Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.
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.
1 Haematology, University Hospital Basel, Basel, Switzerland joerg.halter@usb.ch.
Joerg P
JP
Halter
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
W
W
Michael
2 Department of Neurology, Inselspital, Berne University Hospital, and University of Bern, Switzerland 3 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, France.
M
M
Schüpbach
4 Rambam Medical Centre Haifa, Israel.
Hanna
H
Mandel
5 Dep. SBMC - Sapienza University Roma, Italy.
Carlo
C
Casali
6 University Hospital Southampton, UK.
Kim
K
Orchard
7 Newcastle University, Newcastle upon Tyne, UK.
Matthew
M
Collin
8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
David
D
Valcarcel
9 BMT Unit, MBBM Foundation, Paediatric Dept., University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy.
Attilio
A
Rovelli
10 Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy.
Massimiliano
M
Filosto
11 Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy.
Maria T
MT
Dotti
12 Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Siena, Italy.
Giuseppe
G
Marotta
13 Department of Paediatrics, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
Guillem
G
Pintos
8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Pere
P
Barba
8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Anna
A
Accarino
14 Department of Haematology - Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
Christelle
C
Ferra
15 Hospital de la Santa Creu i Sant Pau Universitat Autònoma Barcelona, Spain.
Isabel
I
Illa
16 CHU Sart-Tilman Liege, Belgium.
Yves
Y
Beguin
17 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
Jaap A
JA
Bakker
18 University Medical Centre Utrecht; Paediatric Blood and Marrow Transplantation Program, Utrecht, The Netherlands.
Jaap J
JJ
Boelens
19 Department of Neurology and Child Neurology SKZ, Erasmus MC - University Medical Centre Rotterdam, The Netherlands.
Irenaeus F M
IF
de Coo
20 Department of Haematology, Royal North Shore and St. Vincent Hospitals Sydney, Australia.
Keith
K
Fay
21 Department of Neurology, Royal North Shore Hospital, University of Sydney, Australia.
Carolyn M
CM
Sue
22 Medical University of Innsbruck, Departments of Medicine II and V, Austria.
David
D
Nachbaur
22 Medical University of Innsbruck, Departments of Medicine II and V, Austria.
Heinz
H
Zoller
23 Department of Neuroscience, Division of Neurology, Ribeirao Preto School of Medicine, Sao Paulo University, Brazil.
Claudia
C
Sobreira
24 Stem Cell Transplantation Unit, Internal Medicine Department, Ribeirao Preto School of Medicine, Sao Paulo University, Brazil.
Belinda
B
Pinto Simoes
25 Wessex Neurological Centre Southampton, UK.
Simon R
SR
Hammans
26 Columbia University New York, USA.
David
D
Savage
8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain 27 Biomedical Network Research Centre on Rare Diseases (CIBERER) ISCIII, Barcelona, Spain.
Ramon
R
Martí
7 Newcastle University, Newcastle upon Tyne, UK.
Patrick F
PF
Chinnery
28 Dana Children's Hospital, Sourasky Medical Centre, Tel Aviv, Israel.
Ronit
R
Elhasid
1 Haematology, University Hospital Basel, Basel, Switzerland.
Alois
A
Gratwohl
29 Department of Neurology, Columbia University Medical Centre, New York, NY, USA.
Michio
M
Hirano
D000293:Adolescent; D000328:Adult; D001835:Body Weight; D001921:Brain / Q000473:pathology; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000601:surgery*; D008279:Magnetic Resonance Imaging; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000601:surgery*; D039141:Muscular Dystrophy, Oculopharyngeal; D009431:Neural Conduction / Q000502:physiology; D009460:Neurologic Examination; D009504:Neutrophils; D009886:Ophthalmoplegia / Q000151:congenital; D012189:Retrospective Studies; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000378:metabolism; D014184:Transplantation, Homologous / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult; D028361:Mitochondrial Diseases
D013939:Thymidine Phosphorylase
allogeneic haematopoietic stem cell transplantation; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); outcome; risk factors; thymidine phosphorylase