Endocrine Abstracts

Thyroid hormone signaling depends on active transport of thyroid hormones across the plasma membrane. The discovery of MCT8 in 2003 fundamentally changed our understanding of thyroid hormone biology by revealing that cellular thyroid hormone availability is transporter-dependent. One year later, mutations in the X-linked SLC16A2 gene were identified as the cause of MCT8 deficiency, a rare but devastating neurodevelopmental disorder. The phenotypic consequences of MCT8 deficiency arise from a complex mixture of hypothyroid and thyrotoxic tissues. Impaired thyroid hormone transport into the brain results in profound intellectual and motor disability. MCT8 deficiency has a characteristic biochemical signature of high (F)T3, low (F)T4, and normal TSH concentrations. Unrestricted exposure of peripheral tissues to T3 causes chronic thyrotoxicosis, which leads to tachycardia, muscle wasting, hypermetabolism and progressive reduction in body weight, constituting significant morbidity and mortality in this vulnerable population. Through a global, multidisciplinary collaboration integrating deep clinical phenotyping, functional assays, computational analyses, and population-based cohorts, we established a direct relationship between the functional severity of SLC16A2 variants and clinical outcomes. Loss-of-function stratification predicts survival and key neurodevelopmental, anthropometric, thyrotoxic features and thyroid hormone concentrations. Combining functional data with different machine learning models, we established disease-specific optimized variant pathogenicity and severity classifier. Preclinical work identified the thyroid hormone analogue TRIAC as a strategy to bypass MCT8. Clinical trial and real-world data demonstrated meaningful improvements in key outcomes, culminating in regulatory approval in the European Union. Ongoing studies address the impact on survival, quality of life, and neurodevelopment.