The pathogenesis of CADASIL: and update

Institute for Ageing and Health, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, NE4 6 BE, UK.
Journal of the Neurological Sciences (Impact Factor: 2.47). 11/2004; 226(1-2):35-9. DOI: 10.1016/j.jns.2004.09.008
Source: PubMed


Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) appears to be the most common form of hereditary stroke disorder. CADASIL is associated with arterial smooth muscle degeneration linked to mutations in the Notch3 gene, whose product is a transmembrane receptor that functions in cell-cell communication. The pathogenesis of CADASIL remains unclear. Current research efforts are directed towards the elucidation of various features of the disorder including investigations on CADASIL-like disorders, early cognitive changes, specificity of neuroimaging for diagnosis, discovery of de novo mutations, the development of Notch3 transgenic mouse models and molecular cellular studies in Notch3 signaling. The genetics of cerebrovascular disorders (CVD) was virtually unknown until recently. Genetic associations may have been evaded because of widely variable phenotypes, even within monogenic disorders such as CADASIL. Several investigators have attempted genotype-phenotype correlation in CADASIL cases but the relationship between genetic alterations and overt manifestation of phenotype remains elusive. However, the elucidation of the genetics and pathogenesis of CADASIL have been important in further understanding of the primary vascular mechanisms that lead to ischemic blood flow and its consequences on neuronal survival. This report summarizes some of the highlights of the satellite symposium on CADASIL at Vas-Cog 2003.

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    • "The genetic basis of all six diseases has been well studied. CADASIL, Marfan syndrome, MOPD II, and Fabry's disease, have been associated with Notch3, FBN1, PCNT, and GALA respectively (Delaval and Doxsey 2010; Fellgiebel et al. 2006; Kalaria et al. 2004; Yuan and Jing 2010). For Moyamoya and HHT, many genes have been found to be associated in the pathogenesis. "
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    ABSTRACT: Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.
    Metabolic Brain Disease 04/2015; 30(5). DOI:10.1007/s11011-015-9668-y · 2.64 Impact Factor
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    • "In human, the congenital cardiac malformation Alagille syndrome , an autosomal dominant disorder characterized by developmental abnormalities, is caused by mutations of Notch ligand JAGGED1 [20]. Another human disease, CADASIL [21] (cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy) is related to a mutation of the Notch3 receptor [22] and affects vascular smooth muscle cell (VSMC) development. "
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    ABSTRACT: The development of the vascular system begins with the formation of hemangioblastic cells, hemangioblasts, which organize in blood islands in the yolk sac. The hemangioblasts differentiate into hematopoietic and angioblastic cells. Subsequently, the hematopoietic line will generate blood cells, whereas the angioblastic cells will give rise to vascular endothelial cells (ECs). In response to specific molecular and hemodynamic stimuli, ECs will acquire either arterial or venous identity. Recruitment towards the endothelial tubes and subsequent differentiation of pericyte and/or vascular smooth muscle cells (vSMCs) takes place and the mature vessel is formed. The Notch signaling pathway is required for determining the arterial program of both endothelial and smooth muscle cells; however, it is simultaneously involved in the generation of hematopoietic stem cells (HSCs), which will give rise to hematopoietic cells. Notch signaling also regulates the function of endothelial progenitor cells (EPCs), which are bone-marrow-derived cells able to differentiate into ECs and which could be considered the adult correlate of the angioblast. In addition, Notch signaling has been reported to control sprouting angiogenesis during blood vessels formation in the adult. In this paper we discuss the physiological role of Notch in vascular development, providing an overview on the involvement of Notch in vascular biology from hematopoietic stem cell to adaptive neovascularization in the adult.
    02/2012; 2012(6):805602. DOI:10.1155/2012/805602
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    • "One patient presented with late onset migraine with aura had an abnormal brain MRI, a feature along with family history is suggestive of this diagnosis.12 Positive brain MRI finding in asymptomatic individual indicate that NOTCH3 signaling may start up to a decade prior to clinical presentation.3 "
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    ABSTRACT: Mutations in the NOTCH3 gene are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an adult onset hereditary angiopathy leading to ischemic stroke, vascular dementia and psychiatric disorders. All mutation of NOTCH3 described so far are striking stereotyped leading to the gain or loss of cystiene residue in a given epidermal growth factor (EGF), like repeat. We report an Arabic family affected with CADASIL mutation, G1790 C, in Exon 11 of the NOTCH3 gene. This is the first novel mutation reported in Arabic CADASIL patients. This finding confirms that mutations in NOTCH3 are associated with the pathogenesis of CADASIL across different ethnic background.
    Neurology International 07/2011; 3(2):e6. DOI:10.4081/ni.2011.e6
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