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Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination

AuthorsLópez-Espíndola, Daniela; Grijota Martínez, María del Carmen; Refetoff, Samuel; Bernal, Juan ; Guadaño-Ferraz, Ana
Issue Date2014
PublisherEndocrine Society
CitationJournal of Clinical Endocrinology and Metabolism 99(12): E2799-E2804 (2014)
Abstract[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 serumt hyroid 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 showed50%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,andpresent 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.
Descriptionet al.
Identifiersissn: 0021-972X
e-issn: 1945-7197
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