Mitochondrial neurogastrointestinal encephalomyopathy: An autosomal recessive disorder due to thymidine phosphorylase mutations

Ichizo Nishino, Antonella Spinazzola, Alexandros Papadimitriou, Simon Hammans, Israel Steiner, Cecil D. Hahn, Anne M. Connolly, Alain Verloes, João Guimarães, Ivan Maillard, Hitoshi Hamano, M. Alice Donati, Carol E. Semrad, James A. Russell, Antonio L. Andreu, Giorgos M. Hadjigeorgiou, Tuan H. Vu, Saba Tadesse, Torbjoern G. Nygaard, Ikuya NonakaIkuo Hirano, Eduardo Bonilla, Lewis P. Rowland, Salvatore Dimauro, Michio Hirano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo-obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26-58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 ± 0.021 μmol/hr/mg (mean ± SD; n = 16), compared with controls, 0.67 ± 0.21 μmol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtdna replication, repair, or both.

Original languageEnglish
Pages (from-to)792-800
Number of pages9
JournalAnnals of Neurology
Issue number6
StatePublished - 2000
Externally publishedYes


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