Severe neurological abnormalities in a young boy with impaired thyroid hormone sensitivity due to a novel mutation in the MCT8 gene

Abstract

Monocarboxylate transporter 8 (MCT8) is an active and specific thyroid hormone transporter into neurons. MCT8 mutations cause an X-linked condition known as Allan-Herndon-Dudley syndrome and are characterized by impaired psychomotor development and typical abnormal thyroid function. we describe a 10-year-old boy with severe cognitive disability, axial hypotonia, spastic quadriplegia and sporadic dyskinetic episodes. He initially presented with thyroid dysfunction (high FT3, low rT3, low FT4 and normal TSH) and generalized retardation of the cerebral and cerebellar myelination in brain magnetic resonance imaging. The clinical and laboratory findings led to sequencing of the SLC16A2/MCT8 gene, which identified a novel missense mutation in exon 5. The study of peripheral markers of thyroid function suggests a paradoxical state of thyrotoxicosis in some peripheral tissues. Our patient had a typical clinical presentation at birth but because of the rarity of his disease his diagnosis was not made until the age of 7. The delay can also be explained by the omission of the free T3 assay in the first thyroid evaluation performed. This case therefore highlights the possible benefit of including the T3 assay in the study of patients with severe psychomotor disability of unknown etiology, thus eliminating extra costs for unnecessary complementary diagnostic tests.

The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes

“…Thyroid dyshormonogenesis, which is caused by defects in thyroid hormone biosynthesis, accounts for approximately 10–15% of primary CH and is associated with the following genes: DUOX2 , DUOXA2 , DUOX1 , TPO , TG , SLC26A4 , SLC5A5 and TSHR ( 5 , 7 , 9 , 10 , 11 ). A small proportion of CH patients are resistant to thyroid hormone because of mutations in THRA ( 12 ) or THRB ( 13 , 14 ), which encode thyroid hormone receptors or mutations in SLC26A2 ( 15 , 16 ), which encodes the thyroid hormone transporter, thereby decreasing the sensitivity of target tissues to thyroid hormone action.…”

Mathematical modeling and simulation of thyroid homeostasis: Implications for the Allan-Herndon-Dudley syndrome

“…For AHDS patients, the estimated (mean) G T , G D1 and G T3 parameters are held constant and only G MT is re-estimated for AHDS patients 3 . To this end, we use steady-state hormone concentrations measured in (22)(23)(24)(25)(26). Note that, in contrast to the parameter estimation related to healthy individuals, we use steady-state hormone measurements to estimate the G MT parameter for AHDS patients.…”

“…Moreover, for healthy individuals and AHDS patients, we compute the parameters individually. Regarding healthy individuals, we use 27 dynamic hormone measurements documented in (16) and regarding AHDS patients, we use 13 measurements from (22)(23)(24)(25)(26). This allows to quantify the variability in the estimated parameters differently, namely by computing the mean, median, standard deviation and the coefficient of variation regarding the individually estimated parameters.…”