Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial

Groeneweg, Stefan; Peeters, Robin P.; Moran, Carla; Stoupa, Athanasia; Auriol, Françoise; Tonduti, Davide; Dica, Alice; Paone, Laura; Roženková, Klára; Malíková, Jana; Walt, Adri van der; Coo, I.F.M. de; McGowan, Anne; Lyons, Greta; Aarsen, Femke K.; Barca, Diana; Beynum, Ingrid M. van; Knoop, Marieke M. van der; Jansen, Jos R. C.; Manshande, Martien; Lunsing, Roelineke J.; Nowak, S; Uil, Corstiaan A. den; Zillikens, M. Carola; Visser, Frank E.; Vrijmoeth, P; Wit, Marie Claire Y. de; Wolf, Nicole I.; Zandstra, Angelique; Ambegaonkar, Gautam; Singh, Yogen; Rijke, Yolanda B. de; Medici, Marco; Bertini, Enrico; Depoorter, Sylvia; Lebl, Jan; Cappa, Marco; Meırleır, Linda De; Krude, Heiko; Craiu, Dana; Zibordi, Federica; Petit, Isabelle; Polak, Michel; Chatterjee, Krishna; Visser, Theo J.; Visser, W. Edward

doi:10.1016/s2213-8587(19)30155-x

Cited by 100 publications

(120 citation statements)

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“…Despite high serum concentrations of T3 (12), intracerebral TH concentrations are likely to be reduced in these patients, since histopathological findings of delayed myelination, synaptogenesis, and neuronal differentiation imply a cerebral hypothyroid state during critical periods of pre-and postnatal brain development (13,14). Importantly, trials to treat MCT8-deficient patients with TH analogues met with very limited success in improving neurological outcomes (15)(16)(17). Only the early postnatal administration of the TH analogue Triac restored Purkinje cell morphology, myelination, and distribution of cortical interneurons in mouse models (18), and it slightly improved the neurological symptoms in six out of seven patients with MCT8 deficiency within the age group of 1.5 to 3.5 years (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, trials to treat MCT8-deficient patients with TH analogues met with very limited success in improving neurological outcomes (15)(16)(17). Only the early postnatal administration of the TH analogue Triac restored Purkinje cell morphology, myelination, and distribution of cortical interneurons in mouse models (18), and it slightly improved the neurological symptoms in six out of seven patients with MCT8 deficiency within the age group of 1.5 to 3.5 years (17,18). Therefore, the development of targeted therapies critically depends on (i) a detailed knowledge of the exact localization of MCT8 within the NVU to facilitate TH transport from the blood to neurons, and (ii) the identification of temporal changes of MCT8 expression to define the time window for therapy.…”

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression

Wilpert

Krueger

Opitz

et al. 2020

Thyroid

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Background: Mutations of monocarboxylate transporter 8 (MCT8), a thyroid hormone (TH)-specific transmembrane transporter, cause a severe neurodevelopmental disorder, the Allan-Herndon-Dudley syndrome. In MCT8 deficiency, TH is not able to reach those areas of the brain where TH uptake depends on MCT8. Currently, therapeutic options for MCT8-deficient patients are missing, as TH treatment is not successful in improving neurological deficits. Available data on MCT8 protein and transcript levels indicate complex expression patterns in neural tissue depending on species, brain region, sex, and age. However, information on human MCT8 expression is still scattered and additional efforts are needed to map sites of MCT8 expression in neurovascular units and neural tissue. This is of importance because new therapeutic strategies for this disease are urgently needed. Methods: To identify regions and time windows of MCT8 expression, we used highly specific antibodies against MCT8 to perform immunofluorescence labeling of postnatal murine brains, adult human brain tissue, and human cerebral organoids. Results: Qualitative and quantitative analyses of murine brain samples revealed stable levels of MCT8 protein expression in endothelial cells of the blood-brain barrier (BBB), choroid plexus epithelial cells, and tanycytes during postnatal development. Conversely, the neuronal MCT8 protein expression that was robustly detectable in specific brain regions of young mice strongly declined with age. Similarly, MCT8 immunoreactivity in adult human brain tissue was largely confined to endothelial cells of the BBB. Recently, cerebral organoids emerged as promising models of human neural development and our first analyses of forebrain-like organoids revealed MCT8 expression in early neuronal progenitor cell populations. Conclusions: With respect to MCT8-deficient conditions, our analyses not only strongly support the contention that the BBB presents a lifelong barrier to TH uptake but also highlight the need to decipher the TH transport role of MCT8 in early neuronal cell populations in more detail. Improving the understanding of the spatiotemporal expression in latter barriers will be critical for therapeutic strategies addressing MCT8 deficiency in the future.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression

Wilpert

Krueger

Opitz

et al. 2020

Thyroid

Self Cite

View full text Add to dashboard Cite

show abstract

“…Theoretical and other considerations have suggested that the T 3 analog, 3,3¢,5-triiodothyroacetic acid (TRIAC), might be effective in reducing circulating T 3 concentrations in patients with the AHDS (5,6). Therefore, in this study (4)…”

Section: Introductionmentioning

confidence: 89%

“…As far as the potential that thyromimetic effects of TRIAC in patients with AHDS are important, a tantalizing observation that is still very preliminary was that very modest improvements in motor function were more prominent in the youngest group of patients who received TRIAC (4). Therefore, the authors have planned "a future clinical trial" (Clini-calTrials.gov no.…”

Section: Commentarymentioning

confidence: 99%

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TRIAC May Ameliorate T₃ Thyrotoxicosis in the Allan–Herndon–Dudley Syndrome with MCT8 Deficiency

EmersonCharles

2019

Clinical Thyroidology

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Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan–Herndon–Dudley Syndrome

Ramon‐Gomez,

Cortés‐Rojas,

Polania‐Puentes

et al. 2024

Movement Disord Clin Pract

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BackgroundDeficiencies in the thyroid hormone transporter monocarboxylate 8 (MCT8) due to pathogenic variants in the SLC16A2 gene (OMIM 300095) result in a complex phenotype with main endocrine and neurologic symptoms. This rare disorder, named Allan–Herndon–Dudley syndrome (AHDS) (OMIM 300523), is inherited in an X‐linked trait. One of the prominent features of AHDS is the presence of movement disorders (MD), which are complex and carry a significant burden of the disease.CasesPatient 1: male with hypotonia since birth, developmental delay, dystonic posturing at 4 months and at 15 months, and startle reaction developed with sensory stimuli. Patient 2: male, at 2 months, shows hypotonia and developmental delay, paroxysmal episodes triggered by a stimulus with sudden blush, tonic asymmetric posture, and no epileptiform activity. At 10 months, generalized dystonic posturing. Patient 3: typical neurodevelopmental milestones until 6 months; at 24 months, dystonia, startle reaction, and upper motoneuron signs.ConclusionsWe aim to describe our patients diagnosed with AHDS, focusing on MD phenomenology and strengthening the phenotype–genotype correlations for this rare condition.

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Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial

Cited by 100 publications

References 30 publications

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression

TRIAC May Ameliorate T₃ Thyrotoxicosis in the Allan–Herndon–Dudley Syndrome with MCT8 Deficiency

Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan–Herndon–Dudley Syndrome

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Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial

Cited by 100 publications

References 30 publications

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression

TRIAC May Ameliorate T3 Thyrotoxicosis in the Allan–Herndon–Dudley Syndrome with MCT8 Deficiency

Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan–Herndon–Dudley Syndrome

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TRIAC May Ameliorate T₃ Thyrotoxicosis in the Allan–Herndon–Dudley Syndrome with MCT8 Deficiency