title: Glutathione metabolism in cobalamin deficiency type C (cblC).
abstract: BACKGROUND
  Methylmalonic aciduria with homocystinuria, cblC defect, is the most frequent disorder of vitamin B12 metabolism. CblC patients are commonly treated with a multidrug therapy to reduce metabolite accumulation and to increase deficient substrates. However the long-term outcome is often unsatisfactory especially in patients with early onset, with frequent progression of neurological and ocular impairment. Recent studies, have shown perturbation of cellular redox status in cblC. To evaluate the potential contribution of oxidative stress into the patophysiology of cblC defect, we have analyzed the in vivo glutathione metabolism in a large series of cblC deficient individuals.
  
  
  METHODS
  Levels of different forms of glutathione were measured in lymphocytes obtained from 18 cblC patients and compared with age-matched controls. Furthermore, we also analyzed plasma cysteine and total homocysteine.
  
  
  RESULTS
  We found an imbalance of glutathione metabolism in cblC patients with a significant decrease of total and reduced glutathione, along with a significant increase of different oxidized glutathione forms.
  
  
  CONCLUSIONS
  These findings show a relevant in vivo disturbance of glutathione metabolism underlining the contribution of glutathione pool depletion to the redox imbalance in treated cblC patients. Our study may be helpful in addressing future research to better understanding the pathogenetic mechanism of the disease and in developing new therapeutic approaches, including the use of novel vitamin B₁₂ derivatives.
authors.affiliation: Laboratory of Metabolomics and Proteomics, Bambino Gesù Children's Hospital, IRCCS, P.zza S. Onofrio, 4-00165, Rome, Italy, anna.pastore@opbg.net.
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.forename: Giulia
authors.initials: G
authors.lastname: Tozzi
authors.forename: Sara
authors.initials: S
authors.lastname: Boenzi
authors.forename: Gianna
authors.initials: G
authors.lastname: Di Giovamberardino
authors.forename: Sara
authors.initials: S
authors.lastname: Petrillo
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
mesh_terms: D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood*; D002352:Carrier Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003545:Cysteine / Q000097:blood*; D018450:Disease Progression; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood*; D006712:Homocystinuria / Q000097:blood*; D006801:Humans; D007223:Infant; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism; D014806:Vitamin B 12 Deficiency / Q000151:congenital
chemical_list: D002352:Carrier Proteins; D017382:Reactive Oxygen Species; D006710:Homocysteine; C508359:MMACHC protein, human; D010088:Oxidoreductases; D005978:Glutathione; D003545:Cysteine; D014805:Vitamin B 12; D010100:Oxygen