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一家系的临床及基因研究

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 autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)患者的临床特征及基因诊断.方法 对1个CADASIL先证者及其家族的发病情况、遗传方式、临床表现、影像学特征、分子遗传学及治疗等方面进行研究.结果 患者均有记忆力减退、乏力、脑卒中样发作等特点,没有高血压、动脉硬化证据,有家族聚集性,头颅CT、MRI示多发性梗死灶、脑白质变性,临床符合CADASIL的诊断.存活者中基因测序显示NOTCH3基因第3、4外显子突变,可确诊为CADASIL.该家系4代中有3代10人呈临床或亚临床发病,符合常染色体显性遗传.结论 该家系的临床及分子遗传学特征符合CADASIL诊断.     

NOTCH基因与CADASIL的分子发生机制

CADASIL 是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 ,近年来 ,有关该病的研究主要着眼于其分子遗传学的研究 ,并已经取得巨大的进步 ,本文就其基因定位、点突变和 NOTCH基因家族在该病发病中的地位和作用进行综述。     

NOTCH基因与CADASIL的分子发生机制

CADASIL是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，近年来，有关该病的研究主要着眼于其分子遗传学的研究，并已经取得巨大的进步，本文就其基因定位、点突变和NOTCH基因家族在该病发病中的地位和作用进行踪述。     

Notch3基因突变引起遗传性脑动脉病CADASIL的研究进展

近年来研究发现Notch3基因是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(CADASIL)的首选致病基因。170多种Notch3基因突变类型显示Notch3基因的突变与CADASIL发病机制有关,但机理不明。CADASIL基因突变类型筛查显示可能存在其它类型的Notch3基因突变。对CADASIL的特点、CADASIL的Notch3基因突变类型、Notch3基因和CADASIL与认知功能障碍之间的关系等方面进行综述,以期为突变筛查、致病机理和临床治疗研究提供参考。     

CADASIL研究新进展

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)是近年来证实遗传因素参与脑血管病发病的重要进展之一.其主要临床特点为家族遗传方式起病、中年发病、逐渐进展的缺血样卒中样病程、进行性血管性痴呆、先兆症状的偏头痛发作和精神症状.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、噬锇颗粒.分子遗传学研究发现19号染色体Notch3基因突变与本病有关.     

莨菪类药物治疗结节性硬化所致癫癎发作的近期临床疗效

结节性硬化(Tuberous sclerosis,TS)是一种少见的常染色体显性遗传性疾病,临床表现以面部血管纤维瘤、智力低下、癫癎发作为主要特点,其癫癎发作多属难治性.现将我们近十年来所见15例患者的治疗情况介绍如下.     

肺泡微石症1例

目的报道1例北京协和医院诊治的肺泡微石症(PAM)病例,并总结该病的临床表现和遗传学特点。方法报道本例的临床表现、影像学表现以及SLC34A2基因扩增及测序结果分析突变类型。结果患者为35岁男性,以咳嗽、咳痰起病,逐渐气短,胸部CT、支气管肺泡灌洗液及肺病变组织病理均符合肺泡微石症病理表现,基因检测发现SLC34A2基因第8外显子纯合子突变(c.A910T)。结论肺泡微石症是一种罕见的遗传性疾病,临床表现不特异,但有着典型的影像学表现。外显子8的c.910AT(Lys304Ter)突变在亚洲人群中最为常见,可能为我们日后的基因筛查或基因治疗提供了潜在的靶点。     

急性病毒性脑炎患者癫(癎)发作症状42例分析

目的:探讨急性病毒性脑炎患者癫(癎)发作症状的临床特点、影像学、脑电图(EEG)改变及抗(癎)药物疗效.方法:回顾性分析42例急性病毒性脑炎患者癫(癎)发作症状患者的临床特点、影像学、视频脑电图(V-EEG)改变及抗(癎)药物的治疗.结果:42例急性病毒性脑炎患者癫(癎)发作症状,以部分性发作为主要发作形式,以颞叶癫(癎)症状多见,脑部磁共振(MRI)主要表现为局灶性炎性水肿、或合并出血等破坏性病灶,V-EEG以慢波改变及局灶性 (癎)样放电为主.结论:患者的临床表现、影像学、V-EEG改变对病毒性脑炎患者癫(癎)发作症状的诊断、治疗及预后评价均具有重要作用,临床需个体化选择抗(癎)药进行有效治疗.     

