title: Altered thymidine metabolism due to defects of thymidine phosphorylase.
abstract: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease due to mutations in the thymidine phosphorylase (TP) gene. TP enzyme catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxy-D-ribose 1-phosphate. We present evidence that thymidine metabolism is altered in MNGIE. TP activities in buffy coats were reduced drastically in all 27 MNGIE patients compared with 19 controls. All MNGIE patients had much higher plasma levels of thymidine than normal individuals and asymptomatic TP mutation carriers. In two patients, the renal clearance of thymidine was approximately 20% that of creatinine, and because hemodialysis demonstrated that thymidine is ultrafiltratable, most of the filtered thymidine is likely to be reabsorbed by the kidney. In vitro, fibroblasts from controls catabolized thymidine in medium; by contrast, MNGIE fibroblasts released thymidine. In MNGIE, severe impairment of TP enzyme activity leads to increased plasma thymidine. In patients who are suspected of having MNGIE, determination of TP activity in buffy coats and thymidine levels in plasma are diagnostic. We hypothesize that excess thymidine alters mitochondrial nucleoside and nucleotide pools leading to impaired mitochondrial DNA replication, repair, or both. Therapies to reduce thymidine levels may be beneficial to MNGIE patients.
authors.affiliation: Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Spinazzola
authors.forename: Ramon
authors.initials: R
authors.lastname: Marti
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Andreu
authors.forename: Ali
authors.initials: A
authors.lastname: Naini
authors.forename: Saba
authors.initials: S
authors.lastname: Tadesse
authors.forename: Ivana
authors.initials: I
authors.lastname: Pela
authors.forename: Enrico
authors.initials: E
authors.lastname: Zammarchi
authors.forename: M Alice
authors.initials: MA
authors.lastname: Donati
authors.forename: Juan A
authors.initials: JA
authors.lastname: Oliver
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
mesh_terms: D002478:Cells, Cultured; D002892:Chromosomes, Human, Pair 22; D006801:Humans; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D013936:Thymidine / Q000378:metabolism*; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*
chemical_list: D013939:Thymidine Phosphorylase; D013936:Thymidine