Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes.
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.
Hirano
Michio
M
Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY, USA. mh29@columbia.edu
Nishigaki
Yutaka
Y
Martí
Ramon
R
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
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