眼咽型肌营养不良症：从分子发病机制到基因治疗

文献信息

中文摘要

眼咽型肌营养不良症（OPMD）是一种罕见的、晚发的、常染色体显性遗传性肌营养不良症，由位于染色体14q11.2上的PABPN1基因中三核苷酸GCN重复扩增引起。该病的临床特征为进行性上睑下垂、吞咽困难和近端肢体无力，发病通常在第五至第六个十年。OPMD在欧洲约影响1：100,000的个体，在特定奠基者人群中患病率显著更高，在布哈拉犹太人中达到1：600，在法裔加拿大人中为1：1,000。PABPN1中扩展的多聚丙氨酸束促进蛋白质错误折叠和管丝状核内包涵体的形成，这是该病的组织病理学标志。致病机制涉及聚集的突变PABPN1的功能获得性毒性、由于多聚腺苷酸化效率降低导致的功能丧失效应，以及显性负性损害多聚(A)尾延伸、mRNA加工和核mRNA输出之间的复杂相互作用。邻近蛋白质组学的最新进展改进了对丙氨酸扩展如何使PABPN1不稳定并改变其相互作用组的理解。诊断依赖于对PABPN1 GCN重复扩增的分子遗传学检测，而肌肉活检上的PABPN1免疫荧光提供了一种高度敏感和特异的辅助工具。目前的治疗仍为对症治疗，包括针对吞咽困难的环咽肌切开术和上睑下垂的手术矫正。治疗领域正在发展，BB-301是一种基于腺相关病毒的基因疗法，采用DNA指导的RNA干扰（ddRNAi）沉默和替换策略，目前正在进行1b/2a期临床试验。本综述提供了OPMD的全面综合，涵盖历史背景、分子遗传学、病理生理学、临床表现、诊断方法和新兴的治疗管线。

英文摘要

Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset, autosomal dominant muscular dystrophy caused by a trinucleotide GCN repeat expansion in the PABPN1 gene on chromosome 14q11.2. The disease is clinically characterised by progressive ptosis, dysphagia, and proximal limb weakness, with onset typically between the fifth and sixth decades. OPMD affects approximately 1:100,000 individuals in Europe, with substantially higher prevalence in specific founder populations, reaching 1:600 among Bukharan Jews and 1:1,000 in French Canadians. The expanded polyalanine tract in PABPN1 promotes protein misfolding and formation of tubulofilamentous intranuclear inclusions, the histopathological hallmark of the disease. Pathogenic mechanisms involve a complex interplay of gain-of-function toxicity from aggregated mutant PABPN1, loss-of-function effects due to reduced polyadenylation efficiency, and dominant-negative impairment of poly(A) tail elongation, mRNA processing and nuclear mRNA export. Recent advances in proximity proteomics have refined the understanding of how the alanine expansion destabilises PABPN1 and alters its interactome. Diagnosis relies on molecular genetic testing of the PABPN1 GCN repeat expansion, while PABPN1 immunofluorescence on muscle biopsy provides a highly sensitive and specific ancillary tool. Current management remains symptomatic, including cricopharyngeal myotomy for dysphagia and surgical correction of ptosis. The therapeutic landscape is evolving, with BB-301, an adeno-associated virus-based gene therapy employing a DNA-directed RNA interference (ddRNAi) silence-and-replace strategy, currently in a Phase 1b/2a clinical trial. This review provides a comprehensive synthesis of OPMD, spanning historical background, molecular genetics, pathophysiology, clinical presentation, diagnostic approach, and the emerging therapeutic pipeline.