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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.
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
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Current GGH - Vol. 24 No. 1
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