Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE;OMIM 603041) is a rare autosomal recessive disease caused by mutations in the TYMP gene encoding thymidine phosphorylase (TP;E.C, 2.4.2.4). Seventeen years ago, we described MNGIE as a clinically distinct disorder characterized by extraocular muscle weakness causing ptosis and ophthalmoplegia, peripheral neuropathy, gastrointestinal dysmotility causing severe cachexia, leukoencephalopathy, and mitochondrial abnormalities including multiple deletions of mitochondrial DNA (mtDNA) in skeletal muscle. The disease is relentlessly progressive and fatal with an average age-at-onset of 19-years-old and an average age-at-death of 37-years-old. We have mapped the disease locus to chromosome 22q13.32-tel, identified the causative gene[3,4], characterized the molecular pathogenesis[5-11] and generated a mouse model [12] Although the prevalence of MNGIE is unknown, at least 140 cases have been identified in diverse ethnic groups. Our studies of MNGIE have demonstrated that TYMP mutations cause severe loss of TP activity that dramatically elevates tissue and plasma levels of the pyrimidine nucleosides thymidine (Thd) and deoxyuridine (dUrd), which produce deoxynucleoside triphosphate (dNTP) pool imbalances that, in turn, produce instability of mitochondrial DNA (mtDNA). The mtDNA instability manifests as somatic multiple deletions, depletion, and site-specific point mutations. Based on these findings, we have hypothesized that TP enzyme replacement via allogeneic hematopoietic stem cell transplantation (AHSCT) will be therapeutic by virtue of eliminating the toxic metabolites, Thd and dUrd, and restoring balanced dNTP pools. In fact, in this U54 application, we are proposing the AHSCT for MNGIE International Collaborative Trial (AMICT) to assess safety and efficacy of AHSCT for MNGIE using biomarkers as the primary and secondary outcome measures. Because therapy is being tested for MNGIE, it is imperative to document the natural history of this disease in order to develop meaningful clinical measures for therapeutic trials. Thus, the overall purpose of this study of MNGIE is to define its natural history and to identify optimal outcome measure that correlate with disease progression and can be used for the assessment of new therapies that seek FDA approval.
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