Background: MCT8 deficiency is a rare disorder caused by mutations in the thyroid hormone  transporter MCT8, comprising severe neurodevelopmental delay and high serum T3 concentrations resulting in thyrotoxicosis in peripheral tissues. This predisposes to substantial morbidity and mortality. Recently, we reported the results of an international trial, in which biochemical and clinical outcomes improved in patients who were treated with Triac for 12 months. However, long-term follow-up data of such patients treated with Triac are lacking, particularly in young children. We investigated the long-term efficacy of Triac therapy in a worldwide cohort of patients with MCT8 deficiency.

Methods: We investigated the efficacy of Triac treatment in 68 patients with MCT8 deficiency in 19 countries. Triac dose was titrated according a predefined dose-escalation scheme aiming to normalize serum T3 concentrations (target 1.4-2.5 nmol/L). Thyroid function tests, body weight, heart rate and biochemical markers reflecting thyroid hormone action in peripheral tissues (SHBG, creatine kinase, creatinine) were measured at baseline and during control visits.

Findings: 68 patients with a median baseline age of 4.4 years (range 6 months–66 years) were treated, including 24 patients aged 0-2.5 years. They were treated during 181 patient years; follow-up time was >5 years in 12 patients and 2-5 years in 26 patients. Median dose was 38 µg/kg/day (range 15-105 µg/kg/day).

Mean serum T3 concentrations decreased from 4.6 to 1.7 nmol/L (normal 1.4–2.5 nmol/L). Body weight-for-age improved compared to treatment-naïve historical controls (0.67 SD increase). Heart rate-for-age improved from 1.56 to 0.96 SD. SHBG and creatinine concentrations improved from 247 to 213 nmol/L (normal 40-140 nmol/L) and from 32 to 39 µmol/L (normal 31-68 μmol/L), respectively. No drug-related severe adverse events were reported.

Interpretation: Triac is a safe treatment resulting in sustainable improvements of the severe thyrotoxic state in paediatric and adult patients with MCT8 deficiency.