Department of Experimental and Clinical Medicine, Section of Anatomy, School of Medicine, Università Politecnica delle Marche, Ancona, Italy.
PLoS One. 2013 Jun 17;8(6):e65482. doi: 10.1371/journal.pone.0065482. Print 2013.
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.
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.
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.
伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是由 NOTCH3 基因突变引起的，导致血管平滑肌细胞（VSMC）变性。电镜（EM）的特征性表现是在 VSMC 的凹陷处和/或靠近 VSMC 的细胞外空间中检测到颗粒状嗜锇物质（GOM）。关于 EM 在检测 CADASIL 患者活检中 GOM 的敏感性的报告存在争议。我们报告了 32 例临床疑似 CADASIL 患者的数据，并在这项回顾性研究中讨论了 EM 在其诊断中的作用。
通过 EM 检查皮肤、骨骼肌、肾脏和心包活检；筛选 NOTCH3 基因突变。12 例无神经症状的皮肤和肌肉活检患者作为对照。
所有 GOM 阳性患者均存在 NOTCH3 突变，反之亦然。本研究：i）证实 EM 对 CADASIL 的诊断具有高度特异性和敏感性；ii）扩展了我们对 GOM 在从未描述过的组织（如心包）中的分布的认识；iii）记录了外显子 3 中的一个新的 NOTCH3 突变；iv）表明 EM 分析对于突出全面 NOTCH3 分析的必要性至关重要。我们的发现还证实了意大利小部分人群中 CADASIL 的遗传异质性，并强调了为分子诊断设计算法的困难。
