Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE): A Comprehensive Review of Pathophysiology, Diagnosis, and Therapeutic Advances

Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) is a rare autosomal recessive multisystem disorder caused by mutations in the TYMP gene, leading to thymidine phosphorylase deficiency and subsequent mitochondrial DNA instability. This results in profound mitochondrial dysfunction primarily affecting the gastrointestinal and nervous systems. Clinically, MNGIE manifests as progressive gastrointestinal dysmotility, including chronic intestinal pseudo-obstruction, nausea, vomiting, diarrhea, and severe cachexia. Neurological features such as peripheral neuropathy, ophthalmoplegia, ptosis, and diffuse leukoencephalopathy further complicate the clinical picture. The disease typically presents in early adulthood but can manifest at any age, with significant variability in severity and progression. Diagnosis involves clinical evaluation, detection of elevated plasma thymidine and deoxyuridine, reduced thymidine phosphorylase activity, characteristic MRI findings, nerve conduction studies, and genetic testing for TYMP mutations. Therapeutic options remain limited but include allogeneic hematopoietic stem cell transplantation to restore enzymatic activity, experimental enzyme replacement therapies, gene therapy, and supportive care for symptom management. Early diagnosis and emerging molecular therapies offer hope for improved outcomes, although the prognosis remains poor due to the progressive and multisystem nature of the disease. This comprehensive review synthesizes current understanding of MNGIE’s pathophysiological mechanisms, diagnostic criteria, and recent advances in treatment strategies, highlighting challenges and future directions in managing this devastating disorder.