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.
Highlights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic vascular disorder
An electron-lucent space had previously been described between the Granular osmiophilic material (GOM) and the cell membrane in skeletal muscle (Ruchoux et al, 1995) and skin (Ishiko et al, 2005) from CADASIL patients
Our group has identified GOM- containing pseudoinclusions in 70% of our 13 CADASIL patients (Morroni, Lorenzi, Castellucci, Ragno, & Scarpelli, 2014), where these GOM deposits were often surrounded by an electron-lucent halo
Summary
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic vascular disorder involving mainly small and middle-sized arteries of the microcirculation. It has been shown that the pathophysiology of the disorder is associated with hypomorphic NOTCH3 activity in VSMCs, consistent with loss of NOTCH3 function (Arboleda- Velasquez et al, 2011; Moccia et al, 2015) It is still debated if GOM deposits are involved in CADASIL pathogenesis or only represent an epiphenomenon in this disease (Erro et al, 2015; Moccia et al, 2015). Studies of extracellular protein aggregates similar to those seen in CADASIL have been performed by EM in amyloidosis diseases (Tosoni, Barbiano di Belgiojoso, & Nebuloni, 2011) such as Alzheimer’s (Yamaguchi et al, 2000) and Parkinson’s (Baba et al, 1998) In these cases, too, EM has provided important etiological insights. The observation of GOM in a renal glomerulus from a CADASIL patient with renal symptoms (Ragno et al, 2012) and its resemblance to the mesangial immunoglobulin deposits found in glomerulonephritis and focal segmental glomerulosclerosis (FSGS) (LaPoint, Patel, & Rubio, 2000) prompted us to compare their respective ultrastructures
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