RARE DISEASE
Allan-Herndon-Dudley syndrome
Allan-Herndon-Dudley syndrome
Allan-Herndon-Dudley syndrome
Synonyms: AHDS, MCT8 deficiency, Monocarboxylate transporter 8 deficiency, X-linked intellectual disability-hypotonia syndrome
Synonyms: AHDS, MCT8 deficiency, Monocarboxylate transporter 8 deficiency, X-linked intellectual disability-hypotonia syndrome
Synonyms: AHDS, MCT8 deficiency, Monocarboxylate transporter 8 deficiency, X-linked intellectual disability-hypotonia syndrome
Drug discovery
6
drugs
With orphan designations
Overview
Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked genetic disorder caused by mutations in the SLC16A2 gene, which disrupts thyroid hormone transport into the brain. This results in severe intellectual disability, motor dysfunction (hypotonia progressing to spasticity), and abnormal thyroid hormone levels (elevated T3, low T4). Affected males exhibit developmental delays, muscle hypoplasia, and characteristic facial features. Neurological deficits arise from cerebral hypothyroidism, while peripheral tissues experience thyrotoxicosis. Diagnosis relies on clinical findings, thyroid function tests, and genetic confirmation [1][6][12].
Burden
Severe disability: Most patients never walk or speak, requiring lifelong caregiver assistance [6][12].
Medical complications: Failure to thrive, respiratory infections, scoliosis, and cardiac arrhythmias [9][12].
Reduced lifespan: Mortality risk increases due to malnutrition and recurrent infections, though some survive into their 60s [1][12].
Economic impact: High costs associated with 24/7 care, specialized therapies, and frequent hospitalizations [4][19].
Therapies
Supportive care: Physical/occupational therapy, antispasmodics (e.g., baclofen), and seizure management [1][12].
Hormonal modulation: PTU/levothyroxine to reduce peripheral thyrotoxicosis [8]; thyroid hormone analogs (TRIAC, DITPA) bypass MCT8 to improve brain T3 availability [3][8].
Emerging therapies: AAV9-MCT8 gene therapy restored motor/cognitive function in preclinical models [2][18]; prenatal DITPA trials aim to mitigate developmental deficits [8].
Categories: rare endocrine diseases, rare genetic diseases, rare neurological diseases
Research Papers
122 drug discovery papers about Allan-Herndon-Dudley syndrome, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
122 drug discovery papers about Allan-Herndon-Dudley syndrome, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-08-09 | Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan-Herndon-Dudley Syndrome Mouse Model.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type-specific pathologies underlying AHDS remain insufficiently defined. To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell-cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell-cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin-neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. Our findings provide the first single-cell-level cortical map of AHDS brain pathology, revealing cilia defects, excitation-inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.
2025-03-23 | Correction of the Allan-Herndon-Dudley syndrome-causing SLC16A2 mutation G401R in a patient derived hiPSC line.
The X-linked Allan-Herndon-Dudley syndrome (AHDS) is a genetic disorder characterized by severe psychomotor impairment, resulting from mutations in the SLC16A2 gene, which encodes the thyroid hormone transporter MCT8 (monocarboxylate transporter 8). Previously, we established a hiPSC line from a patient carrying the SLC16A2:R401G mutation (BIHi045-A). Using CRISPR/Cas9-mediated gene editing, we targeted exon 3 of SLC16A2 and used single-stranded oligodeoxynucleotides as homology-directed repair templates to correct the R401G missense mutation, generating an isogenic control cell line.
2024-07-17 | Cone photoreceptor differentiation regulated by thyroid hormone transporter MCT8 in the retinal pigment epithelium.
The key role of a thyroid hormone receptor in determining the maturation and diversity of cone photoreceptors reflects a profound influence of endocrine signaling on the cells that mediate color vision. However, the route by which hormone reaches cones remains enigmatic as cones reside in the retinal photoreceptor layer, shielded by the blood-retina barrier. Using genetic approaches, we report that cone differentiation is regulated by a membrane transporter for thyroid hormone, MCT8 (SLC16A2), in the retinal pigment epithelium (RPE), which forms the outer blood-retina barrier. Mct8-deficient mice display hypothyroid-like cone gene expression and compromised electroretinogram responses. Mammalian color vision is typically facilitated by cone types that detect medium-long (M) and short (S) wavelengths of light but Mct8-deficient mice have a partial shift of M to S cone identity, resembling the phenotype of thyroid hormone receptor deficiency. RPE-specific ablation of Mct8 results in similar shifts in cone identity and hypothyroid-like gene expression whereas reexpression of MCT8 in the RPE in Mct8-deficient mice partly restores M cone identity, consistent with paracrine-like control of thyroid hormone signaling by the RPE. Our findings suggest that in addition to transport of essential solutes and homeostatic support for photoreceptors, the RPE regulates the thyroid hormone signal that promotes cone-mediated vision.
