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Endocrinological stimulation tests. (a) TRH test in 3 patients. TSH response revealed a pituitary hypothyroid pattern in patient 1, primary hypothyroid pattern in patient 2 and normal pattern in patient 3. (b) Patient 2. GH deficiency was detected by GHRP-2 test and arginine tolerance test. The GnRH test showed a prepubertal response. (c) Patient 3. The GnRH test showed a prepubertal response.
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We performed genetic analysis and clinical investigations for three patients with suspected monocarboxylate transporter 8 (MCT8) deficiency. On genetic analysis of the MCT8 (SLC16A2) gene, novel mutations (c.1333C>A; p.R445S, c.587G>A; p.G196E and c.1063_1064insCTACC; p.R355PfsX64) were identified in each of three patients. Although thyroid functio...
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Citations
... Aside from severe cognitive impairment, AHDS patients present noticeable neuromotor disturbances, such as central hypotonia, pyramidal signs such as Babinski (referable to failure in cortical commands), and extrapyramidal signs such as dystonia, choreoathetosis, and hypokinesia (referable to failure of the basal ganglia inhibitory-excitatory commands) [11][12][13]. General delay in myelination or myelin dysplasia has been shown in AHDS patients by magnetic resonance imaging (MRI) [10,11,[14][15][16][17][18] and histopathological examinations. The first and sole patient with a functional mutation in OATP1C1 was reported in 2018 [19] in a 15.5-year-old girl showing gradual deterioration of cognitive and motor domains, with gait apraxia, myocloniclike movements in the hands, scoliosis, and spasticity of the lower limbs. ...
Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic movement disability related to alterations in basal ganglia motor circuits. Mapping the expression of MCT8/OATP1C1 in those circuits is necessary to explain their involvement in motor control. We studied the distribution of both transporters in the neuronal subpopulations that configure the direct and indirect basal ganglia motor circuits using immunohistochemistry and double/multiple labeling immunofluorescence for TH transporters and neuronal biomarkers. We found their expression in the medium-sized spiny neurons of the striatum (the receptor neurons of the corticostriatal pathway) and in various types of its local microcircuitry interneurons, including the cholinergic. We also demonstrate the presence of both transporters in projection neurons of intrinsic and output nuclei of the basal ganglia, motor thalamus and nucleus basalis of Meynert, suggesting an important role of MCT8/OATP1C1 for modulating the motor system. Our findings suggest that a lack of function of these transporters in the basal ganglia circuits would significantly impact motor system modulation, leading to clinically severe movement impairment.
... Aside from severe cognitive impairment, AHDS patients present noticeable neuromotor disturbances, such as central hypotonia, pyramidal signs such as Babinski (referable to failure in cortical commands), and extrapyramidal signs such as dystonia, choreoathetosis, and hypokinesia (referable to failure of the basal ganglia inhibitory-excitatory commands) [11][12][13]. General delay in myelination or myelin dysplasia has been shown in AHDS patients by magnetic resonance imaging (MRI) [10,11,[14][15][16][17][18], and histopathological examinations [19,20]. But in some cases, MRI also shows various basal ganglia lesions such as high T1 signals in the bilateral globus pallidus [14], low T2 signals in the bilateral globus pallidus, which were designated as calcifications by a computed tomography scan [21], high T2 signals in the bilateral basal ganglia [16], high T2 signal in the bilateral putamen [22], or low T1 and high T2 signals in the left putamen region [23]. ...
... General delay in myelination or myelin dysplasia has been shown in AHDS patients by magnetic resonance imaging (MRI) [10,11,[14][15][16][17][18], and histopathological examinations [19,20]. But in some cases, MRI also shows various basal ganglia lesions such as high T1 signals in the bilateral globus pallidus [14], low T2 signals in the bilateral globus pallidus, which were designated as calcifications by a computed tomography scan [21], high T2 signals in the bilateral basal ganglia [16], high T2 signal in the bilateral putamen [22], or low T1 and high T2 signals in the left putamen region [23]. The first and sole patient with a functional mutation in OATP1C1 was reported in 2018 [24], a 15.5-year-old girl showing gradual deterioration of cognitive and motor domains, with gait apraxia, myoclonic-like movements in the hands, scoliosis, and spasticity of the lower limbs. ...
Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormones (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic movement disability related to alterations in basal ganglia motor circuits. Mapping the expression of MCT8/OATP1C1 in those circuits is necessary to explain their involvement in motor control. We studied the distribution of both transporters in the neuronal subpopulations that configure the direct and indirect basal ganglia motor circuits using immunohistochemistry and double/multiple labeling immunofluorescence for TH transporters and neuronal biomarkers. We found their expression in the medium-sized spiny neurons of the striatum (the receptor neurons of the corticostriatal pathway), and in various types of its local microcircuitry interneurons, including the cholinergic. We also demonstrate the presence of both transporters in projection neurons of intrinsic and output nuclei of the basal ganglia, motor thalamus and nucleus basalis of Meynert, suggesting an important role of MCT8/OATP1C1 for modulating the motor system. Our findings suggest that a lack of function of these transporters in the basal ganglia circuits would significantly impact motor system modulation, leading to clinically severe movement impairment.
... Our case showed a severe phenotype, with both dystonia and cerebral atrophy starting from early infancy. As far as we know, five cases of MCT8 deficiency due to a frameshift variant have been reported (Table 1) [7][8][9][10][11] . In all cases with frameshift mutations, the patients were unable to sit without support or to speak meaningful words, which was consistent with the severe symptoms of our case. ...
MCT8 deficiency is an X-linked recessive disorder. We report the case of a 2-year-old Japanese boy with MCT8 deficiency caused by a novel frameshift variant, NM_006517.5(SLC16A2_v001):c.966dup [p.(Ile323Hisfs*57)]. He presented no head control and spoke no meaningful words, indicating severe developmental delay. Although missense or in-frame mutations of SLC16A2 are usually related to milder phenotypes and later-onset pyramidal signs, loss-of-function mutations are expected to cause severe clinical symptoms.
... TH transporters, which can regulate local TH availability and elicit cell-specific developmental events. Human loss-of-function mutation of MCT8, Allan-Herndon-Dudley syndrome (AHDS) shows cryptorchidism (undescended testes), demonstrating functional significance of TH transporter in testicular development 9,10 . In an attempt to recapitulate phenotypes related to AHDS, mice lacking Mct8 were generated 11,12 . ...
Thyroid hormone (TH) has long been believed to play a minor role in male reproduction. However, evidences from experimental model of thyrotoxicosis or hypothyroidism suggests its role in spermatogenesis. Cellular action of TH requires membrane transport via specific transporters such as monocarboxylate transporter 8 (MCT8). SLC16A2 (encodes for MCT8) inactivating mutation in humans can lead to Allan-Herndon Dudley-syndrome, a X-linked psychomotor and growth retardation. These patients present cryptorchidism which suggests a role of MCT8 during spermatogenesis. In this study, we found that Mct8 is highly expressed during early postnatal development and decreases its expression in the adulthood of testis of wild-type male rats. Histological analysis revealed that spermatogonia largely lacks MCT8 expression while spermatocytes and maturing spermatids highly express MCT8. To further understand the role of Mct8 during spermatogenesis, we generated Slc16a2 (encodes MCT8) knockout rats using CRISPR/Cas9. Serum THs (T3 and T4) level were significantly altered in Slc16a2 knockout rats when compared to wild-type littermates during early to late postnatal development. Unlike Slc16a2 knockout mice, Slc16a2 knockout rats showed growth delay during early to late postnatal development. In adult Slc16a2 knockout rats, we observed reduced sperm motility and viability. Collectively, our data unveil a functional involvement of MCT8 in spermatogenesis, underscoring the importance of TH signaling and action during spermatogenesis.
... No basal ganglia abnormalities other than myelin delay is demonstrated although extrapyramidal symptoms dominate the clinical picture [42]. Small pituitary gland has also been described [43]. ...
Hypomyelinating Leukodystrophies (HLDs) are a genetically heterogeneous, clinically overlapping group of disorders with the unifying MR imaging appearance of myelin deficit in the brain. In fact, it is the MRI phenotype that typically raises the diagnostic suspicion in this single largest group of undiagnosed leukodystrophies and guides gene testing for confirmation. This article reviews the neurobiology of myelination, focussing on the complex interplay of molecular genetic pathways and presents a practical clinico-radiological diagnostic algorithm based on the neuroimaging patterns of the common hypomyelinating disorders. The authors also address the current controversies about the definition and use of the term ‘hypomyelination’.
