CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material

Abstract

IntroductionCerebral 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.MethodsSkin, 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.ResultsIn 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.ConclusionsThis 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.

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

“…Electron microscopy analysis on skin, skeletal muscle, kidney, and pericardial samples of CADASIL patients identified GOMs not only around VSMCs and pericytes of the brain, but also in the above-mentioned tissues, supporting the idea that CADASIL is a systemic disease and not only a disorder confined to the CNS (Lewandowska et al, 2010;Morroni et al, 2013). Moreover, Lorenzi et al found that several GOM deposits were surrounded by an electron-lucent halo, probably made of more densely packed extracellular matrix around the GOM which interferes with ubiquination and transendocytosis of mutant NOTCH3, preventing GOM clearance and promoting protein accumulation (Lorenzi et al, 2017). Therefore, the halo around GOMs may represent the morphological evidence of aberrant NOTCH3 processing, and could be considered as an ultrastructural marker for CADASIL (Lorenzi et al, 2017).…”

“…Moreover, Lorenzi et al found that several GOM deposits were surrounded by an electron-lucent halo, probably made of more densely packed extracellular matrix around the GOM which interferes with ubiquination and transendocytosis of mutant NOTCH3, preventing GOM clearance and promoting protein accumulation (Lorenzi et al, 2017). Therefore, the halo around GOMs may represent the morphological evidence of aberrant NOTCH3 processing, and could be considered as an ultrastructural marker for CADASIL (Lorenzi et al, 2017). However, GOM formation and development over time and their role in disease progression remain largely unknown.…”

CADASIL, Migraine and Multiple Sclerosis (MS) – the Risk of Misdiagnosis, Case Report

“…Thus, patient with sister were directed to Institute Psychiatry and Neurology in Warsaw to perform myo-cutaneous biopsy. In this test presence of granular osmophilicmaterial (GOM) was confirmed in patient and her sister [3]…”

Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

“…GLUT1 is the major glucose transporter in ECs, and its expression level is decreased in CADASIL as shown in brain biopsy studies ( Giwa et al, 2012 ; Craggs et al, 2013 ; Craggs et al, 2015 ). Since GLUTs are expressed in VSMC of systemic organs, and there are few studies that indicate that the VSMC of other organs are bear GOM deposits in CADASIL subjects ( Lorenzi et al, 2017 ) and that endothelium-dependent vasodilation is impaired in forearm resistance arteries ( Stenborg et al, 2007 ) it is not unlikely that GLUT4 and -2 are affected in other organs of CADASIL patients. We were not able to analyze GLUTs in other organs VSMC due the unavailability of systemic tissues.…”