Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome

Abstract

Mutations in the thyroid hormone transporter SLC16A2 (MCT8) cause the Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and peripheral thyrotoxicosis. Here, we report three newly identified AHDS patients. Previously documented mutations were identified in probands 1 (p.R271H) and 2 (p.G564R), resulting in a severe clinical phenotype. A novel mutation (p.G564E) was identified in proband 3, affecting the same Gly564 residue, but resulting in a relatively mild clinical phenotype. Functional analysis in transiently transfected COS-1 and JEG-3 cells showed a near-complete inactivation of TH transport for p.G564R, whereas considerable cell-type-dependent residual transport activity was observed for p.G564E. Both mutants showed a strong decrease in protein expression levels, but differentially affected V and K values of T3 transport. Our findings illustrate that different mutations affecting the same residue may have a differential impact on SLC16A2 transporter function, which translates into differences in severity of the clinical phenotype.

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

“…Clinical data, laboratory test results, and brain imaging from 16 French patients enrolled in the RMLX study between 2013 and 2015 (ethics committee CPP SUD‐EST II, 24th September 2010) were analysed (patients 1–16). The same data from eight Italian patients were also recorded (patients 17–24); five of these patients had already been described in other case reports . Patients’ history, biological assessments, and MRI were collected with the help of medical records and by interviewing parents.…”

“…Clinical data, laboratory test results, and brain imaging from 16 French patients enrolled in the RMLX study between 2013 and 2015 (ethics committee CPP SUD-EST II, 24th September 2010) were analysed (patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. The same data from eight Italian patients were also recorded (patients [17][18][19][20][21][22][23][24]; five of these patients had already been described in other case reports.…”

“…AHDS was first described in males with severe psychomotor disability and central and peripheral hypotonia with poor head control, which progressed to spasticity and/or dystonia . Since then, several patients with a more moderate phenotype consisting of cognitive impairment, hypotonia, preserved walking with spasticity and/or hyperreflexia, and some language and learning abilities, have been described . Affected males usually have low free tetraiodothyronine (T 4 ) and high serum levels of free T 3 with normal or mildly elevated thyroid stimulating hormone (TSH).…”

“…[1][2][3][4][5][6][7] Since then, several patients with a more moderate phenotype consisting of cognitive impairment, hypotonia, preserved walking with spasticity and/or hyperreflexia, and some language and learning abilities, have been described. 4,[8][9][10][11] Affected males usually have low free tetraiodothyronine (T 4 ) and high serum levels of free T 3 with normal or mildly elevated thyroid stimulating hormone (TSH). In some cases, this biological pattern is not clear.…”

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

“…Mutations in the MFSD2A gene (encoding sodium-dependent lysophosphatidylcholine symporter 1 (NLS1), the brain endothelial transporter of essential ω3 fatty acids), leads to lethal or nonlethal microcephaly, cognitive disorder, spasticity and absent speech 248,249 and early BBB breakdown 15 . Genetic defects in endothelial monocarboxylate transporter-8 (MCT8; encoded by SLC16A2 ), which transports thyroid hormones into the CNS, leads to Allan–Herndon–Dudley syndrome with severe psychomotor retardation 250 . Mutations in OCLN (encoding the tight junction BBB protein occludin) lead to early-onset seizures, microcephaly, and grey matter calcification, whereas mutations in the JAM3 gene (encoding another tight junction BBB protein, JAMC) lead to brain haemorrhages and subependymal calcifications due to leakage from the BBB 251,252 .…”