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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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“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
Citations
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Items 101–133 of 133
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“Similarly, a thyromimetic compound diiodothyropropionic acid (DITPA) used on affected children initiated between the ages of 9 and 25 months and carried out for more than 3 years, ameliorated their hypermetabolic states, but resulted in no significant neurologic improvement.(8) Other therapeutic approaches such as use…”
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“…with the thyroid hormone analogue triiodo-thyroacetic acid (TRIAC) 9,10 and individual studies have been reported for compassionate use with diiodothyropropionic acid (DITPA), 11 neither treatment is curative and none is able to reverse the neurological de fi cits when administered postnatally.”
Self-citationMCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency
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Self-citationThyroid Hormone Resistance Syndromes
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“It was evaluated in both experimental and clinical trials and was found to correct the impaired T3 transport and functions [12].”
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“For article see page 1328 Abbreviations: AHDS, Allan-Herndon-Dudley syndrome; DIPTA, 3,5-diiodothyropropionic acid; LDL, low-density lipoprotein;Mct8,monocarboxylate transporter 8; T3, triiodothyronine; T4, thyroxine; TR, thyroid hormone receptor; VLCFA, very long-chain fatty acid; X-ALD, X-linked adrenoleukodystrophy.”
BackgroundInfluentialGlial Origins of Inherited White Matter DisordersPreprint
Sevagamoorthy, A., Vanderver, A. L., Fraser, J. L., & Orthmann‐Murphy, J. L. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041457 · Cited by 2
Hypothyroidism: diagnosis and screening, genetic influences, and treatment options
Torres-Manzo, A. P., Cano-Europa, E., Blas-Valdivia, V., Franco-Colín, M., & Ortiz-Butrón, R. (2014) · Clinical and Experimental Medical Sciences · doi:10.12988/cems.2014.3129 · Cited by 1
“The T3 analog diiodothyropropionic acid (DITPA) has been clinically tested (40), while preclinical studies are in progress to test the analog 3,5,3 ́,5 ́-tetraiodothyroacetic acid (Tetrac); in mouse mutants deficient in the MCT8 transporter, has been proven to be metabolized to the TH receptor active compound 3,3 ́,5-…”
BackgroundDisorders of Thyroid Hormone Transporters and Receptors
Visser, W. E. (2019) · Springer eBooks · doi:10.1007/978-3-319-72102-6_4 · Cited by 1
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Cosmo, C. D. (2022) · L Endocrinologo · doi:10.1007/s40619-021-01008-x · Cited by 1
“Il trattamento con DITPA normalizzava quasi completamente i livelli degli OT, riduceva l’ipermetabolismo e la tendenza al calo ponderale, ma non aveva effetto sul sistema nervoso centrale [26], probabilmente per l’inizio tardivo della terapia.”
BackgroundFetal and Postnatal Disorders of Thyroid Function
Lawrence, S. E., Oettingen, J. E. V., & Deladoëy, J. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814823-5.00044-1 · Cited by 1
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Treatment of Paroxysmal Dystonia
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Self-citationSyndromes of Resistance to Thyroid Hormone
Moran, C., Gurnell, M., & Chatterjee, K. (2022) · doi:10.1093/med/9780198870197.003.0071
An In Vivo Accelerated Developmental Myelination Model for Testing Promyelinating Therapeutics
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MCT8 Deficiency in Two Brothers With a Novel Deletion Mutation in SLC16A2
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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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