2022-11-01 | A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations
Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.
2022-08-05 | Gene therapy targeting the blood–brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency
A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased tri-iodothyronine (T3) levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.
small molecules
2026-07-15 | Loss of Thyroid Hormone Transporters MCT8 and OATP1C1 in Mouse Oligodendroglia Cells Results in a Delayed Oligodendrocyte Maturation and Myelination.
Due to an impaired thyroid hormone (TH) transport across brain barriers, inactivation of the murine TH transporters Mct8/Oatp1c1 causes a profound TH deficiency of the CNS that greatly impacts neural development and function. Since oligodendrocyte maturation and myelination are dependent on local TH signaling, Mct8/Oatp1c1 double knockout (DKO) mice exhibit a persistent state of hypomyelination. Yet, to which extent Mct8/Oatp1c1 inactivation also affects TH transport into oligodendroglia cells has not been addressed. Here, we studied oligodendrocyte maturation and myelination in mice lacking Mct8/Oatp1c1 specifically in oligodendroglia lineage (OL) cells and compared their phenotype with that of control and DKO animals. Conditional Mct8/Oatp1c1 mutants were crossed with mice expressing constitutively Cre-recombinase under the control of the Olig2 promoter to inactivate both transporters in OL cells (so-called OL CKO mice). Neural maturation and myelination were assessed by immunofluorescence (IF) and fluorescence in situ hybridization (FISH) studies at different postnatal time points. Oligodendrocyte precursor cells (OPCs), premyelinating, and myelinating oligodendrocytes were visualized by coimmunolabeling. OL CKO mice exhibited normal serum TH concentrations and hypothalamic Trh transcript levels. Quantification of neuronal TH-target gene transcript levels (Rc3; Klf9; Pde10a) revealed no alterations. Abundance of myelin sheaths-related proteins Mbp and Cnp was significantly reduced in OL CKO mice at postnatal day P12 but reached normal levels at P21 and P120. Quantification of OPC, premyelinating, and myelinating oligodendrocytes disclosed a strongly reduced number of mature OL at P6 and P12, while cell numbers normalized in adult OL CKO mice. Inactivation of murine TH transporters Mct8/Oatp1c1 in OL cells causes a delayed oligodendroglia maturation and myelination. These findings highlight a physiologically relevant function of Mct8/Oatp1c1 in developmental oligodendrogenesis and myelin formation. In contrast to the persistent myelination defect seen in central hypothyroid DKO mice, OL CKO mice exhibit only a transient oligodendrocyte differentiation impairment and transient hypomyelination. These observations indicate the presence of additional, yet unknown, TH transporters that ultimately enable cellular TH entry into oligodendroglia cells even in the absence of Mct8/Oatp1c1.
2026-06-24 | Triiodothyroacetic acid exerts tissue-specific thyromimetic effects without tachycardia and hyperthermia in male mice.
