title: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes.
abstract: BACKGROUND
  Mitochondrial encephalomyopathies are clinically and genetically heterogeneous because mitochondria are the products of 2 genomes: mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Among the mendelian-inherited mitochondrial diseases are defects of intergenomic communication, disorders due to nDNA mutations that cause depletion and multiple deletions of mtDNA.
  
  
  RESULTS
  Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder of intergenomic communication and is defined clinically by 1) severe gastrointestinal dysmotility; 2) cachexia; 3) ptosis, ophthalmoparesis, or both; 4) peripheral neuropathy; and 5) leukoencephalopathy. Skeletal muscle biopsies of patients have revealed abnormalities of mtDNA and mitochondrial respiratory chain enzymes. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. In MNGIE patients, TP enzyme activity is reduced drastically, and plasma thymidine and deoxyuridine are elevated dramatically. We have hypothesized that alterations of nucleoside metabolism cause an imbalanced mitochondrial nucleotide pool that leads to depletion and deletions of mtDNA.
  
  
  CONCLUSIONS
  MNGIE is a recognizable clinical syndrome caused by mutations in TP. The diagnosis can be confirmed by measuring TP activity in buffy coat or plasma levels of thymidine and deoxyuridine. Reduction of circulating thymidine and deoxyuridine in MNGIE patients may be therapeutic.
authors.affiliation: Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY, USA. mh29@columbia.edu
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nishigaki
authors.forename: Ramon
authors.initials: R
authors.lastname: Martí
mesh_terms: D000293:Adolescent; D000328:Adult; D000446:Aldehyde-Lyases / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002100:Cachexia / Q000175:diagnosis / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D056970:Co-Repressor Proteins; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D003704:Dementia / Q000175:diagnosis / Q000209:etiology; D003857:Deoxyuridine / Q000097:blood; D005260:Female; D005769:Gastrointestinal Motility / Q000502:physiology*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D017237:Mitochondrial Encephalomyopathies / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D017354:Point Mutation / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000378:metabolism
chemical_list: C117400:C1D protein, human; D056970:Co-Repressor Proteins; D004272:DNA, Mitochondrial; D012097:Repressor Proteins; D013939:Thymidine Phosphorylase; D000446:Aldehyde-Lyases; C020019:deoxyribose-phosphate aldolase; D003857:Deoxyuridine