Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Hematology-Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Pediatr Blood Cancer. 2021 May;68(5):e28926. doi: 10.1002/pbc.28926. Epub 2021 Feb 3.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy, and brain magnetic resonance imaging (MRI) white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances, and mitochondrial DNA (mtDNA) instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in three patients with MNGIE that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first hematopoietic stem cell transplantation (HSCT) worldwide as a life-long source of TP in a patient with MNGIE.
HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience.
Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully human leukocyte antigen (HLA)-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in two patients. Fifteen years post HSCT, the first transplanted patient is seemingly cured. Severe GI symptoms before transplantation were mostly irreversible and were poor prognostic factors.
Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, presymptomatic, or mildly affected patients. Timing, donor selection, and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.
线粒体神经胃肠脑肌病（MNGIE）是一种进行性常染色体隐性遗传病，其特征为恶病质、胃肠道（GI）动力障碍、上睑下垂、周围神经病和脑磁共振成像（MRI）白质改变。双等位 TYMP 突变导致胸苷磷酸化酶（TP）活性缺乏、血浆核苷（胸苷和脱氧尿苷）毒性积累、核苷酸池失衡和线粒体 DNA（mtDNA）不稳定。死亡主要是由于 GI 并发症：肠穿孔、腹膜炎和/或肝功能衰竭。基于我们之前对三名 MNGIE 患者的观察，血小板输注导致血浆核苷水平暂时降低 40%，因此我们于 2005 年在全球首次进行了造血干细胞移植（HSCT），作为 MNGIE 患者终身 TP 的来源。
共对六名 MNGIE 患者进行了 HSCT。分析了该队列中涉及预后的多个因素，并与文献经验进行了比较。
五名患者的细胞来源为骨髓，一名患者为外周干细胞，均来自完全人白细胞抗原（HLA）匹配的相关供体，其中四名是 TYMP 突变携带者。六名患者中有四名（66%）存活，而文献中的存活率为 37%。强度降低的调理方案导致两名患者出现二次移植物失败。HSCT 后 15 年，首位接受移植的患者似乎已被治愈。移植前严重的 GI 症状大多是不可逆转的，是预后不良的因素。
同种异体 HSCT 可能是精心挑选的、年轻的、无症状或轻度受累患者的一种有治愈潜力的治疗选择。时机、供体选择和最佳调理方案是决定结果的主要因素。HSCT 不适用于晚期 MNGIE 疾病患者。