Thyroid hormones regulate cardiovascular functions and energy homeostasis including thermogenesis through binding to nuclear thyroid hormone receptors. The thyroid hormone analogue 3,3',5-triiodothyroacetic acid (TRIAC) has recently emerged as a therapeutic candidate for thyroid hormone transporter deficiencies (Allan-Herndon-Dudley Syndrome) or thyroid hormone resistance β. Although TRIAC shows promise for these conditions, a comprehensive characterization focussing on heart and body temperature regulation has not been systematically performed in mice. As this knowledge is critical for determining its safety profile and therapeutic advantages over conventional thyroid hormone therapy, we administered TRIAC to wild-type mice for 14 days and assessed molecular (Realtime PCR, Western Blot, Immunoassays) and physiological responses (Infrared Thermography, Blood Pressure). TRIAC treatment reduced circulating thyroxine levels and induced robust upregulation of hepatic thyroid hormone-responsive genes including Dio1 and Me1, demonstrating classical thyromimetic activity. However, cardiovascular analysis revealed normal blood pressure and heart rate, and no signs of cardiac hypertrophy despite specific molecular changes in cardiac gene expression. On the metabolic level, we surprisingly did not observe any effect on brown fat thermogenesis or body temperature, while in muscle Ucp3 and Gpd2 were reduced. Taken together, our comparative in vivo analysis demonstrates variable TRIAC responsiveness across tissues. Under defined conditions, the drug produces defined metabolic responses while avoiding classical hyperthyroid manifestations such as tachycardia or hyperthermia, thus supporting its potential therapeutic use in thyroid hormone resistance conditions.
2026-06-22 | Reduced thyroid hormone transport in a human placental model with inhibited MCT8.
Maternal-to-fetal transfer of the thyroid hormone T4 is essential for prenatal neurodevelopment, but the transporter facilitating trans-placental T4 transport is unknown. Mutations in the thyroid hormone transporter MCT8 cause a neurodevelopmental and metabolic disorder which key clinical features can be ameliorated by the T3 analogue TRIAC. Should placental MCT8 be physiologically relevant, defective T4 transport across the placenta, which is fetal-derived tissue, could represent a hitherto unrecognized mechanism underlying MCT8 deficiency. We investigated the importance of MCT8 and the trans-placental transport of TRIAC using an ex vivo human placental perfusion setup. Uncomplicated term placentas were used for the ex vivo dual perfusion experiments to investigate the maternal-to-fetal transfer of T4 or TRIAC in the absence or presence of the MCT8 inhibitor silychristin. Samples were collected at various time points from both maternal and fetal circulations. T4 and rT3 concentrations in the perfused samples were measured using radio-immunoassay and TRIAC using LCMS/MS. In the presence of silychristin, maternal-to-fetal transfer of 100 nM T4 was reduced by ∼60% (4.2±1.2 nM fetal T4 in MCT8-inhibited placentas versus 10.6±0.6 nM fetal T4 in control placentas). TRIAC was efficiently transferred from the maternal to the fetal circulation. Our study (i) showed that MCT8 has a major role in maternal-to-fetal T4 transport, (ii) implies that disrupted placental transport of thyroid hormones may contribute to neurodevelopmental delays in MCT8 deficiency and (iii) indicated TRIAC is efficiently transported across the placenta, independent of MCT8, holding potential in mothers carrying fetuses with MCT8 deficiency.
2026-01-23 | Delineating the role of monocarboxylate transporter 8 (MCT8) in the context of neuroinflammation–mediated oligodendrocytopathy
Oligodendrocytes (OLs) myelinate central nervous system (CNS) axons and provide metabolic support to maintain axonal integrity. Thyroid hormone (TH) is a mitogen for oligodendroglial precursor cells (OPCs) maturation into myelinating OLs. Cellular uptake of TH is mediated by monocarboxylate transporter 8 (MCT8; encoded by slc16a2 ), and its dysfunction results in intracellular triiodothyronine (T3) deprivation, leading to hypomyelination and myelin degeneration during neuroinflammation. We showed that MCT8 expression is maintained in OPCs residing within the sub–ventricular zone (SVZ) throughout CNS development, suggesting a role during OL development. We identified MCT8 deficiency during neuroinflammatory and cuprizone demyelination models, as well as in secondary progressive multiple sclerosis (SPMS). These conditions were associated with dysregulated AKT–mTOR–PANK2 signaling and abrogated Co Enzyme A and lipid synthesis pathways in the CNS during myelin degeneration. Hence, neuroprotection during SPMS maybe achieved by overcoming MCT8 deficiencies in OLs.
2025-10-27 | Altered Dopamine Metabolism and Response to Treatment with Levodopa/Carbidopa in MCT8 Deficiency.