... Of interest, the neuroradiological evaluation of patient 1 at 29 years of age showed the presence of bilateral pallidal calcifications. This feature has been mentioned in only two (Ono et al. 2016;Dumitrescu et al. 2004) but left unattended ever since. In one case, calcium deposits were found during autopsy at the age of 10 years (Dumitrescu et al. 2004), and in another T1 shortening signals considered suggestive for calcification, were detected in the bilateral globus pallidus and dentate nucleus at the age of 21 years (Ono et al. 2016). ...
... This feature has been mentioned in only two (Ono et al. 2016;Dumitrescu et al. 2004) but left unattended ever since. In one case, calcium deposits were found during autopsy at the age of 10 years (Dumitrescu et al. 2004), and in another T1 shortening signals considered suggestive for calcification, were detected in the bilateral globus pallidus and dentate nucleus at the age of 21 years (Ono et al. 2016). Since brain imaging at these relatively advanced ages is not routinely performed in patients with MCT8 deficiency, it is currently not known to what extent calcifications in the basal ganglia are present at the pediatric age. ...
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.
... TSH concentrations are mostly within target range, but can also be mildly elevated (eg, (14)). In some patients, thyrotropin-releasing hormone (TRH)stimulation tests showed an inadequately low TSH response (327,383). The elevated serum T3 concentrations may result in signs of hyperthyroidism in peripheral organs that rely on transporters other than MCT8. ...
Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporters (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1 and SLC17A4 are currently known as transporters displaying highest specificity towards thyroid hormones. Structure-function studies using homology modelling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight in the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease.
... Low weight was frequent; it was recorded in two-thirds of our cohort, as in Schwartz et al.'s cohort, particularly in non-walking patients, and in one-third of all patients with AHDS. 1,4,5,7,10,12,13,15,16,[27][28][29][31][32][33][34][35][36]38,[41][42][43][44][45][46][47][48][49][50] Short stature was present in one-third of our cohort, more so than reported in the current literature and Schwartz et al.'s cohort. 4,10,27,29,33,36,43,[46][47][48] Failure to thrive, which is classically associated with feeding difficulties and dysthyroidism, 26 could also be related to abnormal myelination. ...
... 1,4,5,7,10,12,13,15,16,[27][28][29][31][32][33][34][35][36]38,[41][42][43][44][45][46][47][48][49][50] Short stature was present in one-third of our cohort, more so than reported in the current literature and Schwartz et al.'s cohort. 4,10,27,29,33,36,43,[46][47][48] Failure to thrive, which is classically associated with feeding difficulties and dysthyroidism, 26 could also be related to abnormal myelination. Absence of weight gain is the hallmark of early-onset hypomyelinating leukodystrophies and is related to severe energy impairment in the brain. ...
... 4,5,7,10,12,13,15,16,21,[52][53][54][55][56][57][58] Spasticity and lower-limb hyperreflexia are classical and frequent signs in AHDS. 1,4,[7][8][9][10][12][13][14][15][16]21,[27][28][29][30][31][33][34][35][36][37][38][39][40][41][42][43][45][46][47][48][49][50][52][53][54][55] Only one patient has been described as having hyporeflexia. 5 Abnormal movements, such as dystonia, choreoathetosis, rigidity, and ataxia are classical symptoms of AHDS. ...
The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
... Hemizygous SLC16A2 loss-of-function mutations in males lead to a rare X-linked disorder called Allan-Herndon-Dudley syndrome (AHDS) (OMIM #300523), which is characterized by severe psychomotor retardation and an abnormal TH profile with high serum T3, low-normal T4, low reverse T3 (rT3), and normalelevated TSH levels [1,21,22]. Psychomotor retardation encompasses several pathological conditions such as moderate-severe cognitive impairment, difficulties or inabilities in sitting, walking or standing alone, dysarthriacompletely absent speech, infantile hypotonia evolving to spastic paraplegia, and gradual development of spasticity [1,3,13,[23][24][25][26]. Although the pathogenic mechanism of MCT8 mutation remains unclear, psychomotor retardation is considered to be due to the lack of TH transporter function, which leads to a hypothyroid state in the brain and subsequent brain damage [27,28]. ...
... Although we could not confirm whether the patient with the p.Arg445Ser mutation can sit up, this protein also maintains residual activity. He was not able to walk at the age of 8 years [26]. The patients harboring the p.Gly276Arg and p.Gly401Arg mutations were unable to sit up and speak even 5-10 years after the initial diagnosis, which most probably points to severely limited MCT8 function. ...