家族性高胆固醇血症亚型--隐性遗传性高胆固醇血症研究进展

家族性高胆固醇血症(familial hypercholesterolemia,FH;MIM 143890)是一种常染色体显性遗传性疾病,是脂质代谢疾病中最严重的一种,导致早期发生较为严重的冠心病(coronary artery disease,CAD)。FH存在一些亚型,其中常染色体隐性遗传性高胆固醇血症(autosomal recessive hypercholesterolemia,ARH;MIM 603813)纯合患者,可表现为胆固醇水平异常升高、皮肤肌腱黄色瘤和早发的冠心病,临床表现与FH极为相似。     

肾上腺-脑白质营养不良与β-半乳糖苷酶缺陷:患者与携带者

肾上腺-脑白质营养不良(ALD)为X连锁隐性遗传性疾病,常累及神经系统白质及肾上腺。本文目的是对ALD患儿及其双亲和其它ALD变型患者的溶酶体酶活性进行研究。     

CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline and dementia. CADASIL usually begins with migraine in about one third of the patients. More severe manifestations, transient ischemic attacks or recurrent strokes, appear between 30 and 50 years of age. CADASIL, however, may be diagnosed well before the first stroke on the basis of characteristic white matter hyperintensities upon magnetic resonance imaging and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries, since the arteriopathy is generalized. Gradual destruction of vascular smooth muscle cells (VSMC) leads to progressive wall thickening and fibrosis and luminal narrowing in small and medium-sized penetrating arteries. The reduced cerebral blood flow finally causes lacunar infarcts, mainly in the basal ganglia and fronto-temporal white matter, which lead to cognitive deficits and dementia of the subcortical vascular type. CADASIL is caused by single missense mutations or small deletions in Notch3 gene encoding a transmembrane receptor Notch3, of which upon ligand binding a nuclear signaling protein is generated by regulated intramembrane proteolysis. Notch signaling is essential during development, regulating cellular differentiation. In adults Notch3 is expressed only in VSMCs and it may promote cell survival by inhibiting apoptosis, but its exact function is unknown. Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of Notch3. It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL.     

Mechanisms regulating cerebral hypoperfusion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the NOTCH3 gene mutation which leads to Notch3 ectodomain deposition and extracellular matrix aggregation around the small vessels. It further causes smooth muscle cell degeneration and small vessel arteriopathy in the central nervous system. Compromised cerebral blood flow occurs in the early stage of CADASIL and is associated with white matter hyperintensity, the typical neuroimaging pathology of CADASIL. This suggests that cerebral hypoperfusion may play an important role in the pathogenesis of CADASIL. However, the mechanistic linkage between NOTCH3 mutation and cerebral hypoperfusion remains unknown. Therefore, in this mini-review, it examines the cellular and molecular mechanisms contributing to cerebral hypoperfusion in CADASIL.     

Functional Cluster Analysis of CT Perfusion Maps: A New Tool for Diagnosis of Acute Stroke?

CT perfusion imaging constitutes an important contribution to the early diagnosis of acute stroke. Cerebral blood flow (CBF), cerebral blood volume (CBV) and time-to-peak (TTP) maps are used to estimate the severity of cerebral damage after acute ischemia. We introduce functional cluster analysis as a new tool to evaluate CT perfusion in order to identify normal brain, ischemic tissue and large vessels. CBF, CBV and TTP maps represent the basis for cluster analysis applying a partitioning (k-means) and density-based (density-based spatial clustering of applications with noise, DBSCAN) paradigm. In patients with transient ischemic attack and stroke, cluster analysis identified brain areas with distinct hemodynamic properties (gray and white matter) and segmented territorial ischemia. CBF, CBV and TTP values of each detected cluster were displayed. Our preliminary results indicate that functional cluster analysis of CT perfusion maps may become a helpful tool for the interpretation of perfusion maps and provide a rapid means for the segmentation of ischemic tissue.     

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.     

CADASIL and CARASIL

CADASIL and CARASIL are hereditary small vessel diseases leading to vascular dementia. CADASIL commonly begins with migraine followed by minor strokes in mid‐adulthood. Dominantly inherited CADASIL is caused by mutations (n > 230) in NOTCH3 gene, which encodes Notch3 receptor expressed in vascular smooth muscle cells (VSMC). Notch3 extracellular domain (N3ECD) accumulates in arterial walls followed by VSMC degeneration and subsequent fibrosis and stenosis of arterioles, predominantly in cerebral white matter, where characteristic ischemic MRI changes and lacunar infarcts emerge. The likely pathogenesis of CADASIL is toxic gain of function related to mutation‐induced unpaired cysteine in N3ECD. Definite diagnosis is made by molecular genetics but is also possible by electron microscopic demonstration of pathognomonic granular osmiophilic material at VSMCs or by positive immunohistochemistry for N3ECD in dermal arteries. In rare, recessively inherited CARASIL the clinical picture and white matter changes are similar as in CADASIL, but cognitive decline begins earlier. In addition, gait disturbance, low back pain and alopecia are characteristic features. CARASIL is caused by mutations (presently n = 10) in high‐temperature requirement. A serine peptidase 1 (HTRA1) gene, which result in reduced function of HTRA1 as repressor of transforming growth factor‐β (TGF β) ‐signaling. Cerebral arteries show loss of VSMCs and marked hyalinosis, but not stenosis.     