Allan-Herndon-Dudley syndrome (AHDS)/monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked encephalopathy caused by SLC16A2 variants, impairing thyroid hormone (TH) transport into the brain. This leads to early central nervous system (CNS) TH deficiency, affecting brain maturation. Dopaminergic circuit involvement is suggested by both pathophysiology and clinical features, reminiscent of infantile parkinsonism. This study investigates dopamine metabolism and levodopa/carbidopa response in MCT8 patients. We retrospectively and prospectively collected clinical, genetic, and neuroimaging data, performed cerebrospinal fluid (CSF) biogenic amine analyses, and conducted neurological assessments before and after the levodopa trial (10 mg/kg/day). Ten patients exhibited developmental delay, spasticity, and infantile parkinsonism. CSF analysis showed reduced homovanillic acid in 3/10 patients, with 7/10 in the lowest quartile. Levodopa improved parkinsonism and reactivity in 7/10 patients. Our findings confirm dopaminergic involvement in AHDS and show that levodopa/carbidopa effectively treats extrapyramidal symptoms. Further investigations could differentiate presynaptic and postsynaptic defects to optimize dopaminergic therapy. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
proteins
2025-05-21 | Pathogenic MCT8V235L creates a steric clash that is alleviated by a compensating mutation of MCT8F285A.
The monocarboxylate transporter (MCT) 8 is a specific transporter for thyroid hormones. Pathogenic variants in MCT8 lead to a severe psychomotor disorder called MCT8 deficiency. A recently published patient carries a MCT8V235 to leucine substitution that was incapable of T3 transport. Analyses of our MCT8 homology model predicted steric clashes between Leu235 and Phe285 as well as Gln288, possibly affecting another transport-sensitive phenylalanine at position 287. We analyzed the occurrence of potential van der Waals (VDW) interactions between Leu235 and Phe285 as well as Gln288 in the homology model. We overexpressed MCT8V235 and MCT8F287 mutants with altered side-chain properties in cells to assess their role in T3 transport function. In addition, we created an MCT8V235L,F285A double mutant. Mutations of MCT8V235 to alanine, threonine or isoleucine, as well as the analysis of potential VDW interactions, helped us to identify Phe285, but not Gln288, as the amino acid responsible for the inactivity of MCT8V235L. The hypothesis was supported by activity measurements of an MCT8V235L,F285A double mutant that showed rescued T3 transport with KM values similar to wild-type MCT8. The analyses of MCT8F287 mutated to tyrosine, tryptophan and valine revealed that the size and/or the aromatic properties of the amino acid side chain are crucial for proper membrane expression and T3 transport. We were able to restore transport activity of MCT8V235L by introducing a second mutation (MCT8V235L,F285A). We speculate that the additional mutation prevents a shift of Phe287 into the potential transport cavity, eventually restoring T3 transport.
2024-01-31 | Defective thyroid hormone transport to the brain leads to astroglial alterations
Abstract Background : Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work we have evaluated astroglial impairments in MCT8 deficiency. Methods : We conducted magnetic resonance imaging on both control subjects and MCT8-deficient patients to examine changes in brain cytoarchitecture. Moreover, to gain further understanding on these alterations in brain cytoarchitecture and the astroglial population, we have performed histological and immunohistochemical approaches in autopsy brain samples from an 11-year-old and a 30 th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. Findings from MCT8-deficient subjects were validated and further explored in a mouse model of the AHDS. Results : Magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients. Further studies confirmed changes in the astroglial population in MCT8 deficiency that arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, and morphology of cortical astrocytes, compatible with an astrogliosis-like phenotype at adult stages. Conclusions : We have identified astrocytes as potential novel therapeutic targets in AHDS. In addition, we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
2017-12-27 | Few Amino Acid Exchanges Expand the Substrate Spectrum of Monocarboxylate Transporter 10.
Monocarboxylate transporters (MCTs) belong to the SLC16 family within the major facilitator superfamily of transmembrane transporters. MCT8 is a thyroid hormone transporter mutated in the Allan-Herndon-Dudley syndrome, a severe psychomotor retardation syndrome. MCT10 is closely related to MCT8 and is known as T-type amino acid transporter. Both transporters mediate T3 transport, but although MCT8 also transports rT3 and T4, these compounds are not efficiently transported by MCT10, which, in contrast, transports aromatic amino acids. Based on the 58% amino acid identity within the transmembrane regions among MCT8 and MCT10, we reasoned that substrate specificity may be primarily determined by a small number of amino acid differences between MCT8 and MCT10 along the substrate translocation channel. Inspecting the homology model of MCT8 and a structure-guided alignment between both proteins, we selected 8 amino acid positions and prepared chimeric MCT10 proteins with selected amino acids changed to the corresponding amino acids in MCT8. The MCT10 mutant harboring 8 amino acid substitutions was stably expressed in Madin-Darby canine kidney 1 cells and found to exhibit T4 transport activity. We then successively reduced the number of amino acid substitutions and eventually identified a minimal set of 2-3 amino acid exchanges which were sufficient to allow T4 transport. The resulting MCT10 chimeras exhibited KM values for T4 similar to MCT8 but transported T4 at a slower rate. The acquisition of T4 transport by MCT10 was associated with complete loss of the capacity to transport Phe, when Tyr184 was mutated to Phe.
