Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 99, Issue 12, Pages E2799-E2804Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2014-2162
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Funding
- Instituto de Salud Carlos III, Spanish Health Ministry (Red Tematica de Investigacion Cooperativa en Salud) [RD09/0076/00073]
- Farmaindustria, through the Cooperation Program in Clinical and Translational Research of the Community of Madrid
- Prince of Wales Hospital, Randwick, Australia
- Wolfson Medical Center, Holon, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Plan Nacional de I + D + i [SAF2011-25608]
- Center for Research on Rare Diseases (Centro de Investigacion Biomedica en Red Enfermedades Raras), Instituto de Salud Carlos III, Madrid, Spain
- National Institutes of Health, Bethesda, Maryland [DK15070]
- Sherman Family
- Fellowship Training Program for Advanced Human Capital, Becas Chile from the National Commission for Scientific and Technological Research, Gobierno de Chile
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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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