title: Skin and sural nerve biopsies: ultrastructural findings in the first genetically confirmed cases of CADASIL in Serbia.
abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular disorder caused by Notch3 gene mutations. The main histopathological hallmark is granular osmiophilic material (GOM) deposited in the close vicinity of vascular smooth muscle cells (VSMCs). The authors report the first 7 ultrastructurally and genetically confirmed cases of CADASIL in Serbia. Samples of skin and sural nerve were investigated by transmission electron microscopy. GOM deposits were observed around degenerated VSMCs in all the skin biopsies examined. Sural nerve biopsies revealed severe alterations of nerve fibers, endoneurial blood vessels with GOM deposits, endoneurial fibroblasts, and perineurial myofibroblasts. Total genomic DNA was extracted from peripheral blood leukocytes, and exons 2-6 of the Notch3 gene were amplified by PCR and subsequently sequenced. Four different mutations in exons 2 (Cys65Tyr), 3 (Gly89Cys and Arg90Cys), and 6 (Ala319Cys), which determine the CADASIL disease, were detected among all described patients. A novel missense mutation Gly89Cys involving exon 3 was detected. Due to the difficulties in the determination of the Notch3 mutations, these data suggest that electron microscopic analysis for GOMs in dermal vessel wall provides a rapid and reliable screening method for this disease.
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. mvlacko@eunet.rs
authors.forename: Vesna
authors.initials: V
authors.lastname: Lackovic
authors.forename: Milos
authors.initials: M
authors.lastname: Bajcetic
authors.forename: Maja
authors.initials: M
authors.lastname: Lackovic
authors.forename: Ivana
authors.initials: I
authors.lastname: Novakovic
authors.forename: Milica
authors.initials: M
authors.lastname: Labudović Borović
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pavlovic
authors.forename: Jasna
authors.initials: J
authors.lastname: Zidverc-Trajkovic
authors.forename: Eleonora
authors.initials: E
authors.lastname: Dzolic
authors.forename: Branislav
authors.initials: B
authors.lastname: Rovcanin
authors.forename: Nadezda
authors.initials: N
authors.lastname: Sternic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kostic
mesh_terms: D001706:Biopsy; D001808:Blood Vessels / Q000648:ultrastructure*; D046589:CADASIL / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000648:ultrastructure; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D055771:Serbia; D012867:Skin / Q000098:blood supply*; D013497:Sural Nerve / Q000648:ultrastructure*
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch