线粒体神经胃肠型脑肌病的治疗进展与展望

Therapeutic Advances and Future Prospects in Mitochondrial Neurogastrointestinal Encephalomyopathy

摘要: 线粒体神经胃肠型脑肌病(mitochondrial neurogastrointestinal encephalomyopathy, MNGIE)是一种罕见的常染色体隐性线粒体疾病，其主要生化异常表现为胸苷磷酸化酶(thymidine phosphorylase, TP)活性显著降低，导致脱氧胸苷(deoxythymidine, dThd)和脱氧尿苷(deoxyuridine, dUrd)在体内异常积聚。毒性核苷的长期累积可扰乱胞质和线粒体内核苷酸池稳态，诱发线粒体DNA (mtDNA)的损伤和耗竭，进而导致进行性胃肠动力障碍、脑白质病变、周围神经病变等临床表现。临床研究表明，残余TP活性与疾病严重程度密切相关，适度恢复TP活性可在一定程度上纠正代谢失衡。目前尚无能够根治MNGIE的标准化特异性治疗方案，现有临床干预策略主要围绕两大目标展开：一是清除血液中毒性核苷；二是永久性恢复缺失的TP活性。近年来，基因治疗在动物实验及早期临床研究中亦展现出一定应用前景。本文综述了MNGIE的病理生理基础及目前的主要治疗策略，并对未来的发展前景进行了展望。

Abstract: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive mitochondrial disorder characterized by a profound deficiency of thymidine phosphorylase (TP) activity, leading to the systemic accumulation of deoxythymidine (dThd) and deoxyuridine (dUrd). Chronic elevation of these toxic nucleosides disrupts the nucleotide pool homeostasis in both the cytosol and mitochondria, resulting in mitochondrial DNA (mtDNA) damage and depletion. These molecular disturbances underlie the progressive clinical manifestations of MNGIE, including severe gastrointestinal dysmotility, leukoencephalopathy, peripheral neuropathy, and other systemic manifestations. Clinical evidence indicates a strong correlation between residual TP activity and disease severity, and partial restoration of TP activity has been shown to ameliorate metabolic imbalance to a certain extent. Currently, no standardized curative therapy for MNGIE is available. Therapeutic strategies primarily focus on two goals: the removal of circulating toxic nucleosides and the permanent restoration of TP activity. In recent years, gene therapy has also demonstrated promising potential in preclinical models and early-stage clinical investigations. This review summarizes the pathophysiological basis of MNGIE and current main treatment strategies, and discusses future directions for the management of this devastating disorder.