Mitochondrial Neurogastrointestinal Encephalomyopathy Disease (MNGIE)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive mitochondrial disease due to mutations in TYMP, which encodes the cytosolic enzyme thymidine phosphorylase (TP). MNGIE is clinically characterized by severe gastrointestinal dysmotility, cachexia, chronic progressive external ophthalmoplegia, sensorimotor peripheral neuropathy, and leukoencephalopathy. The average age at onset is about 18 years old, and the disease progresses to fatality with an average age at death of 35 years old. In this disease, loss of TP catabolic activity leads to toxic accumulations of the nucleosides thymidine and deoxyuridine in blood, tissues, and urine. The elevated levels of these deoxynucleosides lead to imbalances in the mitochondrial deoxynucleoside triphosphate (dNTP) pools that impair mitochondrial DNA (mtDNA) replication, which cause mtDNA depletion, multiple deletions, and site-specific point mutations. MNGIE can be readily diagnosed by the clinical phenotype with confirmation by identification of TYMP mutations or by biochemical demonstration of decreased TP activity, elevated plasma thymidine and deoxyuridine, or both. Strategies to restore TP activity via allogeneic stem cell transplantation, liver transplantation, and erythrocyte-encapsulated TP have shown efficacy in patients, but each approach has limitations. Gene therapy using adeno-associated virus or lentiviral vector to deliver TP have shown promising results in preclinical studies.