Practice points•The neurological ma

Practice points•The neurological manifestations of MCT8 deficiency cannot be explained by the TFT abnormalities and the observed phenotype is different from that of global thyroid hormone deficiency or excess.•Psychomotor abnormalities in the absence of the characteristic high serum T3 and low rT3 concentrations are unlikely to be the cause of MCT8 defects.•Neonatal screening programs for congenital hypothyroidism, based on blood TSH and/or T4 measurements, are likely to miss the presence of TH cell transport defect caused by MCT8 mutations.•As carrier females are asymptomatic, the presence of a MCT8 defect is not suspected until the birth of the first affected male.•Aspiration pneumonia is the most common cause of death in affected males.In several infants, detection of low T4 or elevated TSH by neonatal screening has led to treatment with L-T4. However, no improvement has been noted when used in physiological doses, presumably because of the impaired uptake of the hormone in MCT8-dependent tissues. Administration of T4 during pregnancy and the efficacy of several TH analogs that might bypass the molecular defect by using alternative transporters, have therapeutic potential that are being tested in Mct8-deficient mice.