Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.

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Keywords Cerebral calcifications, Leukoencephalopathy, MCT8, MCT8 deficiency, Thyroid hormone, Thyroid hormone transporter
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Journal Metabolic Brain Disease
Masnada, S. (Silvia), Groeneweg, S, Saletti, V. (Veronica), Chiapparini, L. (Luisa), Castellotti, B. (Barbara), Salsano, E. (Ettore), … Tonduti, D. (Davide). (2019). Novel mutations in SLC16A2 associated with a less severe phenotype of MCT8 deficiency. Metabolic Brain Disease. doi:10.1007/s11011-019-00464-7