title: CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders.
abstract: BACKGROUND
  Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).
  
  
  METHODS
  Here, we describe clinical and molecular features of CoQ(10) deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ(10) deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ(10) biosynthesis, often improve with CoQ(10) supplementation. In vitro and in vivo studies of CoQ(10) deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ(10) deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE.
  
  
  CONCLUSIONS
  CoQ(10) deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules.
  
  
  CONCLUSIONS
  Studies of CoQ(10) deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.forename: Catarina M
authors.initials: CM
authors.lastname: Quinzii
mesh_terms: D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D013939:Thymidine Phosphorylase / Q000172:deficiency*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000172:deficiency
chemical_list: D014451:Ubiquinone; D013939:Thymidine Phosphorylase; C024989:coenzyme Q10