Zedde Marialuisa, Pascarella Rosario
Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy.
Neuroradiology Unit, Ospedale Santa Maria della Misericordia, AULSS 5 Polesana, 45100 Rovigo, Italy.
Genes (Basel). 2025 Jun 23;16(7):728. doi: 10.3390/genes16070728.
ABCC6, a key regulator in ectopic calcification, plays a crucial role in mineralization through the modulation of extracellular purinergic pathways and production of inorganic pyrophosphate (PPi), which inhibits calcification. Inherited deficiencies in ABCC6 lead to pseudoxanthoma elasticum (PXE) and related conditions, characterized by calcification in various tissues, particularly affecting the skin, eyes, and cardiovascular system. Although PXE does not directly impact the nervous system, secondary neurological issues arise from cerebrovascular complications, increasing the risk of strokes linked to arterial blockages resembling atherosclerosis. This review investigates the connection between ABCC6 mutations and cerebral small vessel disease (SVD), expanding the understanding of PXE and related phenotypes. Mutations in ABCC6, identified as causing PXE, contribute to systemic metabolic dysfunction, with significant implications for cerebrovascular health. An association between ABCC6 mutations and cerebral SVD has been suggested in various studies, particularly in populations with distinct genetic backgrounds. Emerging evidence indicates that pathogenic mutations increase the risk of ischemic strokes, with both homozygous and heterozygous carriers showing susceptibility. Mechanistically, ABCC6 deficiency is implicated in dyslipidemia and atherosclerosis, further exacerbating cerebrovascular risks. Increased arterial pulsatility, linked to carotid siphon calcification, may also contribute to microvascular damage and subsequent brain injury. Understanding these mechanisms is vital for developing targeted diagnostic and therapeutic strategies for managing cerebrovascular risks in PXE patients. This review emphasizes the need for comprehensive genetic screening and the consideration of traditional vascular risk factors in patient management, highlighting the complex interplay between genetic mutations and environmental influences affecting cerebrovascular health. Future research should focus on longitudinal studies to elucidate the causal pathways linking arterial calcification, pulsatility, and brain damage in PXE.
ABCC6是异位钙化的关键调节因子，通过调节细胞外嘌呤能途径和抑制钙化的无机焦磷酸（PPi）的产生，在矿化过程中发挥关键作用。ABCC6的遗传性缺陷会导致弹性假黄瘤（PXE）及相关病症，其特征是各种组织出现钙化，尤其影响皮肤、眼睛和心血管系统。虽然PXE不会直接影响神经系统，但脑血管并发症会引发继发性神经问题，增加与类似动脉粥样硬化的动脉阻塞相关的中风风险。本综述研究了ABCC6突变与脑小血管疾病（SVD）之间的联系，以加深对PXE及相关表型的理解。已确定导致PXE的ABCC6突变会导致全身代谢功能障碍，对脑血管健康有重大影响。多项研究表明ABCC6突变与脑SVD之间存在关联，特别是在具有不同遗传背景的人群中。新出现的证据表明，致病突变会增加缺血性中风的风险，纯合子和杂合子携带者均显示出易感性。从机制上讲，ABCC6缺乏与血脂异常和动脉粥样硬化有关，进一步加剧了脑血管风险。与颈动脉虹吸部钙化相关的动脉搏动增加也可能导致微血管损伤和随后的脑损伤。了解这些机制对于制定针对性的诊断和治疗策略以管理PXE患者的脑血管风险至关重要。本综述强调了在患者管理中进行全面基因筛查和考虑传统血管危险因素的必要性，突出了影响脑血管健康的基因突变与环境影响之间的复杂相互作用。未来的研究应侧重于纵向研究，以阐明PXE中动脉钙化、搏动与脑损伤之间的因果途径。
