Shorter telomeres in patients with cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL)

CADASIL is a hereditary systemic vasculopathy which affects mainly small cerebral arteries and is caused by mutations in the Notch3 gene. Misfolding of Notch3 is linked to endoplasmic reticulum stress and increased reactive oxygen species, which may result in dysfunction of endothelial cells, inflammation and ischemia. Oxidative stress and inflammation may induce a rapid telomere shortening in peripheral blood leukocytes (PBLs). The aim of this study was to assess the telomere length in PBLs from 29 patients with a genetic diagnosis of CADASIL by using a modified quantitative real-time polymerase chain reaction based assay. PBL telomere length was significantly shorter in CADASIL patients (T/S ratio?=?0.17, 95% CI, 0.14-0.20) than in the controls (T/S ratio?=?0.31, 95% CI, 0.27-0.35, t-test p?相似文献   

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.     

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.     

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     

Clinical autosomal dominating arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a diffuse disease of small arteries, predominating in the brain. It starts during mid-adulthood and is characterized by recurrent ischaemic events (transient or permanent), attacks of migraine with aura, severe mood disorders, subcortical dementia and at MRI white periventricular leukoencephalopathy. CADASIL is an autosomal dominant disease. The gene Notch3 on which the mutation was detected is located on chromosome 19. There is so far no specific treatment and death occurs after a mean of twenty years.     

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.     

5个CADASIL家族的核磁共振改变特点

目的　分析来自5个CADASIL家族中8名患者的核磁共振(MRI)表现,总结病变不同时期的MRI变化规律及其诊断价值。方法　研究对象为经过超微病理和Notch3基因检查确诊的5个CADASIL家族中的8个患者,均在成年早期发病,主要表现为反复发作的缺血性卒中和进行性痴呆。对先证者1及其母亲、先证者2及其哥哥、姐姐,先证者3、4和5 ,总计8名患者进行了头部MRI检查,其中4名进行了MRI血管成像检查。结果　8名患者的头部MRI均显示多发腔隙性脑梗死,病灶主要分布在基底节、丘脑和脑室旁白质,6例患者出现了外囊梗死,4例出现了胼胝体梗死,3例出现了脑桥梗死。所有8例患者均存在双侧大脑半球多灶性或弥漫性白质疏松,1例患者MRI确诊1年后随访显示多灶性白质病变进展为弥漫性损害,5例患者出现了双侧颞极等T1 长T2 信号。4例患者的头部MRI血管成像检查未见异常。结论　基底节、丘脑和脑室旁白质是CADASIL腔隙性脑梗死的好发部位,外囊和胼胝体梗死以及双侧颞极长T2 信号对本病具有较高的诊断价值。脑干受累可以出现在病程早期,而白质病灶分布形式的变化可以反映病情的进展。     

Cerebrovascular reactivity and dynamic autoregulation in nondemented patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)

Abstract Reduced cerebrovascular reactivity has been reported in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and the measurement has been suggested as a useful surrogate marker of disease progression. Previous studies have not determined whether cerebral autoregulation is also impaired. We measured dynamic cerebral autoregulation and carbon dioxide reactivity in 24 nondemented CADASIL patients and 20 controls, using transcranial Doppler ultrasound (TCD). No impairment in either measure was found in the CADASIL group. We conclude that either cerebrovascular reactivity and autoregulation are not impaired in early disease, or that TCD may not be a sufficiently sensitive tool to detect haemodynamic changes in early disease. TCD is unlikely to be useful for disease monitoring in patients without advanced 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     

Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI

The aim of our work was to evaluate the early presence of white matter changes on magnetic resonance imaging (MRI) in young asymptomatic children of patients with full-blown cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in whom DNA analysis revealed a Notch3 Cys146Tyr missense mutation on chromosome 19. Brain MRI was performed in all subjects using axial and coronal spin-echo proton density and T2-weighted images, axial fluid-attenuated inversion recovery (FLAIR) and sagittal and axial T1-weighted images. In asymptomatic subjects with Notch3 gene mutation, MRI showed small T2 hyperintense foci in periventricular and subcortical white matter. Routine use of MRI in the initial phases of a CADASIL diagnostic work up and the subsequent recognition of early abnormal findings in asymptomatic subjects may lead to prompt diagnosis of the disease in these patients. Moreover, these findings suggest that genetic screening is warranted in the presence of a suspect clinical history with specific MRI abnormalities.     

Dominant autosomal cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A review

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial condition caused by a mutation of the Notch3 gen in chromosome 19. Accumulation of osmiophilic granular material (GOM) on the middle layer of small and medium-sized cerebral arteries leads to progressive narrowing of the blood vessels. As a result, clinical findings include migraine, cerebrovascular ischemic events, vascular dementia and a number of neuropsychiatric disorders associated to an extensive leukoencephalopathy readily shown by MRI studies. GOM deposits, however, are systemic and maybe shown ultrastructuraly on skin vessels by means of a biopsy. Detection of mutations of the Notch3 gen by molecular genetics may also allow accurate diagnosis during life. So far, there is no effective treatment for this disorder.     

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。     

Acute vestibular syndrome in a patient with cerebral autosomal dominant leukoencephalopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary form of small vessel disease in which the pons may show lacunar infarcts and leukoaraiosis. Acute pure vestibular syndrome may be due to caudal pontine lesions and is probably underestimated. We describe a case of CADASIL with acute vestibular syndrome mimicking peripheral vestibulopathy, and evidence of focal infarction in the ponto-medullary junction at gadolinium-enhanced MRI including diffusion-weighted imaging, involving the area of the right vestibular nucleus and root entry zone of the ipsilateral vestibular nerve bundle. In CADASIL, both focal brainstem lesions and leukoaraiosis may parallel supratentorial white matter changes and may be related to poor outcome. Their actual extent should be evaluated in longitudinal studies that might predict clinical outcome and progression of disability.