Verbal memory impairment in subcortical ischemic vascular disease: A descriptive analysis in CADASIL

In the elderly, the high prevalence of Alzheimer's disease neuropathology presents a major challenge to the investigation of memory decline in common diseases such as small vessel disease. CADASIL represents a unique clinical model to determine the spectrum of memory impairment in subcortical ischemic vascular dementia (SIVD). One hundred and forty CADASIL patients underwent detailed clinical, neuropsychological and imaging analyses. The Free and Cued Selective Reminding Test was used as a measure of verbal memory. Forty-four out of 140 CADASIL patients (31.4%) presented with memory impairment according to this test. Eight out of 44 (18.2%) subjects with memory impairment matched the definition of the amnestic syndrome of hippocampal type. While alterations in spontaneous recall were related to the severity of subcortical ischemic lesions, the profile of memory impairment, particularly the sensitivity to cueing was found related to other factors such as hippocampal atrophy.     

Impact of MRI markers in subcortical vascular dementia: a multi-modal analysis in CADASIL

CADASIL is an arteriopathy caused by mutations of the Notch3 gene. White matter hyperintensities (WMH), lacunar lesions (LL), cerebral microhemorrhages (CM), brain atrophy and tissue microstructural changes are detected on MRI. Using an integrated multi-modal approach, we examined the relative impact of lesion burden and location of these MRI markers on cognitive impairment and disability. Multi-modal imaging was performed on 147 patients from a two-center cohort study. Volume of LL, WMH and number of CM was determined. Whole brain mean apparent diffusion coefficient (mean-ADC) and brain parenchymal fraction (BPF) were measured. In multivariate models accounting for lesion burden and location, volume of LL, mean-ADC, and BPF each had an independent influence on global cognitive function and disability. BPF explained the largest portion of the variation in cognitive and disability scores (35-38%). Brain atrophy has the strongest independent influence on clinical impairment in CADASIL when all MRI markers in the disease are considered together. The results suggest that the clinical impact of cerebral tissue loss plays a principal role in this genetic model of subcortical ischemic vascular dementia.     

血清同型半胱氨酸及其代谢相关基因MTHFR多态性与缺血性脑卒中发生及预后的关系

目的 分析血清同型半胱氨酸(HCY)水平及其代谢相关基因多态性与缺血性脑卒中发生关系,并初步评估影响缺血性脑卒中预后的危险因素,为临床的诊治及预后分析提供实验室依据,以便及时进行临床干预.方法 收集187例缺血性脑卒中患者的全血及血清样本,其中短暂性脑缺血发作(TIA)组82例、脑梗死组105例(包括可逆性神经功能障碍、进展性卒中和完全性卒中),以同期188例体检健康者作为健康对照组.全自动生化仪检测血清HCY、GLU、CHO、TG,DNA测序法检测MTHFR基因rs1801133及rs1801131位点基因型及等位基因分布频率.各组间HCY、GLU、CHO及TG比较采用单因素方差分析,MTHFR基因多态性比较使用卡方检验,采用二分类Logistic回归分析对缺血性脑卒中的预后因素进行评估.结果 脑梗死组血清HCY、GLU、CHO及TG水平均显著高于TIA组和健康对照组(P＜0.001),且脑梗死组HCY显著高于TIA组(P＜0.05);脑梗死组和TIA组MTHFR基因rs1801133位点TT基因型及T等位基因频率,rs1801131位点CC基因型及C等位基因频率显著高于健康对照组(P＜0.05),而前两组间差异无统计学意义(P＞0.05),且TT和CC基因型能显著升高各组人群的血清HCY水平(P＜0.05).多因素Logistic回归分析显示血清HCY、GLU、CHO、TG以及年龄是影响缺血性脑卒中90天预后的独立危险因素.结果 血清HCY水平与缺血性脑卒中的发生发展及预后密切相关,体内HCY代谢关键酶MTHFR基因rs1801133及rs1801133位点突变可能通过影响血清HCY水平来影响缺血性脑卒中的发生发展.     

脑动脉瘤 DSA 影像质量控制的研究进展

数字减影血管造影（DSA）是当前脑血管疾病诊断及疗效评估的“金标准”,对出血性脑卒中和缺血性脑卒中具有诊断上的高敏感度、高特异度和高准确度的优点。特别是对颅内动脉瘤进行 DSA 造影,可以明确载瘤血管,并可以多角度观察动脉瘤体的起源、形态、位置、大小、瘤颈等情况,对颅内动脉瘤后期治疗方法的选择及术后评估起着非常重要的作用。介入影像是影像学诊断和治疗的依据,高质量的脑动脉瘤介入影像则是介入手术者在术中的重要指引,介入手术者需要依靠清晰的、实时的介入影像来诊断血管疾病,以确定下一步的检查与治疗方法。因此,介入影像质量的高低与介入手术成功与否息息相关。影响脑动脉瘤介入影像质量的因素较多,而对这些因素进行深入研究的相关文献并不多,需进一步研究。该文将重点分析脑动脉瘤介入影像质量的影响因素,总结提高脑动脉瘤介入影像质量的方法,目的是在合理的 X 射线辐射范围内提升介入影像的质量,提高介入手术的成功率。