BACKGROUND AND PURPOSE: Cerebral 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.
METHODS: Skin, 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 DISCUSSION: All 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.