From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada.
Neurology. 2019 Jan 1;92(1):34-42. doi: 10.1212/WNL.0000000000006686.
Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic arteriovenous malformations (AVMs), including within the brain. However, there have recently been a number of reports correlating HHT with malformations of cortical development, of which polymicrogyria is the most common type. Here we present 7 new cases demonstrating polymicrogyria in HHT, 6 of which demonstrate a brain AVM (bAVM) in close spatial proximity, with the aim of providing a common origin for the association. Upon reviewing patient genetics and imaging data and comparing with previously reported findings, we form 2 new conclusions: (1) polymicrogyria in HHT appears exclusively associated with a subset of mutations in the transmembrane protein endoglin that is involved with blood flow-related mechanotransduction signaling during angiogenesis and (2) the polymicrogyria is characteristically unilateral, typically focal, and correlates with vascular regions experiencing low fluid shear stress during corticogenesis in utero. Integrating these with findings in the literature from genetics and molecular biology experiments, we propose a theory suggesting haploinsufficient endoglin mutations, especially those that are dominant-negative, may predispose focal, aberrant hypersprouting angiogenesis during corticogenesis that leads to the production of polymicrogyria. This hypoxic insult may further serve as the revealing trigger for later development of a spatially coincident bAVM. This hypothesis suggests an essential role for endoglin-mediated hemodynamic mechanotransduction in normal corticogenesis.
遗传性出血性毛细血管扩张症（HHT）通常被认为是一种内皮功能障碍的疾病，其特征是多种全身动静脉畸形（AVMs）的发展，包括在大脑内。然而，最近有许多报道将 HHT 与皮质发育畸形相关联，其中多微小脑回是最常见的类型。在这里，我们报告了 7 例新的 HHT 伴多微小脑回病例，其中 6 例显示脑 AVM（bAVM）在空间上接近，目的是为这种相关性提供一个共同的起源。在回顾患者的遗传学和影像学数据并与先前报道的发现进行比较后，我们得出了 2 个新的结论：（1）HHT 中的多微小脑回仅与跨膜蛋白内皮糖蛋白的一组突变相关，该蛋白涉及血管生成过程中的血流相关机械转导信号；（2）多微小脑回表现为单侧性、局灶性，与子宫内皮质发生过程中经历低流体切应力的血管区域相关。将这些与遗传学和分子生物学实验中的文献发现相结合，我们提出了一个理论，即功能不全的内皮糖蛋白突变，特别是显性负性突变，可能导致皮质发生过程中局灶性、异常的过度发芽血管生成，从而导致多微小脑回的产生。这种缺氧损伤可能进一步作为随后空间上一致的 bAVM 发展的揭示触发因素。该假说表明内皮糖蛋白介导的血流机械转导在正常皮质发生中起关键作用。
