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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The lack of neurological improvement in response to DITPA treatment may also be due to late treatment initiation of MCT8-deficient patients (at ages 9-21 months).
“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
DITPA is a TH analog that can activate the T3 signaling cascade and has been tested in animal models and MCT8-deficient patients.
“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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Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology
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“It almost completely normalizes thyroid tests and reduces hypermetabolism and the tendency to weight loss (56).”
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“Importantly, this DITPA dose was well tolerated by the children and, as in mice, did not have thyrotoxic effects on peripheral organs (Verge et al., 2012), making it an attractive option for therapeutic intervention.”
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“2014), a recent clinical trial in patients treated in the first year of infancy failed to improve mental status, probably because neurological damage was already irreversible at the onset of treatment (Verge et al. 2012).”
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Chen, Z., Meima, M. E., Peeters, R. P., & Visser, W. E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315113 · Cited by 34 · see citing works
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The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency
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Self-citationPrenatal Treatment of Thyroid Hormone Cell Membrane Transport Defect Caused by MCT8 Gene Mutation
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Self-citationSobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain
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“The available treatments consist of a combination of levothyroxine (LT4) and propylthiouracil (PTU) (20), or the TH analog 3,5-diiodothyropropionic acid (DITPA) (21).”
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Genetic disorders of thyroid metabolism and brain development
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“Increased ferritin and decreased cholesterol levels have been observed in some individuals.(30)”
BackgroundPlacenta Passage of the Thyroid Hormone Analog DITPA to Male Wild-Type and Mct8-Deficient Mice
Ferrara, A. M., Liao, X.-H., Gil-Ibáñez, P., Bernal, J., Weiss, R. E., Dumitrescu, A. M., & Refetoff, S. (2014) · Endocrinology · doi:10.1210/en.2014-1085 · Cited by 26 · see citing works
“The capacity of DITPA to cross the placenta, to enter fetal tissues, and to mimic TH action at pituitary and cortical levels in addition to the beneficial effects on the hypermetabolism already described in humans (7), makes this compound particularly suitable for prenatal treatment of MCT8 deficiency in humans.”
BackgroundInfluentialSelf-citationTreatment of congenital thyroid dysfunction: Achievements and challenges
Krude, H., Kühnen, P., & Biebermann, H. (2015) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2015.04.004 · Cited by 25 · see citing works
Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action
Dumitrescu, A. M., & Refetoff, S. (2015) · Cited by 24 · see citing works
Self-citationLiao, X.-H., Avalos, P., Shelest, O., Ofan, R., Shilo, M., Bresee, C. J., Likhite, S. B., Vit, J., Heuer, H., Kaspar, B. K., et al. (2022) · Thyroid · doi:10.1089/thy.2022.0034 · Cited by 24 · see citing works
“In patients with AHDS, DITPA (46) and TRIAC (47) reduced the high serum T 3 concentration; however, there was no evidence for improvement in neurological symptoms.”
Self-citationOligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions
Kim, M., & Petratos, S. (2019) · Stem Cells International · doi:10.1155/2019/5496891 · Cited by 23 · see citing works
“In AHDS patients, elevated levels of serum T3 occur causing hypermetabolism in peripheral tissues, whereas reduced T3 within the brain establishes a hypothyroid state within the CNS [95].”
BackgroundInfluentialEmamnejad, R., Pagnin, M., & Petratos, S. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105788 · Cited by 24 · see citing works
“…DITPA is that it has the unique capacity to bypass the main TH transporter, monocarboxylate transporter 8 (MCT8), located within the blood-brain barrier (BBB) and the plasma membrane (Verge et al., 2012), a property that establishes it as an excellent candidate in a drug development program for MS.”
Anık, A., Kersseboom, S., Demir, K., Çatlı, G., Yiş, U., Böber, E., van Mullem, A. A., van Heerebeek, R., Kurul, S. H., Abacı, A., et al. (2014) · Hormone Research in Paediatrics · doi:10.1159/000365191 · Cited by 23 · see citing works
Braun, D., & Schweizer, U. (2016) · Endocrinology · doi:10.1210/en.2016-1530 · Cited by 23 · see citing works
“Diiodothyropropionic acid is reported to normalize the serum parameters of thyroid hormone function and allow weight gain, but improvements in neurologic impairment remained difficult to assess (46).”
