title: Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency.
abstract: BACKGROUND
  Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. MCT8 deficiency causes severe psychomotor retardation and abnormal thyroid tests. The great majority of affected children cannot walk or talk, and all have elevated serum T(3) levels, causing peripheral tissue hypermetabolism and inability to maintain weight. Treatment with thyroid hormone is ineffective. In Mct8-deficient mice, the thyroid hormone analog, diiodothyropropionic acid (DITPA), does not require MCT8 to enter tissues and could be an effective alternative to thyroid hormone treatment in humans.
  
  
  OBJECTIVE
  The objective of the study was to evaluate the effect and efficacy of DITPA in children with MCT8 deficiency.
  
  
  METHODS
  This was a multicenter report of four affected children given DITPA on compassionate grounds for 26-40 months. Treatment was initiated at ages 8.5-25 months, beginning with a small dose of 1.8 mg, increasing to a maximal 30 mg/d (2.1-2.4 mg/kg · d), given in three divided doses.
  
  
  RESULTS
  DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The following significant changes were also observed: decline in SHBG (in all subjects), heart rate (in three of four), and ferritin (in one of four). Cholesterol increased in two subjects. There was no weight loss and weight gain occurred in two. None of the treated children required a gastric feeding tube or developed seizures. No adverse effects were observed.
  
  
  CONCLUSIONS
  DITPA (1-2 mg/kg · d) almost completely normalizes thyroid tests and reduces the hypermetabolism and the tendency for weight loss. The effects of earlier commencement and long-term therapy remain to be determined.
authors.affiliation: Department of Endocrinology, Sydney Children's Hospital, Randwick, NSW 2031, Australia.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Verge
authors.forename: Daniel
authors.initials: D
authors.lastname: Konrad
authors.forename: Michal
authors.initials: M
authors.lastname: Cohen
authors.forename: Caterina
authors.initials: C
authors.lastname: Di Cosmo
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Dumitrescu
authors.forename: Teresa
authors.initials: T
authors.lastname: Marcinkowski
authors.forename: Shihab
authors.initials: S
authors.lastname: Hameed
authors.forename: Jill
authors.initials: J
authors.lastname: Hamilton
authors.forename: Roy E
authors.initials: RE
authors.lastname: Weiss
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D001921:Brain / Q000187:drug effects / Q000254:growth & development; D002316:Cardiotonic Agents / Q000627:therapeutic use; D002657:Child Development / Q000187:drug effects; D002675:Child, Preschool; D057176:Compassionate Use Trials; D004104:Diiodothyronines / Q000627:therapeutic use*; D004200:Diseases in Twins / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007223:Infant; D008297:Male; D038901:X-Linked Intellectual Disability / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D027501:Monocarboxylic Acid Transporters / Q000172:deficiency*; D015337:Multicenter Studies as Topic; D009123:Muscle Hypotonia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D011422:Propionates / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D027981:Symporters; D013960:Thyroid Function Tests
chemical_list: D002316:Cardiotonic Agents; D004104:Diiodothyronines; D027501:Monocarboxylic Acid Transporters; D011422:Propionates; C090735:SLC16A2 protein, human; D027981:Symporters; C082182:3,5-diiodothyropropionic acid