Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary condition with onset in mid-adulthood and is associated with mutations in the Notch-3 gene. (Joutel, A., Corepechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenda, V., Cecilion, M., Marechal, J., Vayssiere, C., Cruaud, C., Cabanis, E.A., Ruchoux, M.M. , Weissenvach, J., Bach, J.F., Bousser, M.G. and Tournier-Lasserve, E., Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 383 (1996) 707-710) Ultrastructural examination of the pathology of the cerebral infarcts reveals deposits in the vascular smooth muscle cells of the small arteries of the brain, but there is no obvious indication how the Notch-3 mutations give rise the observed pathology, nor is there any information on the exact nature of the deposits. We have investigated cerebrospinal fluid (CSF) from three CADASIL cases with known mutations in Notch-3 using two-dimensional gel electrophoresis. CSF from these patients was compared to that of six controls. We detected a single spot in the protein maps of patients which was absent from all the controls. In-gel tryptic digestion of this protein followed by mass spectrometric analysis of the tryptic fragments and a database search identified the spot as human complement factor B. These preliminary findings suggest that the alternative complement pathway may play a role in the pathogenesis of CADASIL.
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PMID:Detection of complement factor B in the cerebrospinal fluid of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease using two-dimensional gel electrophoresis and mass spectrometry. 1071 13

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) often begins with migraine with aura. Recurrent strokes usually appear between 30 and 50 years of age. The arteriopathy develops slowly, resulting in destruction of smooth muscle cells and thickening and fibrosis of the walls of small and medium-sized penetrating arteries with consequent narrowing of the lumen. This impairs cerebral blood flow, visible in PET, and produces characteristic white-matter hyperintensities in T2-weighted MRI on the basis of which CADASIL may be diagnosed well before the first stroke. Multiple lacunar infarcts, mainly in the frontal white matter and basal ganglia, lead to progressive permanent brain damage manifested as cognitive decline and finally as dementia. At present, no specific therapy is available. Infarcts result from thickening and fibrosis of the walls of small and medium-sized penetrating arteries with consequent obliteration and/or thrombosis. Although the symptoms are almost exclusively neurological, the arteriopathy is generalized and diagnosis can be made on the basis of accumulation of pathognomonic basophilic, PAS-positive and in electron microscopy osmiophilic material between degenerating smooth muscle cells in dermal arteries. CADASIL is caused by missense point mutations in the Notch3 gene, which encodes a transmembrane receptor protein with an important signaling function during development. The gene defects lead to either a gain or loss of a cysteine residue in the extracellular N-terminal part of the molecule, most probably causing a conformational and functional alteration. The function of Notch3 in adults and the definite pathogenesis of CADASIL are still unknown, but interestingly its intramembranous proteolytic cleavage may be regulated or implemented by presenilin similarly as cleavage of amyloid precursor protein in Alzheimer's disease.
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PMID:CADASIL: hereditary arteriopathy leading to multiple brain infarcts and dementia. 1081 16

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.
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PMID:Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. 1085 11

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited adult onset disease characterised most commonly by cerebral ischaemic events and dementia. It is caused by mutations in the Notch3 gene with most clustering in exons 3 and 4. Whether these mutations have any influence on common sporadic ischaemic stroke or dementia cases has not been investigated, partly hampered by the lack of a readily usable genetic test. An easy to use diagnostic array for CADASIL was designed using various restriction endonucleases for the known mutations in exons 3 and 4 and novel mismatch primers were designed where no such enzymes existed. This array was used to identify the allele frequencies of CADASIL mutations and polymorphisms in selected disease cohorts. Seventy patients with radiologically established sporadic ischaemic stroke and 77 patients from a specialist young dementia clinic were recruited. One hundred and seventeen age and sex matched asymptomatic controls were also identified. The diagnostic array was found to work well. None of the 14 known mutations and three previously identified polymorphisms (C474A, A587G, and C594A) in exons 3 and 4 were present in 140 stroke, 110 dementia, or 234 control chromosomes. Molecular variant C381T occurred with a higher frequency of 0.13, whereas G684A occurred with a lower frequency (0.09) than previously reported, although there were no statistical differences between selected cohorts. In conclusion, a readily usable genetic test for CADASIL has been devised that was used to determine allele frequencies in well characterised cohorts of sporadic stroke and dementia patients. The data suggest that despite the clinical resemblance, CADASIL is not a common masquerading cause of stroke or dementia. The test will enable units locally to rapidly screen patients with suspected CADASIL.
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PMID:Description of a simple test for CADASIL disease and determination of mutation frequencies in sporadic ischaemic stroke and dementia patients. 1103 21

Notch3 mutations cause CADASIL, an increasingly recognized cause of subcortical ischemic stroke and vascular dementia in human adults. In the absence of any specific diagnostic criteria, CADASIL diagnosis is based on mutational scanning of Notch3, which is a large gene composed of 33 exons with a high G-C content. In this study we examined the sensitivity of denaturing high performance liquid chromatography (DHPLC). First we established the theoretical optimal parameters, then we examined a large collection of amplicons in which we had previously identified distinct pathogenic mutations or polymorphisms. We further performed Notch3 mutational scanning in five patients suspected of CADASIL diagnosis in which previous scanning, including SSCP and heteroduplexes analysis, failed to detect any pathogenic mutation. DHPLC resolved 97% of mutations previously detected by sequencing and allowed identification of two novel pathogenic mutations: R607C and F984C. These data indicate that DHPLC is a sensitive screening method particularly suitable for epidemio-genetic screening of CADASIL.
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PMID:Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. 1110 81