gene therapies
2026-08-09 | Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan-Herndon-Dudley Syndrome Mouse Model.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type-specific pathologies underlying AHDS remain insufficiently defined. To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell-cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell-cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin-neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. Our findings provide the first single-cell-level cortical map of AHDS brain pathology, revealing cilia defects, excitation-inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.
2025-03-23 | Correction of the Allan-Herndon-Dudley syndrome-causing SLC16A2 mutation G401R in a patient derived hiPSC line.
The X-linked Allan-Herndon-Dudley syndrome (AHDS) is a genetic disorder characterized by severe psychomotor impairment, resulting from mutations in the SLC16A2 gene, which encodes the thyroid hormone transporter MCT8 (monocarboxylate transporter 8). Previously, we established a hiPSC line from a patient carrying the SLC16A2:R401G mutation (BIHi045-A). Using CRISPR/Cas9-mediated gene editing, we targeted exon 3 of SLC16A2 and used single-stranded oligodeoxynucleotides as homology-directed repair templates to correct the R401G missense mutation, generating an isogenic control cell line.
2024-07-17 | Cone photoreceptor differentiation regulated by thyroid hormone transporter MCT8 in the retinal pigment epithelium.
The key role of a thyroid hormone receptor in determining the maturation and diversity of cone photoreceptors reflects a profound influence of endocrine signaling on the cells that mediate color vision. However, the route by which hormone reaches cones remains enigmatic as cones reside in the retinal photoreceptor layer, shielded by the blood-retina barrier. Using genetic approaches, we report that cone differentiation is regulated by a membrane transporter for thyroid hormone, MCT8 (SLC16A2), in the retinal pigment epithelium (RPE), which forms the outer blood-retina barrier. Mct8-deficient mice display hypothyroid-like cone gene expression and compromised electroretinogram responses. Mammalian color vision is typically facilitated by cone types that detect medium-long (M) and short (S) wavelengths of light but Mct8-deficient mice have a partial shift of M to S cone identity, resembling the phenotype of thyroid hormone receptor deficiency. RPE-specific ablation of Mct8 results in similar shifts in cone identity and hypothyroid-like gene expression whereas reexpression of MCT8 in the RPE in Mct8-deficient mice partly restores M cone identity, consistent with paracrine-like control of thyroid hormone signaling by the RPE. Our findings suggest that in addition to transport of essential solutes and homeostatic support for photoreceptors, the RPE regulates the thyroid hormone signal that promotes cone-mediated vision.
2022-11-01 | A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations
Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.
2022-08-05 | Gene therapy targeting the blood–brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency
A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased tri-iodothyronine (T3) levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.
small molecules
2026-07-15 | Loss of Thyroid Hormone Transporters MCT8 and OATP1C1 in Mouse Oligodendroglia Cells Results in a Delayed Oligodendrocyte Maturation and Myelination.
