Diiodothyropropionic Acid (DITPA) in the Treatment of MCT8 Deficiency

Verge, Charles F.; Konrad, Daniel; Cohen, Michal; Cosmo, Caterina Di; Dumitrescu, Alexandra M.; Marcinkowski, Teresa; Hameed, Shihab A.; Hamilton, Jill; Weiss, Roy E.; Refetoff, Samuel

doi:10.1210/jc.2012-2556

Cited by 121 publications

(115 citation statements)

References 23 publications

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“…Despite the normal birth weight in patients, inadequate weight gain and generalized muscle loss are seen probably as a result of increased metabolic rate associated with a hyperthyroid state of liver, skeletal muscle and fat tissue. The hyperthyroid state of the liver is supported by increased serum SHBG and decreased cholesterol levels [16,24,29,30], which was also documented in patient IV-2 of family 1. The poor weight gain in AHDS patients may be explained in part by the hyperthyroid state of different metabolic tissue and in addition by the feeding problems associated with severe psychomotor retardation [26,27,30].…”

Section: Discussionmentioning

confidence: 92%

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Psychomotor Retardation Caused by a Defective Thyroid Hormone Transporter: Report of Two Families with Different MCT8 Mutations

Anık

Kersseboom²,

Demir³

et al. 2014

Horm Res Paediatr

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Background/Aims: Monocarboxylate transporter 8 (MCT8) is essential for thyroid hormone (TH) transport in the brain. Mutations in MCT8 are associated with the Allan-Herndon-Dudley syndrome (AHDS), characterized by severe psychomotor retardation and altered serum thyroid parameters. Here we report two novel mutations in MCT8 and discuss the clinical findings. Case Report and Results: We describe 4 males with AHDS from two unrelated families varying in age from 1.5 to 11 years. All 4 patients presented with typical clinical signs of AHDS, including severe psychomotor retardation, axial hypotonia, lack of speech, diminished muscle mass, increased muscle tone, hyperreflexia, myopathic facies, high T3, low T4 and rT3, and normal/mildly elevated TSH levels. Comparison of patients at different ages suggests the progressive nature of AHDS. Genetic analyses identified a novel missense MCT8 mutation (p.G495A) in family 1 and a 2.8-kb deletion comprising exons 3 and 4 in family 2. Functional analysis of p.G495A revealed impaired TH transport varying from 20 to 85% depending on the cell context. Conclusion: Herewe report 4 AHDS patients in unrelated Turkish families harboring novel MCT8 mutations. Despite the widely different mutations, the clinical phenotypes are very similar and findings support the progressive nature of AHDS.

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Section: Discussionmentioning

confidence: 92%

“…Other cases did not receive any treatment. Studies are ongoing to test the possible benefits of treating AHDS patients with TH analogs such as DITPA, the bioactive TH metabolite Triac or its precursor Tetrac, which do not require MCT8 for cellular uptake [29,35,36]. …”

Section: Discussionmentioning

confidence: 99%

Psychomotor Retardation Caused by a Defective Thyroid Hormone Transporter: Report of Two Families with Different MCT8 Mutations

Anık

Kersseboom²,

Demir³

et al. 2014

Horm Res Paediatr

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“…This was suggested by the responses of several TH-responsive serum markers, such as elevated serum SHBG, ammonium and lactic acid levels, and reduced cholesterol concentration. Of note, three patients showed weight gain closely correlated with the decline of T 3 while on treatment with diiodothyropropionic acid (8) or with combined L-T 4 and propylthiouracil treatment (5).…”

mentioning

confidence: 92%

Mct8-Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Normalization of Serum T3 Levels

