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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a neurovascular disease caused by mutations of the notch3 gene, manifesting with strokes or stroke-like episodes, psychiatric symptoms, migraine and dementia. The diagnosis can be confirmed by screening exons of this gene. Involvement of the anterior temporal lobe and external capsule on MRI and presence of granular osmiophilic material on skin biopsy may help in diagnosis. We present two Norwegian families with eight members who have symptoms indicating CADASIL. The mutation R182C was demonstrated in exon 4 in seven; one refused gene testing. Two brothers without symptoms also tested positively for this gene mutation.
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PMID:[Hereditary cerebral arteriopathy]. 1461 73

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is commonly overlooked or misdiagnosed owing to its recent identification. It is characterized clinically by recurrent cerebral infarcts, usually appearing between the ages of 30 and 50 years, subcortical dementia, and pseudobulbar palsy. It begins with migraine with aura in approximately one-third of patients. The pathological hallmark of angiopathy is the presence of characteristic granular osmiophilic material (GOM) within the basal lamina of smooth muscle cells. The defective gene in CADASIL is Notch3, which encodes a large transmembrane receptor, and 70% of missense mutations are in exons 3 and 4. Each gene defect leads to either a gain or loss of a cysteine residue in the extracellular N-terminal domain of the molecule. We report the case of a 53-year-old woman admitted to the hospital for transient ischemic attack and stroke-like episodes recurrent since age 43 years. The patient had pseudobulbar palsy, pyramidal signs, and cognitive impairment but not frank dementia. Cerebral MRI showed periventricular diffuse and confluent ischemic lesions. Ultrastructural study revealed an abnormal deposition of granular osmiophilic material (GOM) within the basal lamina in skin capillaries. Direct sequence analysis of the Notch3 gene was performed. Since no mutation was detected in exons 3 and 4, the remaining exons were sequenced and a missense mutation, CGC-TGC in codon 1006 of exon 19 was found. The mutation led to a gain of a cysteine residue. This is the first missense mutation in codon 1006 of exon 19 of the Notch3 gene to be described in Italy and the second reported in the literature.
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PMID:An Italian case of CADASIL with mutation CGC-TCG in codon 1006, exon 19 Notch3 gene. 1476 86

We report a 64-year-old Japanese woman with recurrent ischemic strokes and progressive dementia without any cardiovascular risk factors. Her first stroke was at 45 years old, and she has a family history of ischemic strokes compatible with an autosomal dominant trait. Marked leukoaraiosis and multiple lacunar infarcts were shown on brain MR images, and no atherosclerotic changes were observed in her extra- and intra-cranial arteries by cervical arterial echography and intracranial MR angiography. Excluded other inherited or metabolic diseases causing leukodystrophy by examination of her blood samples, her disease was diagnosed as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy). We demonstrated granular osmiophilic materials (GOM) on the wall of small arteries from a biopsied peripheral nerve tissue specimen and detected a mutation Arg169Cys of Notch 3 gene. Many CADASIL patients have been reported and over 28 kinds of mutations of the Notch 3 were identified in western countries, while few CADASIL patients have been reported in Japanese people. Among them, eleven CADASIL families have been reported and only five mutations (Arg133Cys, Cys174Phe, Arg213Lys, Arg90Cys and Arg141Cys) have been determined so far. The mutation of Notch 3 in our patient was determined as Arg169Cys, and this is the first report on a Japanese patient with CADASIL due to this mutation.
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PMID:[A case of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy) with Notch 3 (Arg169Cys) mutation and typical granular osmiophilic materials in peripheral small arteries]. 1528 9

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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PMID:The pathogenesis of CADASIL: an update. 1553 16

Mutations in the NOTCH3 gene trigger adult-onset stroke and vascular dementia in patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). All CADASIL mutations described to date affect the epidermal growth factor-like (EGF-like) repeats located in the extracellular domain of the Notch3 receptor. These domains are also the target of sequential complex O-linked glycosylation mediated by protein O-fucosyltransferase 1 and Fringe. We investigated whether O-fucosylation or Fringe-mediated elongation of O-fucose on Notch3 is impaired by CADASIL mutations. Biochemical studies of a Notch3 fragment containing the first five EGF-like repeats of Notch3, including the mutational hot spot, showed that CADASIL mutations do not affect the addition of O-fucose but do impair carbohydrate chain elongation by Fringe. CADASIL changes also induced aberrant homodimerization of mutant Notch3 fragments and heterodimerization of mutant Notch3 with Lunatic Fringe itself. Together, these data suggest that Fringe plays a role in CADASIL pathophysiology.
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PMID:CADASIL mutations impair Notch3 glycosylation by Fringe. 1585 53

