Download full-text

Full-text

Available from: Berend Feddersen
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase and is characterized by external ophthalmoparesis, gastrointestinal dysmotility, leukoencephalopathy, and neuropathy. The availability of new therapeutic options (peritoneal dialysis, allogeneic stem cell transplantation, enzyme replacement) makes it necessary to diagnose the disease early, which is not always achieved due to the difficulty in recognizing this disorder, especially in case of atypical presentation. We describe three MNGIE patients with atypical onset of the disease. In the first patient the main symptoms were long-standing chronic fever, recurrent acute migrant arthritis, and gastrointestinal disorders mimicking autoimmune or inflammatory intestinal diseases; the second patient complained only of exercise intolerance and muscle cramps, and the third patient had a CIDP-like polyneuropathy. This study stresses the insidious heterogeneous clinical onset of some cases of MNGIE, expands the spectrum of the phenotype, and suggests considering MNGIE in the differential diagnosis of enteropathic arthritis, isolated exercise intolerance, and inflammatory polyneuropathies not responsive to the usual treatment. A better understanding of the clinical heterogeneity of MNGIE is necessary in order to diagnose atypical cases and promote early diagnosis, which is now absolutely necessary in view of the new available therapies.
    Full-text · Article · Apr 2011 · Journal of Inherited Metabolic Disease
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in TYMP, which encodes thymidine phosphorylase (TP). TP dysfunction leads to systemic overload of thymidine (dThd) and deoxyuridine (dUrd), and altered mitochondrial deoxyribonucleotide homeostasis, which interferes with mitochondrial DNA replication and results in mitochondrial dysfunction. In MNGIE, the clinical phenotype is the consequence of an accumulation of noxious metabolites.Areas covered: Knowledge gained about the pathomechanisms involved in MNGIE has allowed the design of plausible treatments aimed to clear the systemic dThd and dUrd overload. This article describes these strategies, from the first attempts to treat the disease through dialysis, to allogeneic hematopoietic stem cell transplantation (allo-HSCT), which has been the most successful treatment in the long term to date. This option, however, is associated with a high risk of severe adverse effects so safer alternatives with long-term efficacy are required such as gene therapy.Expert opinion: The generally poor health of MNGIE patients at the time of treatment aggravates the risks associated with therapies like allo-HSCT. Recently, gene therapy has emerged as a feasible alternative, based on promising preclinical results. To this end, clinical trials should be carefully designed and carried out to investigate the safety and efficacy of this option.
    Full-text · Article · Oct 2015 · Expert Opinion on Orphan Drugs