BackgroundZebrafish – An emerging model to explore thyroid hormone transporters and psychomotor retardation
Zada, D., Blitz, E., & Appelbaum, L. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.03.004 · Cited by 23 · see citing works
Admati, I., Wasserman-Bartov, T., Tovin, A., Rozenblat, R., Blitz, E., Zada, D., Lerer‐Goldshtein, T., & Appelbaum, L. (2019) · Thyroid · doi:10.1089/thy.2019.0320 · Cited by 23 · see citing works
Salas-Lucia, F., Escamilla, S., Bianco, A. C., Dumitrescu, A. M., & Refetoff, S. (2024) · JCI Insight · doi:10.1172/jci.insight.174645 · Cited by 24 · see citing works
Self-citationKim, J. H., Kim, Y., Yum, M., Choi, J., Lee, B. H., Kim, G.-H., & Yoo, H. (2015) · Hormone Research in Paediatrics · doi:10.1159/000371466 · Cited by 19 · see citing works
Hypotonic male infant and MCT8 deficiency - a diagnosis to think about
Rodrigues, F., Grenha, J., Ortez, C., Nascimento, A., Morte, B., Belinchón, M. M., Armstrong, J., & Colomer, J. (2014) · BMC Pediatrics · doi:10.1186/1471-2431-14-252 · Cited by 19 · see citing works
“Some AHDS patients have been treated with TH supplementation, propylthiouracil or diiodothyropropionic acid; the last two result in better thyroid function tests, but without any improvement of motor or cognitive skills [19-21].”
MethodSchweizer, U., Towell, H., Vit, A., Rodriguez-Ruiz, A., & Steegborn, C. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.026 · Cited by 18 · see citing works
A Transgenic Mouse Model for Detection of Tissue-Specific Thyroid Hormone Action
Mohácsik, P., Erdélyi, F., Baranyi, M., Botz, B., Szabó, G., Tóth, M., Haltrich, I., Helyes, Z., Sperlágh, B., Tóth, Z., et al. (2017) · Endocrinology · doi:10.1210/en.2017-00582 · Cited by 18 · see citing works
“The discovery of cellular mechanisms that allow for tissue specificity of TH action inspired the development of TR isoform- and tissue-specific TH analogs (16, 17).”
BackgroundChen, J., Salveridou, E., Liebmann, L., Sundaram, S. M., Doycheva, D., Markova, B., Hübner, C. A., Boelen, A., Visser, W. E., Heuer, H., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043452 · Cited by 17 · see citing works
“In a compassionate study, Ditpa was given for 26–40 months to four affected children at the age of 8–25 months and was able to both normalize high serum T3 concentrations and reduce symptoms of hypermetabolism [18].”
BackgroundGroeneweg, S., van den Berge, A., Meima, M. E., Peeters, R. P., Visser, T. J., & Visser, W. E. (2018) · Endocrinology · doi:10.1210/en.2017-00846 · Cited by 17 · see citing works
Disorders of the thyroid in the newborn and infant
Vliet, G. V., & Deladoëy, J. (2014) · Elsevier eBooks · doi:10.1016/b978-1-4557-4858-7.00016-0 · Cited by 16 · see citing works
Therapeutic applications of thyroid hormone analogues
Visser, W. E. (2020) · Annales d Endocrinologie · doi:10.1016/j.ando.2020.03.004 · Cited by 15 · see citing works
Triiodothyroacetic Acid Treatment in MCT8 Deficiency: A Word of Nuance
Visser, W. E., Heuer, H., & Visser, T. J. (2016) · Thyroid · doi:10.1089/thy.2016.0191 · Cited by 15 · see citing works
“Subsequently, some patients were treated with DITPA, with improvement of serum T3 concentrations and markers of peripheral T3 action (12).”
Trophic Factor, Nutritional, and Hormonal Regulation of Brain Development
Pleasure, J. R., Pleasure, D., & Pleasure, S. J. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-35214-7.00133-5 · Cited by 14 · see citing works
Finding the Way into the Brain without MCT8
Visser, W. E., & Visser, T. J. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3759 · Cited by 14 · see citing works
Bárez‐López, S., Grijota-Martínez, C., Liao, X.-H., Refetoff, S., & Guadaño‐Ferraz, A. (2019) · PLoS ONE · doi:10.1371/journal.pone.0226017 · Cited by 14 · see citing works
“Patients have also been treated with the TH analog 3,5-diiodothyropropionic acid (DITPA), which is an agonist of the T3 nuclear receptor [14].”
