Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency

Abstract

Context: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. MCT8 deficiency causes severe psychomotor retardation and abnormal thyroid tests. The great majority of affected children cannot walk or talk, and all have elevated serum T(3) levels, causing peripheral tissue hypermetabolism and inability to maintain weight. Treatment with thyroid hormone is ineffective. In Mct8-deficient mice, the thyroid hormone analog, diiodothyropropionic acid (DITPA), does not require MCT8 to enter tissues and could be an effective alternative to thyroid hormone treatment in humans.

Objective: The objective of the study was to evaluate the effect and efficacy of DITPA in children with MCT8 deficiency.

Methods: This was a multicenter report of four affected children given DITPA on compassionate grounds for 26-40 months. Treatment was initiated at ages 8.5-25 months, beginning with a small dose of 1.8 mg, increasing to a maximal 30 mg/d (2.1-2.4 mg/kg · d), given in three divided doses.

Results: DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The following significant changes were also observed: decline in SHBG (in all subjects), heart rate (in three of four), and ferritin (in one of four). Cholesterol increased in two subjects. There was no weight loss and weight gain occurred in two. None of the treated children required a gastric feeding tube or developed seizures. No adverse effects were observed.

Conclusion: DITPA (1-2 mg/kg · d) almost completely normalizes thyroid tests and reduces the hypermetabolism and the tendency for weight loss. The effects of earlier commencement and long-term therapy remain to be determined.

Fig. 1.

In vivo clearance of DITPA determined in children receiving two different doses of DITPA. Children were treated with 3.6 mg/d (0.4 mg/kg · d for subjects A1 and A2) or 9 mg/d (1.1 mg DITPA/kg · d for subject B). After withholding DITPA for 12 h, a single dose of 1.8 mg (subjects A1 and A2) or 3.6 mg (subject B) was given orally, and blood samples were obtained for the measurement of DITPA at the indicated times. The half-life of DITPA was 5 h for subject B and 8 h for subjects A1 and A2. The lower serum concentration of DITPA in subject B, despite administration of double the dose given to subjects A1 and A2, may be due to differences in absorption or distribution volume.

Fig. 2.

The evolution of thyroid tests during the course of treatment with DITPA. The shaded area indicates the normal range for all four determinations. DITPA dose, expressed in milligrams per kilogram body weight per day, was calculated at the time the dose was changed. It is indicated by the cross-hatched area. Arrows indicate tests obtained 1 month after interruption of DITPA treatment. Note the simultaneous treatment of the twins (A) with PTU/l-T₄. It is for this reason that TSH was suppressed and T₄ was relatively higher on the sample obtained at age 39.5 months. In panel A, the values from measurements in sera of the twins (A1 and A2) were averaged at each data point, while panels B and C show data for subjects B and C, respectively. T₃ levels are corrected for interference from DITPA, as described in Patients and Methods.

Fig. 3.

Transient increase in serum CK during the course of DITPA treatment and its correlation with the decline in serum T₃. Results from the twins of family 8 are plotted separately in panel A. T₃ levels are corrected for interference from DITPA, as described in Patients and Methods.

Fig. 4.

Correlation of serum free T₃ concentration and body weight in the twins of family 8. Weights, expressed as SDS, obtained from age 17 to 25 months, before treatment, and from 25 to 43 months while on DITPA are plotted (excluding periods when PTU and l-T4 were administered). Serum free T₃ levels are corrected for interference from DITPA, as described in Patients and Methods.