Role of electron microscopy in the diagnosis of cadasil syndrome: a study of 32 patients.

[cadasil]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL ) is caused by NOTCH 3 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 .Skin , skeletal muscle , kidney and pericardial biopsies were examined by EM ; the NOTCH 3 gene was screened for mutations . Skin and muscle biopsies from 12 patients without neurological symptoms served as controls .All GOM-positive patients exhibited NOTCH 3 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 NOTCH 3 mutation in exon 3 ; and iv ) shows that EM analysis is critical to highlight the need for comprehensive NOTCH 3 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 .