Cosmo

Liao

et al. 2013

Endocrinology

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Children with monocarboxylate transporter 8 (MCT8) deficiency lose weight, even when adequately nourished. Changes in serum markers of thyroid hormone (TH) action compatible with thyrotoxicosis suggested that this might be due to T3 excess in peripheral tissues. Mct8-deficient mice (Mct8KO) replicate the human thyroid phenotype and are thus suitable for metabolic studies so far unavailable in humans. In the current work, compared with wild-type (Wt) mice, Mct8KO mice were leaner due to reduced fat mass. They tended to use more carbohydrates and fewer lipids during the dark phase. Mct8KO mice had increased total energy expenditure (TEE) and food and water intake, with normal total activity, indicating hypermetabolism. To determine whether this is due to the high serum T3, we studied mice deficient in both Mct8 and deiodinase 1 (Mct8D1KO) with serum T3 similar to Wt mice and Wt mice given L-T3 to raise their serum T3 to the level of Mct8KO mice. Contrary to Mct8KO, Mct8D1KO mice had similar fat mass, TEE, and food intake as their D1KO littermates, whereas T3-treated Wt mice showed increased food intake and TEE, similar to Mct8KO mice. In skeletal muscle, Mct8KO mice had increased T3 content and TH action and increased glucose metabolism, which improved in Mct8D1KO mice. These studies indicate that the high serum T3 in MCT8 deficiency increases the TEE and fails to maintain weight despite adequate calorie intake. This is mediated by tissues that are not predominantly MCT8 dependent for TH transport, including skeletal muscle. Normalizing serum T3 level by deleting deiodinase 1 corrects body composition and the metabolic alterations caused by the MCT8 deficiency.

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“…Although some of them were shown to have beneficial effects in Mct8 KO zebrafish larvae (Zada et al 2014) and in Mct8/Oatp1c1 double KO mice (Horn et al 2013, Kersseboom et al 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). A better understanding of the function of MCT8 at the neuronal level during embryonic development is therefore an important objective.…”

Section: Introductionmentioning

confidence: 99%

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

Delbaere

Vancamp

Herck

et al. 2017

Journal of Endocrinology

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Inactivating mutations in the human SLC16A2 gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in the Allan-Herndon-Dudley syndrome accompanied by severe locomotor deficits. The underlying mechanisms of the associated cerebellar maldevelopment were studied using the chicken as a model. Electroporation of an MCT8-RNAi vector into the cerebellar anlage of a 3-dayold embryo allowed knockdown of MCT8 in Purkinje cell precursors. This resulted in the downregulation of the thyroid hormone-responsive gene RORα and the Purkinje cell-specific differentiation marker LHX1/5 at day 6. MCT8 knockdown also results in a smaller and less complex dendritic tree at day 18 suggesting a pivotal role of MCT8 for cell-autonomous Purkinje cell maturation. Early administration of the thyroid hormone analogue 3,5,3′-triiodothyroacetic acid partially rescued early Purkinje cell differentiation. MCT8-deficient Purkinje cells also induced non-autonomous effects as they led to a reduced granule cell precursor proliferation, a thinner external germinal layer and a loss of PAX6 expression. By contrast, at day 18, the external germinal layer thickness was increased, with an increase in presence of Axonin-1-positive post-mitotic granule cells in the initial stage of radial migration. The concomitant accumulation of presumptive migrating granule cells in the molecular layer, suggests that inward radial migration to the internal granular layer is stalled. In conclusion, early MCT8 deficiency in Purkinje cells results in both cell-autonomous and non-autonomous effects on cerebellar development and indicates that MCT8 expression is essential from very early stages of development, providing a novel insight into the ontogenesis of the Allan-HerndonDudley syndrome.

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Diiodothyropropionic Acid (DITPA) in the Treatment of MCT8 Deficiency

Abstract: 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.

Cited by 121 publications

References 23 publications

Psychomotor Retardation Caused by a Defective Thyroid Hormone Transporter: Report of Two Families with Different <b><i>MCT8</i></b> Mutations

Psychomotor Retardation Caused by a Defective Thyroid Hormone Transporter: Report of Two Families with Different <b><i>MCT8</i></b> Mutations

Mct8-Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Normalization of Serum T3 Levels

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

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