In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency.

Monocarboxylate transporter 8 (MCT8) transports thyroid hormone (TH) across the plasma membrane. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome, comprising severe psychomotor retardation and elevated serum T3 levels. Because the neurological symptoms are most likely caused by a lack of TH transport into the central nervous system, the administration of a TH analog that does not require MCT8 for cellular uptake may represent a therapeutic strategy. Here, we investigated the therapeutic potential of the biologically active T3 metabolite Triac (TA3) by studying TA3 transport, metabolism, and action both in vitro and in vivo. Incubation of SH-SY5Y neuroblastoma cells and MO3.13 oligodendrocytes with labeled substrates showed a time-dependent uptake of T3 and TA3. In intact SH-SY5Y cells, both T3 and TA3 were degraded by endogenous type 3 deiodinase, and they influenced gene expression to a similar extent. Fibroblasts from MCT8 patients showed an impaired T3 uptake compared with controls, wherea...