Endocrine Abstracts (2006) 11 S47

The spectrum of MCT8 gene mutations

H Krude

Humboldt University, Berlin, Germany.

So far it has been assumed that thyroid hormones -due to their lipophilicity- enter their target cells just by slipping through the membrane. After the initial description of a specific transport molecule for thyroid hormone in 2003 (Friesema et al. JBC) a new paradigm of thyroid hormone physiology has emerged. It turns out that as everything in nature, also the entering of thyroid hormone in its target cell is well regulated and the gate keeper is the MCT8 transporter, at least in the brain. The identification of patients with mutations in this transporter and their severe neurological phenotype accelerated research on this new field of thyreoidology. Based on the neurological phenotype of severe muscular hypotonia and lack of normal development, it is evident that this molecule seems to have a central non-redundant function in brain physiology. A further unusual neurological phenotype associated with MCT8 mutations, namely paroxysmal kinesigenic dyskinesias (PKD), provoked by certain stimuli including changing of their clothes or diapers was described. Further widening of the phenoytpical spectrum of MCT8 deficiency was shown by the most recent report of Schwarzt et al. in patients with Allan-Herndon-Dudley syndrome in older characterised by muscular hypotonia in the first year of life but who later develop spastic paraplegia, a symptom not recognized in the younger patients so far. As in all examples of fundamental new findings, more questions arise than could have been answered so far: What is the real physiological role of MCT8? Why is its impact for brain function much higher than for other organs, e.g. heart? In addition, who can explain why T3 is elevated and T4 is normal with almost normal TSH in these patients? However, the elevated T3 in these patients will give rise to a rebirth of T3 measurements in clinical practice.

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