title: CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material.
abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic vascular disorder. Granular osmiophilic material (GOM) is its ultrastructural marker. We reviewed tissue biopsies from CADASIL patients to establish whether ultrastructural observations help clarify the pathogenic mechanism of CADASIL. Given the resemblance of the GOM deposits to the immunoglobulin deposits seen in glomerulonephritis and focal segmental glomerulosclerosis (FSGS), their morphologies were investigated and compared.
  
  
  
  Skin, skeletal muscle, kidney, and pericardium tissue biopsies from 13 patients with a clinical and molecular diagnosis of CADASIL, and kidney biopsies from five patients with IgA nephropathy and five patients with primary FSGS were subjected to ultrastructural examination.
  
  
  
  In CADASIL patients, several GOM deposits from all sites were partially or totally surrounded by an electron-lucent halo. The deposits frequently had a more electron-dense portion with a regular outline on the inner side and a less osmiophilic, looser outer side displaying a less regular profile. The uniformly dense deposits tended to be more osmiophilic if located close to the cell membrane and less osmiophilic if laid farther away from it. The immunoglobulin deposits from the glomerulonephritis and FSGS patients lacked both the granular pattern and the halo.
  
  
  
  This study demonstrates that GOM deposits may have a nonuniform morphology and describes in detail an electron-lucent halo surrounding several of them. It is conceivable that the halo is the morphological evidence and possibly the cause of an aberrant NOTCH3 processing, already suspected to be involved in CADASIL.
authors.affiliation: Section of Neuroscience and Cell Biology Department of Experimental and Clinical Medicine School of Medicine Università Politecnica delle Marche Ancona Italy.
authors.forename: Teresa
authors.identifier: 0000-0002-3723-5378
authors.initials: T
authors.lastname: Lorenzi
authors.affiliation: Division of Neurology Madonna del Soccorso Hospital San Benedetto del Tronto Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ragno
authors.affiliation: Section of Neuroscience and Cell Biology Department of Experimental and Clinical Medicine School of Medicine Università Politecnica delle Marche Ancona Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Paolinelli
authors.affiliation: Division of Pathology Department of Clinical and Molecular Sciences School of Medicine Università Politecnica delle Marche Ancona Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Castellucci
authors.affiliation: Section of Pathological Anatomy Department of Biomedical Sciences and Public Health School of Medicine Università Politecnica delle Marche United Hospitals Ancona Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Scarpelli
authors.affiliation: Section of Neuroscience and Cell Biology Department of Experimental and Clinical Medicine School of Medicine Università Politecnica delle Marche Ancona Italy; Electron Microscopy Unit United Hospitals Ancona Italy.
authors.forename: Manrico
authors.initials: M
authors.lastname: Morroni
mesh_terms: D001706:Biopsy; D046589:CADASIL / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005922:Glomerulonephritis, IGA / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged
keywords: CADASIL; electron‐lucent halo; granular osmiophilic material deposits; mixed GOM; transmission electron microscopy