title: Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (D.L.-E., C.G.-M., J.B., A.G.-F.), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28029 Madrid, Spain; Carrera de Tecnología Médica (D.L.-E.), Facultad de Medicina, Universidad de Valparaíso, Alcalde Sergio Prieto Nieto 452, 2581907 Viña del Mar, Chile; Department of Pathology (C.M.-B.), La Paz University Hospital, E-28046 Madrid, Spain; Center for Biomedical Research on Rare Diseases (C.G-M., J.B.), Unit 708, E-28040 Madrid, Spain; Departments of Medicine (X.-H.L., S.R.), Pediatrics (S.R.), and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; Institute of Medical Genetics (D.L.), Wolfson Medical Center, Holon 58100, Israel; South Eastern Area Laboratory Services (E.S.), Prince of Wales Hospital, Randwick 2031, Australia; Sydney Children's Hospital (C.F.V.), Randwick, and School of Women's and Children's Health (C.F.V.), University of New South Wales, Sydney 2010, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: López-Espíndola
authors.forename: Carmen
authors.initials: C
authors.lastname: Morales-Bastos
authors.forename: Carmen
authors.initials: C
authors.lastname: Grijota-Martínez
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liao
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.forename: Ella
authors.initials: E
authors.lastname: Sugo
authors.forename: Charles F
authors.initials: CF
authors.lastname: Verge
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Juan
authors.initials: J
authors.lastname: Bernal
authors.forename: Ana
authors.initials: A
authors.lastname: Guadaño-Ferraz
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D001925:Brain Damage, Chronic / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002531:Cerebellum / Q000254:growth & development / Q000473:pathology; D002540:Cerebral Cortex / Q000254:growth & development / Q000473:pathology; D002648:Child; D005260:Female; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009186:Myelin Sheath / Q000235:genetics* / Q000473:pathology*; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000473:pathology; D011247:Pregnancy; D027981:Symporters; D013963:Thyroid Hormones / Q000172:deficiency
chemical_list: D027501:Monocarboxylic Acid Transporters; C090735:SLC16A2 protein, human; D027981:Symporters; D013963:Thyroid Hormones; D007453:Iodide Peroxidase