线粒体神经胃肠性脑肌病的异基因造血干细胞移植
Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.
作者信息
Halter Joerg P, Michael W, Schüpbach M, Mandel Hanna, Casali Carlo, Orchard Kim, Collin Matthew, Valcarcel David, Rovelli Attilio, Filosto Massimiliano, Dotti Maria T, Marotta Giuseppe, Pintos Guillem, Barba Pere, Accarino Anna, Ferra Christelle, Illa Isabel, Beguin Yves, Bakker Jaap A, Boelens Jaap J, de Coo Irenaeus F M, Fay Keith, Sue Carolyn M, Nachbaur David, Zoller Heinz, Sobreira Claudia, Pinto Simoes Belinda, Hammans Simon R, Savage David, Martí Ramon, Chinnery Patrick F, Elhasid Ronit, Gratwohl Alois, Hirano Michio
机构信息
1 Haematology, University Hospital Basel, Basel, Switzerland
1 Haematology, University Hospital Basel, Basel, Switzerland2 Department of Neurology, Inselspital, Berne University Hospital, and University of Bern, Switzerland3 Centre d'Investigation Clinique 9503, Institut du Cerveau et de la Moelle Épinière, Département de Neurologie, Université Pierre et Marie Curie-Paris 6 and INSERM, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France4 Rambam Medical Centre Haifa, Israel5 Dep. SBMC - Sapienza University Roma, Italy6 University Hospital Southampton, UK7 Newcastle University, Newcastle upon Tyne, UK8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain9 BMT Unit, MBBM Foundation, Paediatric Dept., University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy10 Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy11 Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy12 Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Siena, Italy13 Department of Paediatrics, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain14 Department of Haematology - Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain15 Hospital de la Santa Creu i Sant Pau Universitat Autònoma Barcelona, Spain16 CHU Sart-Tilman Liege, Belgium17 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Centre, Leiden, The Netherlands18 University Medical Centre Utrecht; Paediatric Blood and Marrow Transplantation Program, Utrecht, The Netherlands19 Department of Neurology and Child Neurology SKZ, Erasmus MC - University Medical Centre Rotterdam, The Netherlands20 Department of Haematology, Royal North Shore and St. Vincent Hospitals Sydney, Australia21 Department of Neurology, Royal North Shore Hospital, University of Sydney, Australia22 Medical University of Innsbruck, Departments of Medic
出版信息
Brain. 2015 Oct;138(Pt 10):2847-58. doi: 10.1093/brain/awv226. Epub 2015 Aug 10.
Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.
造血干细胞移植已被提议作为线粒体神经胃肠性脑肌病的治疗方法，这是一种罕见的致命常染色体隐性疾病，由TYMP突变导致胸苷磷酸化酶缺乏引起。我们对2005年至2011年间接受异基因造血干细胞移植的所有已知线粒体神经胃肠性脑肌病患者进行了回顾性分析。分析了全球15家机构中24例患者（11例男性和13例女性，中位年龄25岁，范围10 - 41岁），这些患者接受了来自相关供体（n = 9）或无关供体（n = 15）的造血干细胞移植，以评估结局及其相关因素。总体而言，24例患者中有9例（37.5%）在最后一次随访时存活，这些存活患者的中位随访时间为1430天。死亡原因9例归因于移植（包括2例因移植物失败进行第二次移植后死亡），6例归因于线粒体神经胃肠性脑肌病。所有存活者的胸苷磷酸化酶活性从无法检测升至正常水平（中位值697 nmol/h/mg蛋白，范围262 - 1285）。7例移植后植入且存活超过2年的患者（29%），其体重指数、胃肠道表现和周围神经病变有所改善。单因素统计分析表明，生存与两个移植前确定的特征相关：人类白细胞抗原匹配（10/10对<10/10）和疾病特征（肝病、胃肠道假性梗阻病史或两者皆有）。异基因造血干细胞移植可恢复线粒体神经胃肠性脑肌病患者的胸苷磷酸化酶功能，并长期改善线粒体神经胃肠性脑肌病的临床表现。对于有合适供体的选定患者，应考虑进行异基因造血干细胞移植。
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