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Diiodothyropropionic Acid (DITPA) in the Treatment of MCT8 Deficiency
Open accessAbstract
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.
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In the citing paper
“However, the lack of neurological improvement in response to DITPA treatment, which was at doses 1,000-fold higher than replacement doses of T3, may also be due to the late treatment initiation of MCT8-deficient patients (at ages of 9–21 months) (Verge et al., 2012).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Verge et al., 2012
In the citing paper
“As an example, DITPA is a TH analog that can activate the T3 signaling cascade and has been tested in animal models and MCT8-deficient patients (Ferrara et al., 2015; Verge et al., 2012).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Verge et al., 2012
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Thyroid Hormone Regulation of Metabolism
Mullur, R., Liu, Y.-Y., & Brent, G. A. (2014) · Physiological Reviews · doi:10.1152/physrev.00030.2013 · Cited by 2,421
“Treatment with diiodothyropropionic acid (DITPA), in animal models and humans with inactivation or mutation in the MCT8 gene, results in reduction in serum TSH and serum T3, and an improvement in hypermetabolism with weight gain and reduced caloric needs (60, 262).”
BackgroundJonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., et al. (2014) · Thyroid® · doi:10.1089/thy.2014.0028 · Cited by 1,928
“These individuals have peripheral hypermetabolism and abnormal serum thyroid levels with elevated serum T3, low serum T4, and slightly high TSH (486,500,501).”
Paradigms of dynamic control of thyroid hormone signaling
Bianco, A. C., Dumitrescu, A., Gereben, B., Ribeiro, M. O., Fonseca, T. L., Fernandes, G. W., & Bocco, B. M. L. C. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00275 · Cited by 293
Self-citationTreatment with thyroid hormone
Biondi, B., & Wartofsky, L. (2014) · Endocrine Reviews · doi:10.1210/er.2013-1083 · Cited by 259
Thyroid hormone signaling in energy homeostasis and energy metabolism
McAninch, E. A., & Bianco, A. C. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12374 · Cited by 245
Metadata
- Authors
- Verge, C. F., Konrad, D., Cohen, M., Di Cosmo, C., Dumitrescu, A. M., Marcinkowski, T., Hameed, S., Hamilton, J., Weiss, R. E., & Refetoff, S.
- Affiliations
- UNSW Sydney (AU)
- University Children's Hospital Zurich (CH)
- Hospital for Sick Children (CA)
- Departments of Medicine (C.D.C., A.M.D., T.M., R.E.W., S.R.), Chicago, Illinois 60637
- Pediatrics (R.E.W., S.R.), Chicago, Illinois 60637
- University of Chicago (US)
- Corresponding author
- Refetoff, Samuel
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-12-01
- Volume
- 97
- Issue
- 12
- Pages
- 4515-4523
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3513545
- OpenAlex
- W2123696673
- Cited by
- 134
- References
- 22
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 16 · 2023: 4 · 2022: 9 · 2021: 8 · 2020: 10 · 2019: 12 · 2018: 5 · 2017: 13 · 2016: 11 · 2015: 13 · 2014: 14 · 2013: 12 · 2012: 2
- FWCI
- 10.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pediatric Endocrine Society
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R37-DK 15070, P60DK20595, R37DK015070, F32DK091016, P60DK020595)
- National Center for Research Resources (5M01RR04999)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- MCT8 deficiency, MCT8, thyroid hormone transport, thyroid hormone analogs, hypermetabolism, psychomotor retardation, serum thyroid hormones, thyroid-stimulating hormone, sex hormone-binding globulin, children, compassionate use
- MeSH terms
- Brain, Cardiotonic Agents, Child Development, Child, Preschool, Diiodothyronines, Diseases in Twins, Humans, Infant, Male, Muscle Hypotonia, Muscular Atrophy, Propionates, Psychomotor Performance, Thyroid Function Tests, Multicenter Studies as Topic, Monocarboxylic Acid Transporters, Symporters, X-Linked Intellectual Disability, Mental Retardation, X-Linked, Compassionate Use Trials
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