ESPE Abstracts

Background: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. Thyroid hormone (TH) profile is characterized by high T3 and low T4 levels, with normal or elevated TSH. Recent studies have shown that the chemical chaperone phenylbutyrate (PB) restored mutant MCT8 function and increased TH content in a patient-derived cell model, making it a potential treatment for MCT8 deficiency.

Methods: We treated two monozygotic twins aged 14.5 years and one toddler aged 18 months with MCT8 deficiency due to P321L and V235L mutation in SLC16A2 gene, respectively, with accelerating doses of PB over 14 months. TH and related parameters were recorded. Serum metabolites of PB were monitored as a safety measure. Vital signs, anthropometric measurements and neuro-cognitive functions were evaluated. The biochemical effects of sodium PB (NaPB) in vitro were evaluated in MDCK1 cells stably expressing both mutations.

Results: NaPB restored the expression of the two mutants of MCT8 in stably transfected MDCK1 cells, but increased T3 trans-membrane transport only in cells carrying the P321L mutation. PB treatment at high doses led to a significant improvement in TH levels, especially reduction in T3 and TSH and elevation in T4 levels. TH levels were correlated with PB doses. Total cholesterol levels were increased, without a change in sex-hormone binding protein levels. Body mass index SDS of the twins increased significantly, and the underweight toddler reached the third percentile in weight. Only minor neuro-cognitive improvements were observed during PB treatment in the twins, including reduction in hyperreflexia and mild improvement in gross motor and cognitive functions. The main adverse effects were gastrointestinal complains in the toddler and nausea and vomiting in the twins, associated with elevated liver enzymes, at the time of the highest dose of PB. Notably, maximal PB dose in the toddler was within the recommended range, and PB metabolites in the twins were measured below toxic levels. A full clinical and biochemical recovery was observed 7 to 10 days after treatment interruption.

Conclusions: In the first report of PB treatment in MCT8 deficiency, we found a significant improvement in TH profile, with minor neuro-developmental changes. Hepatotoxicity may represent a limiting factor in PB treatment of patients with MCT8 deficiency.