Due to an impaired thyroid hormone (TH) transport across brain barriers, inactivation of the murine TH transporters Mct8/Oatp1c1 causes a profound TH deficiency of the CNS that greatly impacts neural development and function. Since oligodendrocyte maturation and myelination are dependent on local TH signaling, Mct8/Oatp1c1 double knockout (DKO) mice exhibit a persistent state of hypomyelination. Yet, to which extent Mct8/Oatp1c1 inactivation also affects TH transport into oligodendroglia cells has not been addressed. Here, we studied oligodendrocyte maturation and myelination in mice lacking Mct8/Oatp1c1 specifically in oligodendroglia lineage (OL) cells and compared their phenotype with that of control and DKO animals. Conditional Mct8/Oatp1c1 mutants were crossed with mice expressing constitutively Cre-recombinase under the control of the Olig2 promoter to inactivate both transporters in OL cells (so-called OL CKO mice). Neural maturation and myelination were assessed by immunofluorescence (IF) and fluorescence in situ hybridization (FISH) studies at different postnatal time points. Oligodendrocyte precursor cells (OPCs), premyelinating, and myelinating oligodendrocytes were visualized by coimmunolabeling. OL CKO mice exhibited normal serum TH concentrations and hypothalamic Trh transcript levels. Quantification of neuronal TH-target gene transcript levels (Rc3; Klf9; Pde10a) revealed no alterations. Abundance of myelin sheaths-related proteins Mbp and Cnp was significantly reduced in OL CKO mice at postnatal day P12 but reached normal levels at P21 and P120. Quantification of OPC, premyelinating, and myelinating oligodendrocytes disclosed a strongly reduced number of mature OL at P6 and P12, while cell numbers normalized in adult OL CKO mice. Inactivation of murine TH transporters Mct8/Oatp1c1 in OL cells causes a delayed oligodendroglia maturation and myelination. These findings highlight a physiologically relevant function of Mct8/Oatp1c1 in developmental oligodendrogenesis and myelin formation. In contrast to the persistent myelination defect seen in central hypothyroid DKO mice, OL CKO mice exhibit only a transient oligodendrocyte differentiation impairment and transient hypomyelination. These observations indicate the presence of additional, yet unknown, TH transporters that ultimately enable cellular TH entry into oligodendroglia cells even in the absence of Mct8/Oatp1c1.
2026-06-24 | Triiodothyroacetic acid exerts tissue-specific thyromimetic effects without tachycardia and hyperthermia in male mice.
Thyroid hormones regulate cardiovascular functions and energy homeostasis including thermogenesis through binding to nuclear thyroid hormone receptors. The thyroid hormone analogue 3,3',5-triiodothyroacetic acid (TRIAC) has recently emerged as a therapeutic candidate for thyroid hormone transporter deficiencies (Allan-Herndon-Dudley Syndrome) or thyroid hormone resistance β. Although TRIAC shows promise for these conditions, a comprehensive characterization focussing on heart and body temperature regulation has not been systematically performed in mice. As this knowledge is critical for determining its safety profile and therapeutic advantages over conventional thyroid hormone therapy, we administered TRIAC to wild-type mice for 14 days and assessed molecular (Realtime PCR, Western Blot, Immunoassays) and physiological responses (Infrared Thermography, Blood Pressure). TRIAC treatment reduced circulating thyroxine levels and induced robust upregulation of hepatic thyroid hormone-responsive genes including Dio1 and Me1, demonstrating classical thyromimetic activity. However, cardiovascular analysis revealed normal blood pressure and heart rate, and no signs of cardiac hypertrophy despite specific molecular changes in cardiac gene expression. On the metabolic level, we surprisingly did not observe any effect on brown fat thermogenesis or body temperature, while in muscle Ucp3 and Gpd2 were reduced. Taken together, our comparative in vivo analysis demonstrates variable TRIAC responsiveness across tissues. Under defined conditions, the drug produces defined metabolic responses while avoiding classical hyperthyroid manifestations such as tachycardia or hyperthermia, thus supporting its potential therapeutic use in thyroid hormone resistance conditions.
2026-06-22 | Reduced thyroid hormone transport in a human placental model with inhibited MCT8.