MethodSelf-citationEmamnejad, R., Dass, M., Mahlis, M., Bozkurt, S., Ye, S., Pagnin, M., Theotokis, P., Grigoriadis, N., & Petratos, S. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.934971 · Cited by 13 · see citing works
“For example, DITPA can normalize peripheral hyperthyroidism and reduce hypermetabolism in AHDS patients.”
BackgroundResultInfluentialWilpert, N., Tonduti, D., Vaia, Y., Krude, H., Sarret, C., & Schuelke, M. (2023) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s379703 · Cited by 13 · see citing works
“14 23, 25 Whether the reported Concluding considerations for development of therapies for MCT8 deficiency: (i) The full downstream effects of SLC16A2 mutations are not yet fully understood.”
BackgroundUnmet patient needs in monocarboxylate transporter 8 (MCT8) deficiency: a review
Bauer, A. J., Auble, B. A., Clark, A. L., Hu, T. Y., Isaza, A. R., McNerney, K. P., Metzger, D. L., Nicol, L. E., Pierce, S. R., & Sidlow, R. (2024) · Frontiers in Pediatrics · doi:10.3389/fped.2024.1444919 · Cited by 13 · see citing works
“DITPA (diiodothyropropionic acid) is a synthetic T3 analog that can enter the CNS independent of MCT8 and stimulate thyroid hormone action by binding to the thyroid hormone receptors, TR α and TR β (45, 47).”
BackgroundKrude, H., Biebermann, H., Schuelke, M., Müller, T. D., & Tschöp, M. H. (2020) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1108-1456 · Cited by 12 · see citing works
The Influence of Thyroid Hormone on Growth Hormone Secretion and Action
Leung, A. M., & Brent, G. A. (2016) · Springer eBooks · doi:10.1007/978-3-319-28038-7_4 · Cited by 12 · see citing works
Valcárcel-Hernández, V., Guillén-Yunta, M., Scanlan, T. S., Bárez‐López, S., & Guadaño‐Ferraz, A. (2023) · Thyroid · doi:10.1089/thy.2022.0612 · Cited by 11 · see citing works
The Role of Thyroid Hormone in Neuronal Protection
Liu, Y., & Brent, G. A. (2021) · Comprehensive physiology · doi:10.1002/j.2040-4603.2021.tb00174.x · Cited by 11 · see citing works
“Treatment with diiodothyropropionic acid (DITPA), a thyroid hormone analog, that bypass the transporter to enter the brain, has not been shown effectiveness in promoting neurological improvement (175), but does result in reduction in serum T3 and marked improvement of the associated hypermetabolism.”
Intranasal delivery of Thyroid hormones in MCT8 deficiency
Grijota-Martínez, C., Bárez‐López, S., Ausó, E., Refetoff, S., Frey, W. H., & Guadaño‐Ferraz, A. (2020) · PLoS ONE · doi:10.1371/journal.pone.0236113 · Cited by 11 · see citing works
Self-citationValcárcel-Hernández, V., Guillén-Yunta, M., Bueno-Arribas, M., Montero‐Pedrazuela, A., Grijota-Martínez, C., Markossian, S., García-Aldea, Á., Flamant, F., Bárez‐López, S., & Guadaño‐Ferraz, A. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105896 · Cited by 12 · see citing works
“reported to be epilepsy-prone (Vaurs-Barrière et al., 2009; Verge et al., 2012) consistent with our current findings in the P253L mice, alterations in the GABAergic system could be underlying the predisposition to epilepsy in some patients.”
