Abstract：
mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.
摘要：
线粒体神经胃肠脑肌病（MNGIE）是一种罕见的遗传性疾病，其特征是胸苷磷酸化酶（TP）酶缺陷。缺乏TP活性诱导线粒体核苷酸库的失衡，导致线粒体DNA（mtDNA）复制和消耗受损。由于mtDNA是确保氧化磷酸化所必需的，代谢活跃的组织可能无法获得足够的能量生产。MNGIE中唯一有效的挽救生命的方法是通过异基因造血干细胞或肝移植永久替代TP。然而,移植患者的随访表明，肠道组织变化不会逆转和致命的并发症，比如消化道大出血,可以发生。这项研究的目的是阐明移植后重新引入TP是否可以在正常范围内恢复mtDNA拷贝数。使用激光捕获显微切割和液滴数字PCR，我们评估了幼稚MNGIE队列的每层全厚度回肠样本中的mtDNA拷贝数与控制和患者在TP置换前后。该治疗导致肠道组织mtDNA量的显着恢复，从而显示其功效。我们的结果表明，在MNGIE发生不可逆的变性组织变化之前，需要及时的TP替换以最大程度地提高治疗成功率。