... He has not shown much development since then. The other patients with p.Gly196Glu and p.Arg355Profs*64 had clinical findings characteristics of AHDS [26] and revealed minimal MCT8 function. The patients harboring p.Asp498Asn (11M) and p.Gly312Arg (1Y) mutations were too young to assess phenotypic severity (Table 1). ...
Monocarboxylate transporter 8 (MCT8) facilitates T3 uptake into cells. Mutations in MCT8 lead to Allan-Herndon-Dudley syndrome (AHDS), which is characterized by severe psychomotor retardation and abnormal thyroid hormone profile. Nine uncharacterized MCT8 mutations in Japanese patients with severe neurocognitive impairment and elevated serum T3 levels were studied regarding the transport of T3. Human MCT8 (hMCT8) function was studied in wild-type (WT) or mutant hMCT8-transfected human placental choriocarcinoma cells (JEG3) by visualizing the locations of the proteins in the cells, detecting specific proteins, and measuring T3 uptake. We identified 6 missense (p.Arg445Ser, p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, and p.Gly312Arg), 2 frameshift (p.Arg355Profs*64 and p.Tyr550Serfs*17), and 1 deletion (p.Pro561del) mutation(s) in the hMCT8 gene. All patients exhibited clinical characteristics of AHDS with high free T3, low-normal free T4, and normal-elevated TSH levels. All tested mutants were expressed at the protein level, except p.Arg355Profs*64 and p.Tyr550Serfs*17, which were truncated, and were inactive in T3 uptake, excluding p.Arg445Ser and p.Pro561del mutants, compared with WT-hMCT8. Immunocytochemistry revealed plasma membrane localization of p.Arg445Ser and p.Pro561del mutants similar with WT-hMCT8. The other mutants failed to localize in significant amount(s) in the plasma membrane and instead localized in the cytoplasm. These data indicate that p.Arg445Ser and p.Pro561del mutants preserve residual function, whereas p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, p.Gly312Arg, p.Arg355Profs*64, and p.Tyr550Serfs*17 mutants lack function. These findings suggest that the mutations in MCT8 cause loss of function by reducing protein expression, impairing trafficking of protein to plasma membrane, and disrupting substrate channel.
... The loss of Cajal-Retzius cells, a reduced cortical thickness, cortical atrophy, blurring of cortical layers and an altered cerebellar structure in AHDS patients could similarly originate very early in brain development (Charzewska et al., 2016;Lopez-Espindola et al., 2014). Although slight MRI abnormalities in the cerebellum and cortex of some AHDS patients have been reported (Biebermann et al., 2005;Fuchs et al., 2009;Herzovich et al., 2007;Kakinuma et al., 2005;Lopez-Espindola et al., 2014;Novara et al., 2017;Ono et al., 2016;Tonduti et al., 2013), this type of structural damage is probably more subtle and difficult to observe using MRI. ...
Monocarboxylate transporter 8 (MCT8) facilitates transmembrane transport of thyroid hormones (THs) ensuring their action on gene expression during vertebrate neurodevelopment. A loss of MCT8 in humans results in severe psychomotor deficits associated with the Allan-Herndon-Dudley Syndrome (AHDS). However, where and when exactly a lack of MCT8 causes the neurological manifestations remains unclear because of the varying expression pattern of MCT8 between specific brain regions and cells. Here, we elaborate on the animal models that have been generated to elucidate the mechanisms underlying MCT8-deficient brain development. The absence of a clear neurological phenotype in Mct8 knockout mice made it clear that a single species would not suffice. The evolutionary conservation of TH action on neurodevelopment as well as the components regulating TH signalling however offers the opportunity to answer different aspects of MCT8 function in brain development using different vertebrate species. Moreover, the plethora of tools for genome editing available today facilitates gene silencing in these animals as well. Studies in the recently generated mct8-deficient zebrafish and Mct8/Oatp1c1 double knockout mice have put forward the current paradigm of impaired TH uptake at the level of the blood-brain barrier during peri- and postnatal development as being the main pathophysiological mechanism of AHDS. RNAi vector-based, cell-specific induction of MCT8 knockdown in the chicken embryo points to an additional function of MCT8 at the level of the neural progenitors during early brain development. Future studies including also additional in vivo models like Xenopus or in vitro approaches such as induced pluripotent stem cells will continue to help unravelling the exact role of MCT8 in developmental events. In the end, this multispecies approach will lead to a unifying thesis regarding the cellular and molecular mechanisms responsible for the neurological phenotype in AHDS patients.