Maternal-to-fetal transfer of the thyroid hormone T4 is essential for prenatal neurodevelopment, but the transporter facilitating trans-placental T4 transport is unknown. Mutations in the thyroid hormone transporter MCT8 cause a neurodevelopmental and metabolic disorder which key clinical features can be ameliorated by the T3 analogue TRIAC. Should placental MCT8 be physiologically relevant, defective T4 transport across the placenta, which is fetal-derived tissue, could represent a hitherto unrecognized mechanism underlying MCT8 deficiency. We investigated the importance of MCT8 and the trans-placental transport of TRIAC using an ex vivo human placental perfusion setup. Uncomplicated term placentas were used for the ex vivo dual perfusion experiments to investigate the maternal-to-fetal transfer of T4 or TRIAC in the absence or presence of the MCT8 inhibitor silychristin. Samples were collected at various time points from both maternal and fetal circulations. T4 and rT3 concentrations in the perfused samples were measured using radio-immunoassay and TRIAC using LCMS/MS. In the presence of silychristin, maternal-to-fetal transfer of 100 nM T4 was reduced by ∼60% (4.2±1.2 nM fetal T4 in MCT8-inhibited placentas versus 10.6±0.6 nM fetal T4 in control placentas). TRIAC was efficiently transferred from the maternal to the fetal circulation. Our study (i) showed that MCT8 has a major role in maternal-to-fetal T4 transport, (ii) implies that disrupted placental transport of thyroid hormones may contribute to neurodevelopmental delays in MCT8 deficiency and (iii) indicated TRIAC is efficiently transported across the placenta, independent of MCT8, holding potential in mothers carrying fetuses with MCT8 deficiency.
2026-01-23 | Delineating the role of monocarboxylate transporter 8 (MCT8) in the context of neuroinflammation–mediated oligodendrocytopathy
Oligodendrocytes (OLs) myelinate central nervous system (CNS) axons and provide metabolic support to maintain axonal integrity. Thyroid hormone (TH) is a mitogen for oligodendroglial precursor cells (OPCs) maturation into myelinating OLs. Cellular uptake of TH is mediated by monocarboxylate transporter 8 (MCT8; encoded by slc16a2 ), and its dysfunction results in intracellular triiodothyronine (T3) deprivation, leading to hypomyelination and myelin degeneration during neuroinflammation. We showed that MCT8 expression is maintained in OPCs residing within the sub–ventricular zone (SVZ) throughout CNS development, suggesting a role during OL development. We identified MCT8 deficiency during neuroinflammatory and cuprizone demyelination models, as well as in secondary progressive multiple sclerosis (SPMS). These conditions were associated with dysregulated AKT–mTOR–PANK2 signaling and abrogated Co Enzyme A and lipid synthesis pathways in the CNS during myelin degeneration. Hence, neuroprotection during SPMS maybe achieved by overcoming MCT8 deficiencies in OLs.
2025-10-27 | Altered Dopamine Metabolism and Response to Treatment with Levodopa/Carbidopa in MCT8 Deficiency.
Allan-Herndon-Dudley syndrome (AHDS)/monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked encephalopathy caused by SLC16A2 variants, impairing thyroid hormone (TH) transport into the brain. This leads to early central nervous system (CNS) TH deficiency, affecting brain maturation. Dopaminergic circuit involvement is suggested by both pathophysiology and clinical features, reminiscent of infantile parkinsonism. This study investigates dopamine metabolism and levodopa/carbidopa response in MCT8 patients. We retrospectively and prospectively collected clinical, genetic, and neuroimaging data, performed cerebrospinal fluid (CSF) biogenic amine analyses, and conducted neurological assessments before and after the levodopa trial (10 mg/kg/day). Ten patients exhibited developmental delay, spasticity, and infantile parkinsonism. CSF analysis showed reduced homovanillic acid in 3/10 patients, with 7/10 in the lowest quartile. Levodopa improved parkinsonism and reactivity in 7/10 patients. Our findings confirm dopaminergic involvement in AHDS and show that levodopa/carbidopa effectively treats extrapyramidal symptoms. Further investigations could differentiate presynaptic and postsynaptic defects to optimize dopaminergic therapy. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
proteins
2025-05-21 | Pathogenic MCT8V235L creates a steric clash that is alleviated by a compensating mutation of MCT8F285A.
