Intracerebroventricular High Doses of 3,3′,5-Triiodothyroacetic Acid at Juvenile Stages Improve Peripheral Hyperthyroidism and Mediate Thyromimetic Effects in Limited Brain Regions in a Mouse Model of Monocarboxylate Transporter 8 Deficiency

Grijota-Martínez, Carmen; Montero-Pedrazuela, Ana; Hidalgo-Álvarez, Jorge; Bárez-López, Soledad; Guadaño-Ferraz, Ana

doi:10.1089/thy.2022.0562

Cited by 2 publications

(1 citation statement)

References 42 publications

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“…Until recently, postnatal treatment of these patients with TH supplementation, with the TH analogs, TRIAC ( 24 ) or DITPA that do not require transport by MCT8 results in better thyroid function tests, improving hypermetabolism. However, no motor or cognitive skills improvement was observed ( 25 ). Very recently, prenatal treatment using levothyroxine (LT4) ameliorated the neuromotor and neurocognitive function of an AHDS patient ( 26 )…”

Section: Introductionmentioning

confidence: 99%

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

Silva

Campinho

2023

Front. Endocrinol.

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BackgroundMaternally derived thyroid hormone (T3) is a fundamental factor for vertebrate neurodevelopment. In humans, mutations on the thyroid hormones (TH) exclusive transporter monocarboxylic acid transporter 8 (MCT8) lead to the Allan-Herndon-Dudley syndrome (AHDS). Patients with AHDS present severe underdevelopment of the central nervous system, with profound cognitive and locomotor consequences. Functional impairment of zebrafish T3 exclusive membrane transporter Mct8 phenocopies many symptoms observed in patients with AHDS, thus providing an outstanding animal model to study this human condition. In addition, it was previously shown in the zebrafish mct8 KD model that maternal T3 (MTH) acts as an integrator of different key developmental pathways during zebrafish development.MethodsUsing a zebrafish Mct8 knockdown model, with consequent inhibition of maternal thyroid hormones (MTH) uptake to the target cells, we analyzed genes modulated by MTH by qPCR in a temporal series from the start of segmentation through hatching. Survival (TUNEL) and proliferation (PH3) of neural progenitor cells (dla, her2) were determined, and the cellular distribution of neural MTH-target genes in the spinal cord during development was characterized. In addition, in-vivo live imaging was performed to access NOTCH overexpression action on cell division in this AHDS model. We determined the developmental time window when MTH is required for appropriate CNS development in the zebrafish; MTH is not involved in neuroectoderm specification but is fundamental in the early stages of neurogenesis by promoting the maintenance of specific neural progenitor populations. MTH signaling is required for developing different neural cell types and maintaining spinal cord cytoarchitecture, and modulation of NOTCH signaling in a non-autonomous cell manner is involved in this process.DiscussionThe findings show that MTH allows the enrichment of neural progenitor pools, regulating the cell diversity output observed by the end of embryogenesis and that Mct8 impairment restricts CNS development. This work contributes to the understanding of the cellular mechanisms underlying human AHDS.

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Section: Introductionmentioning

confidence: 99%

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

Silva

Campinho

2023

Front. Endocrinol.

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Unmet patient needs in monocarboxylate transporter 8 (MCT8) deficiency: a review

Bauer,

Auble,

Clark

et al. 2024

Front. Pediatr.

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Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport. This disorder is characterized by profound neurodevelopmental delay and motor disability due to a lack of thyroid hormone in the brain, and coexisting endocrinological symptoms, due to chronic thyrotoxicosis, resulting from elevated thyroid hormone outside the central nervous system (CNS). In February 2024, we reviewed the published literature to identify relevant articles reporting on the current unmet needs of patients with MCT8 deficiency. There are several main challenges in the diagnosis and treatment of MCT8 deficiency, with decreased awareness and recognition of MCT8 deficiency among healthcare professionals (HCPs) associated with misdiagnosis and delays in diagnosis. Diagnostic delay may also be attributed to other factors, including the complex symptomology of MCT8 deficiency only becoming apparent several months after birth and pathognomonic serum triiodothyronine (T3) testing not being routinely performed. For patients with MCT8 deficiency, multidisciplinary team care is vital to optimize the support provided to patients and their caregivers. Although there are currently no approved treatments specifically for MCT8 deficiency, earlier identification and diagnosis of this disorder enables earlier access to supportive care and developing treatments focused on improving outcomes and quality of life for both patients and caregivers.

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Intracerebroventricular High Doses of 3,3′,5-Triiodothyroacetic Acid at Juvenile Stages Improve Peripheral Hyperthyroidism and Mediate Thyromimetic Effects in Limited Brain Regions in a Mouse Model of Monocarboxylate Transporter 8 Deficiency

Cited by 2 publications

References 42 publications

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

Unmet patient needs in monocarboxylate transporter 8 (MCT8) deficiency: a review

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