Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 ( MCT 8 ) mutations in a cohort of adult patients with mental retardation

Summary Objective Monocarboxylate transporter 8 ( MCT 8) is an essential thyroid hormone ( TH ) transporter as humans with MCT 8 mutations have severe neurological and endocrine abnormalities. The objectives are (i) to identify novel MCT 8 mutations and (ii) to assess their functional relevance; (iii) to describe the effects of block‐and‐replace treatment in an MCT8 patient. Design The TOP‐R study is a cross‐sectional nation‐wide multicentre study. Patients Subjects with unexplained mental retardation ( MR ) were screened for MCT 8 mutations. Results We identified three mutations: p.F501del (previously described), p.L492P and p.T162T. The F501del and L492P mutants, but not the T162T mutant, showed diminished T3, T4 and rT 3 transport in transfected cells. TH transport in T162T fibroblasts was also not affected. One patient was treated with block‐and‐replace therapy to normalize serum TH levels. The results indicated a slow onset of the decrease in serum T4 and T3 by successive treatment with methimazole and PTU , and eventually their complete normalization by administration of LT 4 with PTU but not with methimazole. The frequency of MCT 8 mutations in males with X ‐linked MR approximately 3·9%. Conclusions We identified several MCT 8 mutations in a cohort of subjects with unexplained MR . We demonstrated the pathogenicity of two missense mutations. The synonymous variant did not affect TH transport. Block‐and‐replace therapy of one patient reversed the TH abnormalities. Our data suggest a decreased TH secretion rate and an increased T4 to T3 conversion by the type I deiodinase in patients with MCT 8 mutations. Our study indicates that MCT 8 mutations are a relatively frequent cause of X‐linked MR .