PDF(Pubmed)
Abstract：
Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen species production. This cascade results in fibrotic thickening, endothelial dysfunction, hypercontractility, vasospasm, and a pro-thrombotic phenotype. AFD patients display increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating heightened cardiovascular risk. Nailfold capillaroscopy (NFC) shows promise in diagnosing and monitoring microcirculatory disorders in AFD, though it remains underexplored. Morphological evidence of AFD as a storage disorder can be demonstrated through electron microscopy and immunodetection of Gb3. Secondary pathophysiological disturbances at cellular, tissue, and organ levels contribute to the clinical manifestations, with prominent lysosomal inclusions observed in vascular, cardiac, renal, and neuronal cells. Chronic accumulation of Gb3 represents a state of ongoing toxicity, leading to increased cell turnover, particularly in vascular endothelial cells. AFD-related vascular pathology includes increased renin-angiotensin system activation, endothelial dysfunction, and smooth muscle cell proliferation, resulting in IMT increase. Furthermore, microvascular alterations, such as atypical capillaries observed through NFC, suggest early microvascular involvement. This review aims to unravel the complex interplay between inflammation, oxidative stress, and endothelial dysfunction in AFD, highlighting the potential connections between metabolic disturbances, oxidative stress, inflammation, and fibrosis in vascular and cardiac complications. By exploring novel cardiovascular risk factors and potential diagnostic tools, we can advance our understanding of these mechanisms, which extend beyond sphingolipid accumulation to include other significant contributors to disease pathogenesis. This comprehensive approach can pave the way for innovative therapeutic strategies and improved patient outcomes.
摘要：
安德森-法布里病（AFD），由α-半乳糖苷酶-A（GLA）基因突变引起的遗传性疾病，破坏溶酶体功能，导致血管并发症.球形神经酰胺（Gb3）在动脉壁中的积累引发粘附分子的上调，减少内皮一氧化氮合成，并诱导活性氧的产生。这种级联导致纤维化增厚，内皮功能障碍,过度收缩,血管痉挛,和促血栓形成表型。AFD患者表现出增加的内中膜厚度（IMT）和减少的血流介导的扩张（FMD），表明心血管风险增加。甲褶毛细管镜检查（NFC）在诊断和监测AFD的微循环障碍方面显示出希望，尽管它仍未被充分开发。通过电子显微镜和Gb3的免疫检测可以证明AFD作为储存障碍的形态学证据。细胞的继发性病理生理紊乱，组织,和器官水平有助于临床表现，在血管中观察到突出的溶酶体包裹体，心脏,肾,和神经元细胞。Gb3的慢性积累代表一种持续的毒性状态，导致细胞周转增加，特别是在血管内皮细胞中。AFD相关的血管病理包括肾素-血管紧张素系统激活增加，内皮功能障碍,和平滑肌细胞增殖，导致IMT增加。此外，微血管改变,例如通过NFC观察到的非典型毛细血管，提示早期微血管受累。这篇综述旨在解开炎症之间复杂的相互作用，氧化应激，和AFD中的内皮功能障碍，强调代谢紊乱之间的潜在联系，氧化应激，炎症,血管和心脏并发症的纤维化。通过探索新的心血管危险因素和潜在的诊断工具，我们可以加深对这些机制的理解，这超出了鞘脂的积累，包括疾病发病机理的其他重要贡献者。这种全面的方法可以为创新的治疗策略和改善患者预后铺平道路。
