title: Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.
abstract: 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 micromol/hr/mg (mean +/- SD; n = 16), compared with controls, 0.67 +/- 0.21 micromol/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.
authors.affiliation: Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: I
authors.initials: I
authors.lastname: Nishino
authors.forename: A
authors.initials: A
authors.lastname: Spinazzola
authors.forename: A
authors.initials: A
authors.lastname: Papadimitriou
authors.forename: S
authors.initials: S
authors.lastname: Hammans
authors.forename: I
authors.initials: I
authors.lastname: Steiner
authors.forename: C D
authors.initials: CD
authors.lastname: Hahn
authors.forename: A M
authors.initials: AM
authors.lastname: Connolly
authors.forename: A
authors.initials: A
authors.lastname: Verloes
authors.forename: J
authors.initials: J
authors.lastname: Guimarães
authors.forename: I
authors.initials: I
authors.lastname: Maillard
authors.forename: H
authors.initials: H
authors.lastname: Hamano
authors.forename: M A
authors.initials: MA
authors.lastname: Donati
authors.forename: C E
authors.initials: CE
authors.lastname: Semrad
authors.forename: J A
authors.initials: JA
authors.lastname: Russell
authors.forename: A L
authors.initials: AL
authors.lastname: Andreu
authors.forename: G M
authors.initials: GM
authors.lastname: Hadjigeorgiou
authors.forename: T H
authors.initials: TH
authors.lastname: Vu
authors.forename: S
authors.initials: S
authors.lastname: Tadesse
authors.forename: T G
authors.initials: TG
authors.lastname: Nygaard
authors.forename: I
authors.initials: I
authors.lastname: Nonaka
authors.forename: I
authors.initials: I
authors.lastname: Hirano
authors.forename: E
authors.initials: E
authors.lastname: Bonilla
authors.forename: L P
authors.initials: LP
authors.lastname: Rowland
authors.forename: S
authors.initials: S
authors.lastname: DiMauro
authors.forename: M
authors.initials: M
authors.lastname: Hirano
mesh_terms: D000328:Adult; D017668:Age of Onset; D001763:Blepharoptosis; D005006:Ethnicity; D005091:Exons; D005260:Female; D005767:Gastrointestinal Diseases / Q000235:genetics*; D005808:Genes, Recessive; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics*; D007438:Introns; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D009679:Nuclear Family; D016366:Open Reading Frames; D009886:Ophthalmoplegia; D017354:Point Mutation; D017384:Sequence Deletion; D013577:Syndrome; D013939:Thymidine Phosphorylase / Q000235:genetics*
chemical_list: D013939:Thymidine Phosphorylase