痛、进行性认知功能障碍、共济失调、假性延髓性麻痹及锥体束征，头颅MRI均表现为大脑半球弥漫性白质病变，伴皮质下多发梗死灶。例1腓肠神经活体组织检查可见小动脉内弹力层轻度分裂、中层肥厚、血管腔呈向心性狭窄，PAS染色未见颗粒状沉积物，淀粉染色阴性，电镜下在小动脉平滑肌细胞层没有发现嗜锇颗粒。对第19号染色体Notch3的2～6外显子全段测序未观察到突变。结论2例病例的临床病理改变符合Fukutake总结的CARASIL的诊断标准。     

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

The clinicopathologic features of two Japanese sisters with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) are described. Neither patient had a history of hypertension, and both experienced cerebrovascular events before reaching their forties. Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs. MRI showed extensive cerebral white matter lesions, which revealed remarkable arteriosclerotic changes on autopsy.