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      A CADASIL-Like Case with a Novel Noncysteine Mutation of the NOTCH3 Gene and Granular Deposits in the Renal Arterioles

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          Abstract

          We herein report the finding of a 62-year-old male, who developed dysarthria and dysphagia, with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy- (CADASIL-) like cerebral lesions. He also suffered from slowly progressive renal failure with the findings of granular deposits similar to electron-dense granular osmiophilic material in the renal arterioles. We found a novel heterozygous missense mutation of the NOTCH3 gene, c.4039G>C in exon 24, resulting in a p.Gly1347Arg substitution in its extracellular domain. The noncysteine substitution may underlie the pathogenesis of white matter lesions in the brain and of the chronic renal failure in the present case.

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          Regulation of vascular morphogenesis by Notch signaling.

          David Adams, Cristina Roca (2007)
          The Notch pathway is a versatile regulator of cell fate specification, growth, differentiation, and patterning processes in metazoan organisms. In the vertebrate cardiovascular system, multiple Notch family receptors and several of their Jagged and Delta-like ligands are expressed during critical stages of embryonic and postnatal development. Functional studies in mice, fish, tumor models, and cell culture systems have shown that the angiogenic growth of the blood vessel network, the proliferation of endothelial cells, and the differentiation of arteries and veins are controlled by Notch signaling. Moreover, Notch pathway components play important roles in human pathological conditions involving the vasculature, namely CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and Alagille syndrome. Recent findings highlight the Notch ligand Delta-like 4 as a key regulator of tumor angiogenesis and suggest that this protein might be a promising target for cancer therapy.
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            Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12.

            J Weissenbach, Juan Carrique-Mas, E. Tournier … (1993)
            Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been recently reported as a cause of stroke. It is characterized, in the absence of hypertension, by recurrent subcortical ischaemic strokes, starting in early or midadulthood and leading in some patients to dementia. Magnetic resonance imaging and pathological examination show numerous small subcortical infarcts and a diffuse leukoencephalopathy underlaid by a non-arteriosclerotic, non-amyloid angiopathy. We performed genetic linkage analysis in two unrelated families and assigned the disease locus to chromosome 19q12. Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19S222 loci.
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              Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies.

              Martin Dichgans, Jürgen Herzog, Nils Peters … (2005)
              Mutations in the NOTCH3 gene are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an important cause of stroke in young adults. Mutations are typically located within epidermal growth factor-like repeat domains in the extracellular part of the Notch3 receptor. Identification of the mutation is critical for genetic counseling and testing of relatives at risk. To identify the spectrum of NOTCH3 mutations in CADASIL and to discuss the implications for diagnostic strategies. Screening for NOTCH3 mutations was performed in 125 unrelated German CADASIL patients with biopsy-proven disease by direct sequencing of exons coding for epidermal growth factor-like repeats. Results were compared with those of previously published studies. We detected 54 distinct mutations (117 missense mutations and 3 in-frame deletions) in 120 (96.0%) of the 125 patients. Of the mutations, 58.3% were located in exon 4 and 85.8% in exons 2 through 6. In 5 patients (4.0%), no mutation was identified. Almost 90% of mutations could be detected within a few exons (exons 2-6). Thus, genetic testing should initially be focused on these exons, with some variation depending on the population in whom it is being performed. Yet, genetic testing for CADASIL is associated with a nameable proportion of false-negative results. Cases with a high index of clinical suspicion should be investigated by skin biopsy if genetic testing is negative.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Case Rep Neurol Med
                Journal ID (iso-abbrev): Case Rep Neurol Med
                Journal ID (publisher-id): CRINM
                Title: Case Reports in Neurological Medicine
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-6668
                ISSN (Electronic): 2090-6676
                Publication date (Print): 2015
                Publication date (Electronic): 9 March 2015
                Volume: 2015
                Electronic Location Identifier: 431461
                Affiliations
                1Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
                2Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka 814-0193, Japan
                3Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
                Author notes

                Academic Editor: Pablo Mir

                Article
                DOI: 10.1155/2015/431461
                PMC ID: 4365362
                PubMed ID: 25834748
                SO-VID: d1469c04-db29-4178-8cc3-1b8543e8696a
                Copyright © Copyright © 2015 Kuniyuki Nakamura et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 19 December 2014
                Date revision received : 28 January 2015
                Date accepted : 26 February 2015
                Categories
                Subject: Case Report

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