ESPE Yearbook of Paediatric Endocrinology

Nat Commun 2025 Mar 12;16:2479. doi: 1038/s41467-025-56628-w

Brief Summary: This international consortium (53 sites, 23 countries) has been investigating the X-linked disease (1:70,000 males) caused by rare variants in the MCT8 transmembrane transporter. The transport of thyroid hormones depends on this molecule in many tissues, including the brain, and when it is defective, there are a wide range of clinical manifestations which include central hypothyroidism, developmental delay, and chronic peripheral thyrotoxicosis. Severe forms result in very compromised survival, with death before age 30.

This study assembled a comprehensive description of the genetics, neurodevelopment, and clinical/biochemical phenotype in 371 patients with MCT8 defects. It describes genotype-phenotype associations which explain divergent presentations of the disease. They characterise both disease-causing variants and other non-synonymous common variants from population studies that maintained normal to only minimal decreases in transporter activity. A total of 8151 MCT8 variants were classified according to severity, and their association to survival and to 24 of 32 disease features was examined. This deep phenotyping will permit more personalised anticipatory guidance.

The T3 analogue tri-iodothyroacetic acid (Triac) has been used, because smaller trials show that it ameliorates the peripheral hyperthyroidism and decreases TSH. This paper reports real world efficacy of Triac in 80 patients, showing that thyrotoxic symptoms are improved irrespective of the underlying phenotype. Structural modeling identified a 'linker' region in the protein containing mutation hotspots, and thus could be an important target for developing small molecules to correct aberrant transporter activity. But the most important aspect of this work is disease awareness: investigation of hypotonic newborns should always include TSH and thyroid hormones even if their interpretation may not always be clear, particularly if there is hypomyelination for age. This latter should prompt immediate genetic testing, including for MCT8.