CADASIL, an autosomal dominant adult onset arteriopathy causing stroke and dementia in humans, is underlaid by a non atherosclerotic non amyloid angiopathy involving mainly the media of small cerebral arteries; it is characterized by major lesions of vascular smooth muscle cells. Using a positional cloning approach, we mapped CADASIL locus on chromosome 19 and identified the mutated gene as being Notch3. This gene, previously unknown in humans, encodes for a large transmembrane receptor belonging to the Notch/lin12 gene family which are known to be involved in cell fate specification during development. Genetic analysis of more than 120 CADASIL unrelated families allowed us to show that these mutations are highly stereotyped and affect only the extra cellular domain of the protein. On the basis of these data, a molecular diagnostic test has been set up and is now widely required by clinicians involved in the diagnosis of vascular leukoencephalopathies. Using this test, we recently showed that CADASIL can also occur in patients who do not have any affected relative due to the existence of notch3 de novo mutations. As a first step to investigate the molecular and cellular mechanisms leading from Notch3 mutations to CADASIL phenotype, we analyzed by in-situ hybridization and immunohistochemistry the pattern of expression of this gene. Notch3 expression is highly restricted to the vascular smooth muscle cell in normal human adults. In CADASIL tissues there is a dramatic accumulation of the extracellular domain of the protein which suggests that one of the main mechanisms of CADASIL involves anomalies in the proteolytical cleavage and clearance of this protein. These data provide important clues to the mechanisms of this condition and current work should lead in the next future to a complete understanding of CADASIL and set up the basis of a rational therapeutical approach of this condition.
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PMID:[CADASIL: genetics and physiopathology]. 1126 Dec 57

We report a 52-year-old man with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting dementia, alopecia and lumbar herniated disk. He had an episode of stroke and migraine-like headache lasting for 5 minutes. A lot of members had cerebral infarction in this family. Brain magnetic resonance imaging demonstrated, on T2-weighted images, numerous hyperintense lesions suggestive of small infarcts in the basal ganglia and diffuse hyperintense lesions in the cerebral white matter. The clinical symptoms, the family history and the MRI findings suggested the diagnosis of CADASIL. However, the patient also showed alopecia and lumbar herniated disk, both are characteristic features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). The DNA analysis of the Notch 3 gene identified a novel missense mutation Cys174Phe in this patient. Our case report indicated the importance of the DNA analysis for the diagnosis of CADASIL.
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PMID:[Report of a patient with CADASIL having a novel missense mutation of the Notch 3 gene--association with alopecia and lumbar herniated disk]. 1148 59

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is a recently described cause of stroke or stroke-like episodes. It is caused by mutations in the Notch3 gene on chromosome 19p. We sought to demonstrate mutations of the Notch3 gene in Australian patients suspected of having CADASIL. Patients from several families were referred to the study. A diagnosis was determined clinically and by neuroimaging. Those suspected of having CADASIL had sequencing of exons 3 and 4 of the Notch3 gene. Eight patients, two of whom were siblings, were suspected of having CADASIL. Five patients (including the siblings) had mutations. Because of strong clustering of Notch3 mutations in CADASIL, this has potential as a reliable test for the disease in Australian patients.
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PMID:CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy): an Australian perspective. 1153 4

Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) was first reported in European families and since 1993 it has been observed in America, Africa and Asia, suggesting that today the disease probably still remains largely underdiagnosed. CADASIL appears to be essentially a disorder of the arteries linked to single missense mutations in the Notch3 gene locus on chromosome 19; the aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of the disorder. It is characterized by recurrent stroke episodes and focal neurologic deficits progressing to pseudobulbar palsy and dementia, caused by multiple lacunar infarctions with ischemic and diffuse white matter abnormalities on neuroimaging. Migraine with aura, epileptic seizures and affective disorders are frequent additional symptoms of CADASIL. It is usually observed in the 3rd decade, but some individuals remain asymptomatic close to the age of 60. MRI displays a marked leukoencephalopathy in affected individuals as early as in the age of 20. The authors emphasize the role of a direct DNA test for gene mutation to make a differential diagnosis between CADASIL and other forms of vascular leukoencephalopathy as Alzheimer's dementia, multiple sclerosis and Binswanger's subcortical arteriopathic encephalopathy where CADASIL's arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits.
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PMID:[Two case reports of cerebral autosomal dominant arteriophaty with subcortical infarctions and leukoencephalopathy (CADASIL)]. 1167 81

We report a 26-year-old woman who showed recurrent migrainous attacks and convulsions since her childhood. Neurological examination revealed no focal abnormality except mental retardation (MR). T2-and fluid-attenuated inversion-recovery (FLAIR)-weighted brain MRI revealed apparent high intensities in the deep subcotical white matter. Ultrastructual studies revealed an abnormal deposition of granular osmiophilic materials (GOM) on the surface of vascular smooth muscle cells in dermis. Her mother developed recurrent strokes without risk factor since age 41. A heterozygosis Arg133Cys mutation of Notch 3 gene has already presented in patient and her mother. This case might be an early stage in CADASIL before stroke onset and suggested that systemic vasculopathy was presented in this stage. The correlation between MR and phenotype of CADASIL were unclear.
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PMID:[A case of CADASIL in early stage]. 1177 Nov 60


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