Role of Electron Microscopy in the Diagnosis of Cadasil Syndrome: A Study of 32 Patients

Abstract

Background and PurposeCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 gene mutations that result in vascular smooth muscle cell (VSMC) degeneration. Its distinctive feature by electron microscopy (EM) is granular osmiophilic material (GOM) detected in VSMC indentations and/or the extracellular space close to VSMCs. Reports of the sensitivity of EM in detecting GOM in biopsies from CADASIL patients are contradictory. We present data from 32 patients clinically suspected to have CADASIL and discuss the role of EM in its diagnosis in this retrospective study.MethodsSkin, skeletal muscle, kidney and pericardial biopsies were examined by EM; the NOTCH3 gene was screened for mutations. Skin and muscle biopsies from 12 patients without neurological symptoms served as controls.Results and DiscussionAll GOM-positive patients exhibited NOTCH3 mutations and vice versa. This study i) confirms that EM is highly specific and sensitive for CADASIL diagnosis; ii) extends our knowledge of GOM distribution in tissues where it has never been described, e.g. pericardium; iii) documents a novel NOTCH3 mutation in exon 3; and iv) shows that EM analysis is critical to highlight the need for comprehensive NOTCH3 analysis. Our findings also confirm the genetic heterogeneity of CADASIL in a small Italian subpopulation and emphasize the difficulties in designing algorithms for molecular diagnosis.

CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material

“…Muscle (#1 and #3) or skin (#2) tissue were examined in three affected siblings (Table 1). These data have recently been published (Morroni et al., 2013; Ragno et al., 2012). …”

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) – literature review apropos an autopsy case

“…At the ultrastructural level, presence of pathognomonic granular osmiophilic material (GOM) deposits confirms the diagnosis with 100% specificity, even without genetic results [10,14,16,17]. Typical GOM, containing Notch3 extracellular domain, is a round granular deposit located in vascular smooth muscle cells (VSMC)/pericyte membrane infoldings.…”

What factors determine phenotype of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)? Considerations in the context of a novel pathogenic R110C mutation in the NOTCH3 gene

“…Based on our previous studies on CADASIL we have suggested that GOM deposits can be formed on the surface of VSMC/pericytes, can penetrate from the cell into the basement membrane, and then can disperse in the extracellular matrix [7]. Although qualitative or semi-quantitative changes in GOM do not correlate directly with patients' age [10], there are some data indicating a possible relationship of the deposits with progression of histopathological changes in CADASIL. GOM deposits are very early alterations whose development precedes detectable morphological changes in cerebral vessels [4] but not their dysfunction [14].…”