PhD defence S. (Stefan) Groeneweg

Thyroid hormone is indispensable for normal development of tissues, in particular the brain. In order to enter the brain, thyroid hormone requires specific channels in the cell membrane, of which MCT8 is most critical. Mutations that inactivate MCT8 abolish thyroid hormone uptake into the brain and cause severe intellectual and motor disability, a rare condition known as MCT8 deficiency. In addition, affected patients have high thyroid hormone concentrations in the blood; the consequences of which are largely unknown. At present, there is no effective therapy available. The scope of this thesis was to characterize the clinical features associated with MCT8 deficiency and develop therapeutic strategies to overcome defective MCT8. By deep-phenotyping a large international cohort of patients, this work confirmed that MCT8 deficiency results in severe developmental delay, but also newly revealed that the excessive thyroid hormone concentrations in the blood exert toxic effects on other tissues, including heart, liver and muscle. Most affected patients were severely underweight and exhibited a rapid heart rate, hypertension and cardiac arrhythmias. These features predispose significant morbidity and are potentially life-limiting. We showed that treatment with the thyroid hormone analogue Triac – which bypasses MCT8 – effectively reduces the thyroid hormone concentrations in the blood and alleviates the toxic symptoms in peripheral tissues. Further studies will reveal if Triac may also rescue brain development once treatment is commenced early in life. The molecular studies on MCT8 structure and function described in this thesis will help to distinguish pathogenic mutations from benign variants, which will facilitate timely diagnostics.

The public defence will take place at the Prof. Andries Queridoroom, 3rd floor Education Center, Erasmus MC. The ceremony will begin exactly at 13.30 hrs. In light of the solemn nature of the ceremony, we recommend that you do not take children under the age of 6 to the first part of the ceremony.