Endocrine Abstracts

Thyroid hormone transporters at the plasma membrane govern intracellular thyroid hormone concentrations. MCT8 represents a key thyroid hormone transporter. MCT8 deficiency (also known as Allan-Herndon-Dudley syndrome) is a devastating developmental disorder caused by mutations in the MCT8 gene (located on the X-chromosome), with an estimated prevalence of 1:70.000 males. The phenotype comprises (1) a ‘metabolic’ or endocrine component dominated by signs of toxic high serum T3 concentrations and (2) a ‘neurocognitive’ component due to impaired neurological development. As a consequence of impaired thyroid hormone entry into the brain, individuals with MCT8 deficiency exhibit severe intellectual and motor disability and fail to achieve early developmental milestones. The endocrine hallmark of MCT8 deficiency are high serum T3, low T4 and normal TSH concentrations. Peripheral tissues that rely on transporters other than MCT8 are exposed to elevated T3 levels. Such chronic thyrotoxicosis leads to tachycardia, muscle wasting, hypermetabolism and progressive reduction in body weight, constituting significant morbidity and mortality in this vulnerable population. Preclinical studies indicated that the T3 analog TRIAC can bypass MCT8 at the cellular level and, thus, restore thyroid hormone signaling in MCT8-deficient cells. Recently, the results were published from a multicentre, international clinical trial (Triac Trial I) in which patients were treated with TRIAC. Key clinical outcomes improved with TRIAC treatment in patients with MCT8 deficiency. Data in animal models showed that TRIAC can completely normalize the brain phenotype. An ongoing trial (Triac Trial II) investigates if TRIAC can ameliorate the neurocognitive phenotype when administered in young individuals.