BackgroundResultToward a treatment for thyroid hormone transporter MCT8 deficiency – achievements and challenges
Markova, B., Mayerl, S. E., & Heuer, H. (2024) · European Thyroid Journal · doi:10.1530/etj-24-0286 · Cited by 10 · see citing works
Chan, S. L., Refetoff, S., Babić, N., Jin, M., Garg, U. C., & Yeo, K.-T. J. (2021) · American Journal of Clinical Pathology · doi:10.1093/ajcp/aqab124 · Cited by 10 · see citing works
Self-citationTsh Induces Agrp1 Neuron Proliferation in Oatp1c1-Deficient Zebrafish
Wasserman-Bartov, T., Admati, I., Lebenthal-Loinger, I., Sharabany, J., Lerer‐Goldshtein, T., & Appelbaum, L. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0002-22.2022 · Cited by 9 · see citing works
Gurnell, M., Visser, T. J., Beck‐Peccoz, P., & Chatterjee, K. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00095-0 · Cited by 9 · see citing works
Brent, G. A. (2013) · Thyroid · doi:10.1089/thy.2013.0679 · Cited by 9 · see citing works
“Thyroid hormone transport by moncarboxylate transporter 8 (Mct8) has gone from characterization in basic studies, to clinical studies identifying Mct8 gene mutations in patients with severe psychomotor retardation and abnormal thyroid function studies, to mouse models of Mct8 mutations, and then back to clinical treat…”
BackgroundChincarini, G., Walker, D. W., Wong, F. Y., Richardson, S. J., Cumberland, A. L., & Tolcos, M. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16124 · Cited by 7 · see citing works
“…boys with AHDS (congenital MCT8 mutation) have reported overall positive outcomes and ameliorated peripheral thyrotoxicosis (Groeneweg et al., 2019; Verge et al., 2012 ); follow-up trials evaluating the long-term neurodevelopmental outcomes following early life intervention are currently ongoing…”
InfluentialCheetham, T. D., & Wood, C. L. (2024) · Clinical Endocrinology · doi:10.1111/cen.15110 · Cited by 7 · see citing works
“51,52 A key question is whether early treatment will impact on neurodevelopmental outcome. that can include attention deficit hyperactivity disorder (ADHD).”
An in vivo accelerated developmental myelination model for testing promyelinating therapeutics
Lariosa-Willingham, K. D., Leonoudakis, D., Bragge, T., Tolppanen, L., Nurmi, A., Flanagan, M., Gibson, J., Wilson, D. L., Stratton, J., Lehtimäki, K. K., et al. (2022) · BMC Neuroscience · doi:10.1186/s12868-022-00714-y · Cited by 7 · see citing works
Interpreting Minor Variations in Thyroid Function or Echostructure
Vliet, G. V., & Deladoëy, J. (2015) · Pediatric Clinics of North America · doi:10.1016/j.pcl.2015.04.008 · Cited by 7 · see citing works
Thyroid Hormone Analogs: Recent Developments
Freund, M., van Geest, F. S., Groeneweg, S., van Geest, F. S., & Visser, W. E. (2025) · Thyroid · doi:10.1089/thy.2025.0245 · Cited by 6 · see citing works
Schreiner, F., Vollbach, H., Sonntag, N., Schempp, V., Gohlke, B. C., Friese, J., Woelfle, J., Braun, D., & Schweizer, U. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae356 · Cited by 6 · see citing works
Diagnostic and Therapeutic Challenges in the Allan—Herndon—Dudley Syndrome
Groeneweg, S., Peeters, R. P., Visser, T. J., & Visser, W. E. (2016) · US Endocrinology · doi:10.17925/use.2016.12.02.90 · Cited by 6 · see citing works
Iwayama, H., Tanaka, T., Aoyama, K., Moroto, M., Adachi, S., Fujisawa, Y., Matsuura, H., Takano, K., Mizuno, H., & Okumura, A. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.657820 · Cited by 6 · see citing works
Syndromes of Impaired Sensitivity to Thyroid Hormone
Weiss, R. E., Dumitrescu, A. M., & Refetoff, S. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800892-8.00009-9 · Cited by 6 · see citing works
Self-citationWilpert, N., Hewitt, A. L., Pons, R. M., Henke, M., Dell’Orco, A., Bauer, M., Grolik, C., Menz, S., Wahle, M., Zink, A., et al. (2025) · Movement Disorders · doi:10.1002/mds.30152 · Cited by 5 · see citing works
Glycerol Phenylbutyrate Treatment of 2 Patients With Monocarboxylate Transporter 8 Deficiency
Zung, A., Sonntag, N., Schweizer, U., Banne, E., & Braun, D. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae146 · Cited by 5 · see citing works
Identification of Human TRIAC Transmembrane Transporters
Becker, P. C., Güth-Steffens, M., Lazarow, K., Sonntag, N., Braun, D., Masfaka, S., Renko, K., Schomburg, L., Köhrle, J., von Kries, J. P., et al. (2024) · Thyroid · doi:10.1089/thy.2023.0592 · Cited by 5 · see citing works
Funkquist, A., Bengtsson, A. A., Johansson, P., Svensson, J., Bjellerup, P., Blennow, K., Wandt, B., & Sjöberg, S. (2020) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2020.100218 · Cited by 5 · see citing works
“The monocarboxylate transporter 8 (MCT8) [16,29] is a specific transporter for thyroid hormones (TH) into the CNS. Allan-HerndonDudleys Syndrome (AHDS) is a disease specifically with - a MCT8 mutation [30].”
BackgroundInfluential
- 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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