Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

Rana Yadak*, Peter Sillevis Smitt, Marike W. van Gisbergen, Niek P. van Til, Irenaeus F. M. de Coo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Web of Science)

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 in Tymp(-/-)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.

Original languageEnglish
Article number31
Number of pages14
JournalFrontiers in Cellular Neuroscience
Volume11
DOIs
Publication statusPublished - 15 Feb 2017

Keywords

  • mitochondrial neurogastrointestinal encephalomyopathy
  • MNGIE
  • thymidine phosphorylase
  • metabolic disease
  • HSCT
  • HSCGT
  • lentiviral vector
  • CELL GENE-THERAPY
  • CHRONIC GRANULOMATOUS-DISEASE
  • LONG-TERM SAFETY
  • LENTIVIRAL VECTOR
  • MNGIE SYNDROME
  • DNA DEPLETION
  • REPLACEMENT THERAPY
  • HEMATOPOIETIC-CELLS
  • MURINE MODEL
  • BONE-MARROW

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