title: Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options.
abstract: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested inTymp-/-Upp1-/-mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease.
authors.affiliation: Department of Neurology, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Rana
authors.initials: R
authors.lastname: Yadak
authors.affiliation: Department of Neurology, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Sillevis Smitt
authors.affiliation: Department of Radiation Oncology (MaastRO-Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre Maastricht, Netherlands.
authors.forename: Marike W
authors.initials: MW
authors.lastname: van Gisbergen
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht Utrecht, Netherlands.
authors.forename: Niek P
authors.initials: NP
authors.lastname: van Til
authors.affiliation: Department of Neurology, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Irenaeus F M
authors.initials: IF
authors.lastname: de Coo
keywords: HSCGT; HSCT; MNGIE; lentiviral vector; metabolic disease; mitochondrial neurogastrointestinal encephalomyopathy; thymidine phosphorylase