Peripheral manifestations of monocarboxylate transporter 8 deficiency: hepatic and skeletal muscle involvement

Monocarboxylate transporter 8 (MCT8) deficiency, also known as Allan-Herndon-Dudley syndrome, is a rare X-linked disorder caused by pathogenic variants in the SLC16A2 gene. It leads to impaired transport of thyroid hormones, particularly triiodothyronine (T3) and thyroxine (T4), across the blood-brain barrier and into neural cells. Consequently, the brain experiences reduced thyroid hormone availability, resulting in central hypothyroidism and severe neurodevelopmental impairment. In contrast, peripheral tissues remain exposed to elevated circulating T3, leading to chronic peripheral thyrotoxicosis. This review focuses on the effects of MCT8 deficiency beyond the neurological phenotype, with particular attention to liver involvement, skeletal muscle impairment, and hyperlactatemia. Current evidence suggests that peripheral organs are significantly affected by excess thyroid hormone signaling due to compensatory uptake through alternative thyroid hormone transporters. These alterations may contribute to metabolic disturbances and organ-specific manifestations that extend the clinical spectrum of the disease beyond the central nervous system. MCT8 deficiency should be considered a multisystem disorder rather than an isolated neurodevelopmental disease. Recognition of peripheral organ involvement may facilitate earlier diagnosis, improve clinical monitoring, and support the development of more targeted therapeutic strategies. Further research is needed to better understand the mechanisms underlying peripheral manifestations and their implications for patient care.