The importance of thyroid hormone (TH) transporters for brain development has been unequivocally demonstrated by the identification of mutations in the transporter MCT8. Patients have mental retardation, hypotonia and low body weight (BW). Their biochemical phenotype typically shows high serum T3, low serum T4 and normal TSH levels. Recently, it has been shown that MCT8 is prerequisite for normal TH release from the thyroid. To date, no curative therapy is available, although block-and-replace therapy was reported to normalize thyroid parameters in a boy with an MCT8 mutation.
We identified a loss-of-function MCT8 mutation (p.F501del) in a 40-year-old male with MR. Initial serum levels were: FT4 8.9 pmol/l (N: 1125), T3 2.84 nmol/l (N: 1.42.5) and TSH 1.78 mU/l (N: 0.44.3). BW had decreased towards 50 kg. Furthermore, he showed progressive behavioural changes. Therefore, we initiated block-and-replace therapy. Thyroid parameters did not change after 2 months treatment with methimazole (MMI) 30 mg/day. During initial treatment weight loss continued, requiring additional feeding via a gastric catheter. Switching to propylthiouracil (PTU) 200 mg/day resulted in a decrease in T3 and T4 levels and elevated TSH levels. After 2 months, L-thyroxine was added and titrated up to 100 μg/day, until a relatively normal thyroid state was reached (FT4 20.6 pmol/l, T3 2.0 nmol/l, TSH 5.6 mU/l). At 1 year, BW increased 2 kg and behaviour had somewhat normalized. Temporary replacement of PTU by MMI resulted in a decrease in FT4 and an increase in T3 and TSH levels.
The present data demonstrate that serum TH levels slowly decrease after blocking synthesis. This may be explained by an accumulation of TH due to an impaired release in thyroids lacking functional MCT8. PTU appears more effective than MMI in reversing serum TH abnormalities. Since PTU also inhibits D1 activitity, D1 likely plays a role in the biochemical phenotype.
30 Apr - 04 May 2011
European Society of Endocrinology