Monocarboxylate transporter 8 deficiency: update on clinical characteristics and treatment

Abstract

Defective thyroid hormone transport due to deficiency in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) results in severe neurodevelopmental delay due to cerebral hypothyroidism and in clinical negative sequelae following a chronic thyrotoxic state in peripheral tissues. The life expectancy of patients with MCT8 deficiency is severely impaired. Increased mortality is associated with lack of head control and being underweight at young age. Treatment options are available to alleviate the thyrotoxic state; particularly, treatment with the thyroid hormone analogue triiodothyroacetic acid seems a promising therapy. This review provides an overview of key clinical features and treatment options available and under development for this rare disorder.

Keywords: MCT8 deficiency; Thyroid hormone signalling; Treatment.

Fig. 1

Pathophysiology and clinical characteristics of MCT8 deficiency. Tissues that rely on MCT8 for thyroid hormone transport are relatively hypothyroid, whereas tissues that are independent of MCT8 are in a thyrotoxic state, caused by the increased serum T3 concentrations. TH thyroid hormone, PACs premature atrial complexes, SHBG sex hormone binding globulin, CK creatine kinase, BMI body mass index

Fig. 2

Mean ± SEM (black lines) serum concentrations of T3 (panel (A)), free T4 (panel (B)), mean ± SEM (black lines) T3/T4 ratio (panel (C)) and serum concentrations of thyroid stimulating hormone (TSH) (panel (D)). Blue dots represent measurements in individual patients and grey areas the normal range

Fig. 3

Overall survival of a cohort of 150 patients with MCT8 deficiency (Kaplan–Meier estimates) (A). Kaplan–Meier estimates of MCT8-specific survival in patients who attained head control (red line) by the age of 1.5 years versus those who did not (blue line) (B)

Fig. 4

Schematic representation of the development of (potential) therapies for MCT8 deficiency. Arrows indicate that therapies can be/are being evaluated in the next stage. For in vivo and clinical evaluation, treatment effect is divided in effects on peripheral thyrotoxicosis and neurodevelopmental delay. The median age of at clinical evaluation was 1.7 years (range 0.0–38.0) for T4 + PTU, 2.1 years (range 0.7–2.1) for DITPA and 7.1 years (range: 0.8–66.8) for Triac. PT peripheral thyrotoxicosis, ND neurodevelopmental delay