Mutations of the Thyroid Hormone Transporter MCT8 Cause Prenatal Brain Damage and Persistent Hypomyelination
Open accessAbstract
CONTEXT: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. OBJECTIVE: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. DESIGN: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. METHODS: Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. RESULTS: The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. CONCLUSIONS: The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.
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In Allan-Herndon Dudley syndrome, clinical parameters indicate a hyperthyroid situation in peripheral tissues, while histopathological observations and reduced TH tissue brain content point to an overall TH-deficient situation inside the CNS.
“While several clinical parameters such as low body weight, muscle wasting, tachycardia, and increased sex hormone binding globulin are indicative of a hyperthyroid situation in peripheral tissues, histopathological observations (including hypomyelination, compromised GABAergic maturation in cerebral and cerebellar cortex), as well as reduced TH tissue brain content point to an overall TH-deficient”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [43]
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Experimental — accuracy not yet measuredThe one published post-mortem analysis of a MCT8-deficient fetus revealed a decrease in T3 and T4 contents in the cerebral cortex.
“The one published post-mortem analysis of a MCT8-deficient fetus revealed a decrease in T3 and T4 contents in the cerebral cortex (López-Espíndola et al., 2014)”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as López-Espíndola et al., 2014
Since MCT8-deficient patients manifest lower free T4 serum concentrations, it is likely that lower T4 concentrations observed in post-mortem MCT8-deficient brain reflect serum concentrations rather than abrogated MCT8-mediated transport.
“Thus, since MCT8-deficient patients manifest lower free T4 serum concentrations, it is likely that the lower T4 concentrations observed in the post-mortem MCT8-deficient brain (López-Espíndola et al., 2014) reflect the serum concentrations rather than abrogated MCT8-mediated transport.”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as López-Espíndola et al., 2014
These results align with reduced synaptophysin expression in post-mortem human brain and neuronal deficiencies in Mct8/Oatp1c1 dKO mouse and zebrafish Mct8 mutant.
“These results align with several findings in MCT8 deficiency, including reduced synaptophysin expression in the post-mortem human brain (López-Espíndola et al., 2014) and neuronal deficiencies observed in the Mct8/Oatp1c1 double KO (dKO) mouse (Mayerl et al., 2014) and zebrafish Mct8 mutant model (Zada et al., 2014).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as López-Espíndola et al., 2014
Several clinical parameters such as low body weight, muscle wasting, tachycardia, and increased sex hormone binding globulin are indicative of a hyperthyroid situation in peripheral tissues, while histopathological observations and reduced TH tissue brain content point to an overall TH-deficient situation inside the CNS.
“While several clinical parameters such as low body weight, muscle wasting, tachycardia, and increased sex hormone binding globulin are indicative of a hyperthyroid situation in peripheral tissues, histopathological observations (including hypomyelination, compromised GABAergic maturation in cerebral and cerebellar cortex), as well as reduced TH tissue brain content point to an overall TH-de”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [43]
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- Authors
- López-Espíndola, D., Morales-Bastos, C., Grijota-Martínez, C., Liao, X.-H., Lev, D., Sugo, E., Verge, C. F., Refetoff, S., Bernal, J., & Guadaño-Ferraz, A.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Hospital Universitario La Paz (ES)
- Prince of Wales Hospital (AU)
- UNSW Sydney (AU)
- University of Chicago (US)
- Corresponding author
- Bernal, Juan
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-12
- Volume
- 99
- Issue
- 12
- Pages
- E2799-E2804
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4255116
- OpenAlex
- W1965357288
- Cited by
- 155
- References
- 19
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 19 · 2023: 12 · 2022: 16 · 2021: 22 · 2020: 10 · 2019: 15 · 2018: 8 · 2017: 11 · 2016: 12 · 2015: 10
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Comunidad de Madrid
- Tel Aviv University
- Universidad Autónoma de Madrid
- National Institutes of Health (UL1TR000430, DK 15070)
- Comisión Nacional de Investigación Científica y Tecnológica
- Consejo Superior de Investigaciones Científicas
- Instituto de Salud Carlos III
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 15070, R37DK015070, R01DK015070)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- MCT8, SLC16A2, thyroid hormone transporters, hypomyelination, prenatal brain damage, cerebellar development, myelination, parvalbumin, calbindin-D28k, synaptophysin, type 2 deiodinase, type 3 deiodinase, fetal brain, psychomotor retardation, axonal maturation
- MeSH terms
- Adult, Brain, Brain Damage, Chronic, Cell Differentiation, Cerebellum, Cerebral Cortex, Child, Female, Humans, Iodide Peroxidase, Male, Mutation, Myelin Sheath, Neurons, Pregnancy, Thyroid Hormones, Monocarboxylic Acid Transporters, Symporters, Neurogenesis
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