Thyroid Hormone Transporter and X-linked Psychomotor Retardation

These 2 groups of investigators demonstrated that loss-of-function mutations in the transmembrane thyroid hormone transporter termed monocarboxylate transporter 8 (MCT8) [chromosome Xq13.2, OMIM 300095, encoded as Solute Carrier Family 16 Member 2 = SLC16A2] were associated with marked developmental delay and elevated values of T₃. The authors described patients with global developmental delay, either spastic quadriplegia or proximal hypotonia and inability to stand, dystonic movements, decreased communication skills, and variable hearing. The children were not myxedematous nor did they have constipation, hoarseness, or brittle hair. Serum concentrations of total and free T₄ were within the low normal ranges while TSH values were normal or slightly elevated. Serum T₃ concentrations were increased (300-400 ng/dL)(Figure). Treatment with thyroid hormone did not result in clinical improvement. After excluding mutations in the genes encoding the deiodinases and nuclear T₃ receptor, the authors demonstrated deletions, missense, and nonsense mutations in SLC16A2 that would lead to its inactivation including: del ex 1, del ex 3, 4, 5, Ala150Val, Arg171Stop, Leu397Pro, and 1 bp del 1212T. The authors concluded that T₃ is essential for normal development of the central nervous system and that transport of T₄ and T₃ into fetal neurons are of critical importance in this process.

Serum T₄, free T₄, T₃, and TSH concentrations
Blue shaded areas represent normal ranges in healthy individuals. Patient 3 was treated with 50µg T₄ per day and patient 4 with 3.8µg T₄ per kg bodyweight per day.

Editor’s Comment: MCT8 is a 67 kDa, 539 amino acid protein with 12 transmembrane domains that specifically transports iodothyronines, but not tyrosine, phenylalanine, leucine, or tryptophan. Its 6 exon gene (SLC16A2) is located within the X-inactivation center, and thus it is expressed only from the active X chromosome. Thus, these reports further support the absolutely crucial role that thyroid hormone plays in neural development and add another cause of hypertriiodothyroninemia. Other causes include ingestion of desiccated thyroid hormone and aberrations of serum T₃ binding proteins, thyroid hormone nuclear receptors, and deiodination.

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Table of Contents 21-1 Thyroid Hormone Transporter and X-linked Psychomotor Retardation
Volume 21, Issue 1, March 2005 © 2005 Prime Health Consultants, Inc.

These 2 groups of investigators demonstrated that loss-of-function mutations in the transmembrane thyroid hormone transporter termed monocarboxylate transporter 8 (MCT8) [chromosome Xq13.2, OMIM 300095, encoded as Solute Carrier Family 16 Member 2 = SLC16A2] were associated with marked developmental delay and elevated values of T₃. The authors described patients with global developmental delay, either spastic quadriplegia or proximal hypotonia and inability to stand, dystonic movements, decreased communication skills, and variable hearing. The children were not myxedematous nor did they have constipation, hoarseness, or brittle hair. Serum concentrations of total and free T₄ were within the low normal ranges while TSH values were normal or slightly elevated. Serum T₃ concentrations were increased (300-400 ng/dL)(Figure). Treatment with thyroid hormone did not result in clinical improvement. After excluding mutations in the genes encoding the deiodinases and nuclear T₃ receptor, the authors demonstrated deletions, missense, and nonsense mutations in SLC16A2 that would lead to its inactivation including: del ex 1, del ex 3, 4, 5, Ala150Val, Arg171Stop, Leu397Pro, and 1 bp del 1212T. The authors concluded that T₃ is essential for normal development of the central nervous system and that transport of T₄ and T₃ into fetal neurons are of critical importance in this process. Dumitrescu AM, Liao XH, Best TB,Brokman K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004;74:168-75. Friesema ECH, Grueters A, Biebermann H, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004;364:1435-38. Serum T₄, free T₄, T₃, and TSH concentrations Blue shaded areas represent normal ranges in healthy individuals. Patient 3 was treated with 50µg T₄ per day and patient 4 with 3.8µg T₄ per kg bodyweight per day. Reprinted with permission Friesema ECH, Grueters A, Biebermann H, et al. Lancet 2004;364:1435-38. Copyright © 2004 Elsevier. All rights reserved. Editor’s Comment: MCT8 is a 67 kDa, 539 amino acid protein with 12 transmembrane domains that specifically transports iodothyronines, but not tyrosine, phenylalanine, leucine, or tryptophan. Its 6 exon gene (SLC16A2) is located within the X-inactivation center, and thus it is expressed only from the active X chromosome. Thus, these reports further support the absolutely crucial role that thyroid hormone plays in neural development and add another cause of hypertriiodothyroninemia. Other causes include ingestion of desiccated thyroid hormone and aberrations of serum T₃ binding proteins, thyroid hormone nuclear receptors, and deiodination. Allen W. Root, MD