Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients.
Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients.
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DOI：
10.1093/brain/awn364
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Kalimo H
中科院分区：
文献类型：
--
作者：
Tikka S;Mykkänen K;Ruchoux MM;Bergholm R;Junna M;Pöyhönen M;Yki-Järvinen H;Joutel A;Viitanen M;Baumann M;Kalimo H
伴有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）是最常见的遗传性皮质下血管性痴呆。它是由编码大型跨膜受体Notch3的NOTCH3基因突变引起的。关键的病理发现是颗粒状嗜锇物质（GOM）在退化的血管平滑肌细胞（VSMC）上积聚，其中含有Notch3的细胞外结构域。 GOM 被认为是 CADASIL 的特异性诊断药物，但有关在患者皮肤活检中检测 GOM 的敏感性的报告相互矛盾。为了解决这一矛盾，我们对 131 名芬兰、瑞典和法国 CADASIL 患者进行了回顾性调查，这些患者都经过了充分的 NOTCH3 突变和 GOM 检测。根据每个国家的诊断实践对患者进行检查。通过特定突变的限制性酶分析或序列分析来评估NOTCH3突变。通过电子显微镜（EM）在皮肤活检中检查 GOM 的存在。来自 CADASIL 家族的 26 名突变阴性亲属的活组织检查作为对照。在所有 131 名突变阳性患者中均检测到 GOM。我们的患者总共有 34 种不同的致病性突变，其中包括三种新的点突变（p.Cys67Ser、p.Cys251Tyr 和 p.Tyr1069Cys）和一种新的重复（p.Glu434_Leu436dup）。在皮肤活检中通过电镜检测 GOM 是一种高度可靠的诊断方法：在该队列中，NOTCH3 突变与 GOM 存在之间的一致性为 100%。然而，由于这项研究的回顾性，无法确定准确的敏感性数字，但需要进行前瞻性研究来排除可能的选择偏差。致病性 NOTCH3 突变的鉴定是 CADASIL 无可争议的证据，但 GOM 的演示提供了一种具有成本效益的指南，用于估计人们应该在目前已知的 170 多种不同的 NOTCH3 基因缺陷中广泛搜索新的或不常见的突变。诊断性皮肤活检应包括深层真皮和上皮下组织之间的边界区域，那里有大小正确的小动脉血管。 GOM 的检测需要技术上充分的活组织检查，并将真正的 GOM 与错误的沉积物区分开来。如果在第一个血管或活检中未发现 GOM，则应检查其他血管或额外的活检。
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by mutations in NOTCH3 gene, which encodes a large transmembrane receptor Notch3. The key pathological finding is the accumulation of granular osmiophilic material (GOM), which contains extracellular domains of Notch3, on degenerating vascular smooth muscle cells (VSMCs). GOM has been considered specifically diagnostic for CADASIL, but the reports on the sensitivity of detecting GOM in patients’ skin biopsy have been contradictory. To solve this contradiction, we performed a retrospective investigation of 131 Finnish, Swedish and French CADASIL patients, who had been adequately examined for both NOTCH3 mutation and presence of GOM. The patients were examined according to the diagnostic practice in each country. NOTCH3 mutations were assessed by restriction enzyme analysis of specific mutations or by sequence analysis. Presence of GOM was examined by electron microscopy (EM) in skin biopsies. Biopsies of 26 mutation-negative relatives from CADASIL families served as the controls. GOM was detected in all 131 mutation positive patients. Altogether our patients had 34 different pathogenic mutations which included three novel point mutations (p.Cys67Ser, p.Cys251Tyr and p.Tyr1069Cys) and a novel duplication (p.Glu434_Leu436dup). The detection of GOM by EM in skin biopsies was a highly reliable diagnostic method: in this cohort the congruence between NOTCH3 mutations and presence of GOM was 100%. However, due to the retrospective nature of this study, exact figure for sensitivity cannot be determined, but it would require a prospective study to exclude possible selection bias. The identification of a pathogenic NOTCH3 mutation is an indisputable evidence for CADASIL, but demonstration of GOM provides a cost-effective guide for estimating how far one should proceed with the extensive search for a new or an uncommon mutations among the presently known over 170 different NOTCH3 gene defects. The diagnostic skin biopsy should include the border zone between deep dermis and upper subcutis, where small arterial vessels of correct size are located. Detection of GOM requires technically adequate biopsies and distinction of true GOM from fallacious deposits. If GOM is not found in the first vessel or biopsy, other vessels or additional biopsies should be examined.
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影响因子：
--
作者：
Peters, N;Opherk, C;Dichgans, M
通讯作者：
Dichgans, M
影响因子：
4.4
作者：
Dichgans, M
通讯作者：
Dichgans, M
影响因子：
14.5
作者：
Opherk, C;Peters, N;Dichgans, M
通讯作者：
Dichgans, M
影响因子：
3.5
作者：
Ebke, M;Dichgans, M;Schwendemann, G
通讯作者：
Schwendemann, G
影响因子：
168.9
作者：
Joutel, A;Vahedi, K;TournierLasserve, E
通讯作者：
TournierLasserve, E