Brain Advance Access published online on January 27, 2009
Brain, doi:10.1093/brain/awn364
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Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients
1 Protein Chemistry Unit, Institute of Biomedicine/Anatomy, University of Helsinki, Finland 2 Department of Pathology, University of Helsinki, Helsinki, Finland 3 Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland 4 Institute of Emerging Diseases and Innovative Therapies, CEA, Fontenay-aux-Roses, France 5 Department of Medicine, University of Helsinki, Helsinki, Finland 6 Minerva Medical Research Institute, Helsinki, Finland 7 Department of Medical Genetics, University of Helsinki, Finland 8 Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland 9 INSERM, U740, Paris, F-75010, France 10 7-Denis Diderot, Faculté de Médecine, Site Lariboisière, Université Paris, Paris F-75010, France 11 Department of Geriatrics, Turku City Hospital and University of Turku, Turku, Finland 12 Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden 13 Departments of Pathology and Forensic Medicine, University of Turku, Turku, Finland 14 Department of Genetics and Pathology, University of Uppsala, Uppsala, Sweden
Correspondence to:
Hannu Kalimo, Department of Pathology, University of Helsinki, PO Box 21, FI-00014 Helsingin yliopisto, Finland E-mail: hannu.kalimo{at}helsinki.fi
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by mutations in NOTCH3 gene, which encodes a large transmembrane receptor Notch3. The key pathological finding is the accumulation of granular osmiophilic material (GOM), which contains extracellular domains of Notch3, on degenerating vascular smooth muscle cells (VSMCs). GOM has been considered specifically diagnostic for CADASIL, but the reports on the sensitivity of detecting GOM in patients’ skin biopsy have been contradictory. To solve this contradiction, we performed a retrospective investigation of 131 Finnish, Swedish and French CADASIL patients, who had been adequately examined for both NOTCH3 mutation and presence of GOM. The patients were examined according to the diagnostic practice in each country. NOTCH3 mutations were assessed by restriction enzyme analysis of specific mutations or by sequence analysis. Presence of GOM was examined by electron microscopy (EM) in skin biopsies. Biopsies of 26 mutation-negative relatives from CADASIL families served as the controls. GOM was detected in all 131 mutation positive patients. Altogether our patients had 34 different pathogenic mutations which included three novel point mutations (p.Cys67Ser, p.Cys251Tyr and p.Tyr1069Cys) and a novel duplication (p.Glu434_Leu436dup). The detection of GOM by EM in skin biopsies was a highly reliable diagnostic method: in this cohort the congruence between NOTCH3 mutations and presence of GOM was 100%. However, due to the retrospective nature of this study, exact figure for sensitivity cannot be determined, but it would require a prospective study to exclude possible selection bias. The identification of a pathogenic NOTCH3 mutation is an indisputable evidence for CADASIL, but demonstration of GOM provides a cost-effective guide for estimating how far one should proceed with the extensive search for a new or an uncommon mutations among the presently known over 170 different NOTCH3 gene defects. The diagnostic skin biopsy should include the border zone between deep dermis and upper subcutis, where small arterial vessels of correct size are located. Detection of GOM requires technically adequate biopsies and distinction of true GOM from fallacious deposits. If GOM is not found in the first vessel or biopsy, other vessels or additional biopsies should be examined.
Key Words: CADASIL; GOM; skin biopsy; NOTCH3; genetic testing
Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; EGF, epidermal growth factor; EM, electron microscopy; GOM, granular osmiophilic material; VSMC, vascular smooth muscle cells
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Received July 2, 2008. Revised November 24, 2008. Accepted December 12, 2008.
*These authors contributed equally to this work.