Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare genetic disease caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase (TP). The loss of TP activity due to mutations leads to the accumulation of toxic circulating nucleosides, which, over time, damage mitochondrial DNA. The disease manifests with severe and debilitating symptoms affecting both the central and peripheral nervous systems as well as the gastrointestinal tract, resulting in a highly disabling condition that is typically fatal by the third decade of life.
To date, hematopoietic stem cell transplantation or liver transplantation represents the only life-saving option, as it allows for the reintroduction of stable TP activity through an exogenous source. This intervention has been shown to clear the toxic nucleosides from circulation and restore mitochondrial DNA integrity. However, patient follow-up has revealed that some symptoms persist, particularly gastrointestinal manifestations such as chronic intestinal pseudo-obstruction (a severe form of intestinal dysmotility) and leukoencephalopathy.
This observation has led us to examine the role of TP from a new perspective, investigating it as a potential angiogenic factor. Our research has revealed that MNGIE is not only a mitochondrial disease but also a vascular pathology. Our data suggest that the systemic alteration of small blood vessels could explain the persistence of gastrointestinal abnormalities and leukoencephalopathy, broadening our understanding of the disease’s pathophysiology and opening new possibilities for targeted therapeutic approaches.
Following, some questions we try to answer through the research in our laboratories:
Question 1: TP is a key protein in vascularization and nucleoside metabolism. We have demonstrated that MNGIE patients lose 70% of their enteric neurons. Is its absence neurotoxic? What about the underling mechanism?
Question 2: We have demonstrated that in MNGIE patients, the mucosal layer of the gastrointestinal tract fails to recover mitochondrial DNA copy numbers following transplantation. What occurs at the level of intestinal crypts in these patients, and how does this contribute to the persistence of gastrointestinal dysfunction?
Question 3: Leukoencephalopathy in MNGIE does not regress after transplantation. What factors contribute to its onset, and are there potential therapeutic strategies to address it?
Question 4: Is the liver a target organ in MNGIE? Can an explanted liver be used for a "Domino Liver Transplant"?