The monocarboxylate transporter (MCT) 8 is a specific transporter for thyroid hormones. Pathogenic variants in MCT8 lead to a severe psychomotor disorder called MCT8 deficiency. A recently published patient carries a MCT8V235 to leucine substitution that was incapable of T3 transport. Analyses of our MCT8 homology model predicted steric clashes between Leu235 and Phe285 as well as Gln288, possibly affecting another transport-sensitive phenylalanine at position 287. We analyzed the occurrence of potential van der Waals (VDW) interactions between Leu235 and Phe285 as well as Gln288 in the homology model. We overexpressed MCT8V235 and MCT8F287 mutants with altered side-chain properties in cells to assess their role in T3 transport function. In addition, we created an MCT8V235L,F285A double mutant. Mutations of MCT8V235 to alanine, threonine or isoleucine, as well as the analysis of potential VDW interactions, helped us to identify Phe285, but not Gln288, as the amino acid responsible for the inactivity of MCT8V235L. The hypothesis was supported by activity measurements of an MCT8V235L,F285A double mutant that showed rescued T3 transport with KM values similar to wild-type MCT8. The analyses of MCT8F287 mutated to tyrosine, tryptophan and valine revealed that the size and/or the aromatic properties of the amino acid side chain are crucial for proper membrane expression and T3 transport. We were able to restore transport activity of MCT8V235L by introducing a second mutation (MCT8V235L,F285A). We speculate that the additional mutation prevents a shift of Phe287 into the potential transport cavity, eventually restoring T3 transport.
2024-01-31 | Defective thyroid hormone transport to the brain leads to astroglial alterations
Abstract Background : Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work we have evaluated astroglial impairments in MCT8 deficiency. Methods : We conducted magnetic resonance imaging on both control subjects and MCT8-deficient patients to examine changes in brain cytoarchitecture. Moreover, to gain further understanding on these alterations in brain cytoarchitecture and the astroglial population, we have performed histological and immunohistochemical approaches in autopsy brain samples from an 11-year-old and a 30 th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. Findings from MCT8-deficient subjects were validated and further explored in a mouse model of the AHDS. Results : Magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients. Further studies confirmed changes in the astroglial population in MCT8 deficiency that arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, and morphology of cortical astrocytes, compatible with an astrogliosis-like phenotype at adult stages. Conclusions : We have identified astrocytes as potential novel therapeutic targets in AHDS. In addition, we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
2017-12-27 | Few Amino Acid Exchanges Expand the Substrate Spectrum of Monocarboxylate Transporter 10.
Monocarboxylate transporters (MCTs) belong to the SLC16 family within the major facilitator superfamily of transmembrane transporters. MCT8 is a thyroid hormone transporter mutated in the Allan-Herndon-Dudley syndrome, a severe psychomotor retardation syndrome. MCT10 is closely related to MCT8 and is known as T-type amino acid transporter. Both transporters mediate T3 transport, but although MCT8 also transports rT3 and T4, these compounds are not efficiently transported by MCT10, which, in contrast, transports aromatic amino acids. Based on the 58% amino acid identity within the transmembrane regions among MCT8 and MCT10, we reasoned that substrate specificity may be primarily determined by a small number of amino acid differences between MCT8 and MCT10 along the substrate translocation channel. Inspecting the homology model of MCT8 and a structure-guided alignment between both proteins, we selected 8 amino acid positions and prepared chimeric MCT10 proteins with selected amino acids changed to the corresponding amino acids in MCT8. The MCT10 mutant harboring 8 amino acid substitutions was stably expressed in Madin-Darby canine kidney 1 cells and found to exhibit T4 transport activity. We then successively reduced the number of amino acid substitutions and eventually identified a minimal set of 2-3 amino acid exchanges which were sufficient to allow T4 transport. The resulting MCT10 chimeras exhibited KM values for T4 similar to MCT8 but transported T4 at a slower rate. The acquisition of T4 transport by MCT10 was associated with complete loss of the capacity to transport Phe, when Tyr184 was mutated to Phe.
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Drug Discovery Landscape
6 orphan drug designations for Allan-Herndon-Dudley syndrome, including 1 approved therapy.
6 orphan drug designations for Allan-Herndon-Dudley syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
3,5-diiodothyropropionic acid | small molecules | EMA | 2021-07-19 | — | Dexcel Pharma GmbH |
3,5-diiodothyropropionic acid | small molecules | FDA | 2020-07-28 | — | Dexcel Pharma Technologies Ltd. |
tiratricol | small molecules | FDA | 2019-01-16 | — | Rare Thyroid Therapeutics |
Tiratricol [Emcitate] | small molecules | EMA | 2017-11-08 | 2025-02-17 | Rare Thyroid Therapeutics International AB |
3,5-diiodothyropropionic acid | small molecules | EMA | 2013-10-07 | — | CATS Consultants GmbH |
3,5-diiodothyropropionic acid | small molecules | FDA | 2013-05-14 | — | Zarion Pharmaceuticals P/L |
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