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an important cause of hereditary stroke. Mutations in the Notch3 gene are clearly causally linked to this progressive vascular disorder. Cerebral ischemic attacks, cognitive decline, strokes, and vascular dementia constitute the major manifestations of this disorder. This report details the prenatal detection of a Notch3 mutation in the fetus of a couple where the father had a known mutation in this gene. This is the first report of a prenatal diagnosis of CADASIL, and another example of a serious, highly penetrant, and relentlessly progressive degenerative genetic disorder presenting decades after birth and for which prenatal diagnosis is an option.
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PMID:The prenatal diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by mutation analysis. 1630 68

Mutations in Notch3 gene are responsible for the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). It is a late onset neurological disorder recognized by recurrent strokes and dementia. We describe here the clinical and molecular findings of three unrelated Turkish families with CADASIL syndrome. Two of the families were identified to have the same mutation, p.R110C (c.C328T), located in exon 3 of the Notch3 gene. Interestingly, the phenotypic expression of the disease in these two families was markedly different in severity and age of onset implicating additional genetic and/or non-genetic modulating factors involved in the pathogenesis. In addition, we identified the novel p.C201R (c.T601C) mutation in exon 4 of the Notch3 gene in a proband of the third family with two consecutive stroke-like episodes and typical MRI findings. Mutations described here cause an odd number of cysteines in the N-terminal of the EGF domain of Notch3 protein, which seems to have an important functional effect in the pathophysiology of CADASIL. The phenotypic variability in families carrying the same molecular defect as presented here makes the prediction of prognosis inconceivable. Although DNA analysis is effective and valuable in diagnosing approximately 90% of the CADASIL patients, lack of genotype-phenotype correlation and prognostic parameters makes the presymptomatic genetic counseling very difficult.
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PMID:The R110C mutation in Notch3 causes variable clinical features in two Turkish families with CADASIL syndrome. 1673 Jul 48

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common hereditary forms of stroke, and migraine with aura, mood disorders, or dementia, are also frequently found in these patients. Missense mutations in the Notch3 gene that create or destroy cysteine residues, have been found in most cases with a family history of the disease, although a few sporadic cases harbouring Notch3 mutations have also been described. Here, we describe a 44-year-old patient with clinical features of CADASIL who was a carrier of a new Notch3 mutation: cys128-->gly. Both parents were alive and healthy, and negative for the mutation. This case illustrates the interest of analysing the Notch3 gene in cases with clinical features of CADASIL, even in the absence of a family history of the disease.
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PMID:A new de novo Notch3 mutation causing CADASIL. 1679 87

Stroke can be viewed as a paradigm for late-onset, complex polygenic diseases. There are two main clinical phenotypes for stroke: ischemic stroke, responsible for 80-90% of stroke events, and hemorrhagic stroke, responsible for the remaining 10-20%. Stroke may either be the outcome of a number of monogenic disorders or, more commonly, a polygenic multifactorial disease. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the Notch 3 gene, is the best example of monogenic pathology leading to stroke. The identification of individual causative mutations for polygenic stroke is problematic due to the complexity of such condition. The two main methods of genetic investigation are linkage analyses and association studies, each with advantages and limitations. Associations with polymorphisms in a variety of candidate genes have been investigated, including hemostatic genes, genes controlling homocystein metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The combination of linkage and association approaches has led to the identification of the first putative gene associated with common polygenic stroke, PDE4D, mapped to chromosome 5q21. The biological revolution of the past years, spurred by the Human Genome Project, promises the advent of novel technologies supported by bioinformatics, which will transform the study of polygenic disorders such as stroke. Understanding the causes of stroke and its effect will allow definition of high-risk populations and make possible specific programs of primary and secondary prevention as well as new therapeutic approaches where prevention has failed.
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PMID:Research actuality in the genetics of stroke. 1683 24

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migrane, recurrent stroke, subcortical dementia, and pseudobulbar palsy. It begins with migraine with aura in -33% of patients. CADASIL is commonly overlooked or misdiagnosed owing to its recent identification. The pathological hallmark of angiopathy is the presence of multiple, small, deep cerebral infarcts, leucoencephalopathy, and nonatherorosclerotic, nonamyloid angiopathy involving mainly small, deep perforating cerebral arteries. Changes also are present in vascular smooth muscle cells and consist in the presence of granular osmiophilic material (GOM). The defective gene in CADASIL is Notch 3, which encodes a large transmembrane receptor. Magnetic resonance imaging shows high intensity signal lesions, often confluent, and areas of cystic degeneration of subcortical white matter and basal ganglia. Diagnostic strategies in CADASIL are matter of discussions because the electron microscopic demonstration of GOM was reported in 100% of symptomatic patients of French authors, but only in 45% of a British study. GOMs are not present in presymptomatic patients.
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PMID:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 1683 34


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