Abstract
Over the last 15 years, important research has expanded our knowledge of the clinical, molecular genetic, and biochemical features of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The characterization of mitochondrial involvement in this disorder and the seminal determination of its genetic cause, have opened new possibilities for more detailed and deeper studies on the pathomechanisms in this progressive and fatal disease. It has been established that MNGIE is caused by mutations in the gene encoding thymidine phosphorylase (TP), which lead to absolute or nearly complete loss of its catalytic activity, producing systemic accumulations of its substrates, thymidine (dThd) and deoxyuridine (dUrd). Findings obtained from in vitro and in vivo studies indicate that the biochemical imbalances specifically impair mitochondrial DNA (mtDNA) replication, repair, or both leading to mitochondrial dysfunction. We have proposed that therapy for MNGIE should be aimed at reducing the concentrations of these toxic nucleosides to normal or nearly normal levels. The first treatment, allogeneic stem-cell transplantation (alloSCT) reported in 2006, produced a nearly full biochemical correction of the dThd and dUrd imbalances in blood. Clinical follow-up of this and other patients receiving alloSCT is necessary to determine whether this and other therapies based on a permanent restoration of TP will be effective treatment for MNGIE.
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Acknowledgements
This work was supported by grants from the Spanish Fondo de Investigación Sanitaria (FIS 03/0343; FIS 04/0242 and FIS 06/0735), a grant from the United Mitochondrial Disease Foundation (UMDF 04–42), a grant from the Muscular Dystrophy Association USA, NIH grant NS11766, and the Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF).
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Lara, M.C., Valentino, M.L., Torres-Torronteras, J. et al. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Biochemical Features and Therapeutic Approaches. Biosci Rep 27, 151–163 (2007). https://doi.org/10.1007/s10540-007-9043-2
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DOI: https://doi.org/10.1007/s10540-007-9043-2