CONTEXT: 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. CONCLUSION: 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.
CONTEXT: 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-deficientmice, 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. CONCLUSION: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: Charles E Schwartz; Melanie M May; Nancy J Carpenter; R Curtis Rogers; Judith Martin; Martin G Bialer; Jewell Ward; Javier Sanabria; Silvana Marsa; James A Lewis; Roberto Echeverri; Herbert A Lubs; Kytja Voeller; Richard J Simensen; Roger E Stevenson Journal: Am J Hum Genet Date: 2005-05-11 Impact factor: 11.025
Authors: Alexandra M Dumitrescu; Xiao-Hui Liao; Roy E Weiss; Kathleen Millen; Samuel Refetoff Journal: Endocrinology Date: 2006-05-18 Impact factor: 4.736
Authors: Edith C H Friesema; Annette Grueters; Heike Biebermann; Heiko Krude; Arpad von Moers; Maarten Reeser; Timothy G Barrett; Edna E Mancilla; Johan Svensson; Monique H A Kester; George G J M Kuiper; Sahila Balkassmi; André G Uitterlinden; Josef Koehrle; Patrice Rodien; Andrew P Halestrap; Theo J Visser Journal: Lancet Date: 2004 Oct 16-22 Impact factor: 79.321
Authors: Alexandra M Dumitrescu; Xiao-Hui Liao; Thomas B Best; Knut Brockmann; Samuel Refetoff Journal: Am J Hum Genet Date: 2003-12-05 Impact factor: 11.025
Authors: Edith C H Friesema; Sumita Ganguly; Amal Abdalla; Jocelyn E Manning Fox; Andrew P Halestrap; Theo J Visser Journal: J Biol Chem Date: 2003-07-18 Impact factor: 5.157
Authors: Hideyuki Iwayama; Xiao-Hui Liao; Lyndsey Braun; Soledad Bárez-López; Brian Kaspar; Roy E Weiss; Alexandra M Dumitrescu; Ana Guadaño-Ferraz; Samuel Refetoff Journal: Thyroid Date: 2016-08-23 Impact factor: 6.568
Authors: Caterina Di Cosmo; Xiao-Hui Liao; Honggang Ye; Alfonso Massimiliano Ferrara; Roy E Weiss; Samuel Refetoff; Alexandra M Dumitrescu Journal: Endocrinology Date: 2013-09-12 Impact factor: 4.736
Authors: Jacqueline Jonklaas; Antonio C Bianco; Andrew J Bauer; Kenneth D Burman; Anne R Cappola; Francesco S Celi; David S Cooper; Brian W Kim; Robin P Peeters; M Sara Rosenthal; Anna M Sawka Journal: Thyroid Date: 2014-12 Impact factor: 6.568
Authors: Antonio C Bianco; Alexandra Dumitrescu; Balázs Gereben; Miriam O Ribeiro; Tatiana L Fonseca; Gustavo W Fernandes; Barbara M L C Bocco Journal: Endocr Rev Date: 2019-08-01 Impact factor: 19.871
Authors: Soledad Bárez-López; Meredith D Hartley; Carmen Grijota-Martínez; Thomas S Scanlan; Ana Guadaño-Ferraz Journal: Thyroid Date: 2018-06-29 Impact factor: 6.568