Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study

Abstract

Context Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Objective Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. Methods In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. Results From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. Conclusions Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Genetic disorders of thyroid development, hormone biosynthesis and signalling

“…Different T3 analogues (Triac [triiodothyroacetic acid], DITPA [diiodothyropropionic acid] and sobetirome and its prodrug Sob‐AM2) have been investigated in (pre)clinical studies with varying effects on different outcomes 27–29 . Substantial clinical experience with Triac therapy of both adults and children has been obtained 30,31 . Triac treatment lowers elevated T3 concentrations markedly, with consequent, sustained improvements in body weight, heart rate and blood pressure.…”

“…[27][28][29] Substantial clinical experience with Triac therapy of both adults and children has been obtained. 30,31 Triac treatment lowers elevated T3 concentrations markedly, with consequent, sustained improvements in body weight, heart rate and blood pressure. An ongoing trial (NCT02396459) may determine whether Triac administration in early childhood can modify brain development.…”

Allan-Herndon-Dudley syndrome: Report of a novel pathogenic variant in MCT8 gene

“…[2] A state of peripheral thyrotoxicosis in spite of neuronal T3 deficiency suggests possible presence of tissue specific TH transporters. [4] Tri-iodothyroacetic acid is a thyroid hormone analog derived by conversion of T3 to its acetic acid derivative and its cellular entry is independent of MCT8. Tri-iodothyroacetic acid ameliorates thyrotoxic features in patients with MCT8 deficiency across ages and neurodevelopmental improvement is observed in the patients treated early.…”

Ganglioglioma with novel molecular features presenting in a child with Allan-Herndon-Dudley syndrome

“…10 11 Cerebral hypothyroidism is severely detrimental to neurodevelopment, 12 13 and clinical supplementation with thyroid hormone or its derivative has produced mixed results. [14][15][16][17] AHDS consequently exhibits a profound, heterogeneous clinical presentation featuring craniofacial deformity, intellectual disability and neurological abnormalities including seizures, developmental delay and impaired mobility. 18 19 We report the first case of a ganglioglioma-and perhaps the first CNS tumour overall-in a paediatric patient with AHDS.…”