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.
Highlights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by mutations in the NOTCH3 gene, which maps to chromosome 19 and encodes the transmembrane receptor NOTCH3 [1,2]
This study i) confirms that electron microscopy (EM) is highly specific and sensitive for CADASIL diagnosis; ii) extends our knowledge of granular osmiophilic material (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
Even though GOM was originally described in the CNS, it is accepted that CADASIL is a systemic disease [13,14,15,16,17]; GOM has been identified in skin and muscle biopsies [4,18,19]
Summary
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by mutations in the NOTCH3 gene, which maps to chromosome 19 and encodes the transmembrane receptor NOTCH3 [1,2]. The mutations are associated with accumulation of the NOTCH3 extracellular domain in the wall of small cerebral arteries, resulting in VSMC degeneration [4,5,6]. Electron microscopy (EM) shows deposits of granular osmiophilic material (GOM) in VSMC indentations or in the extracellular space in close vicinity to VSMCs [11,12,13]. 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
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