Allan-Herndon-Dudley Syndrome Research Articles

Combined levothyroxine and propylthiouracil treatment in children with MCT8 deficiency: A multi-center case series of 12 patients.

To evaluate the combined administration of propylthiouracil (PTU) and levothyroxine (LT4) in managing MCT8 deficiency and identify optimal therapeutic dosages. This multi-center case series involved 12 male patients with MCT8 deficiency whose parents/guardians consented to PTU and LT4 treatment. Data were collected from January 2008 to June 24, 2024. The study focused on treatment safety and outcomes, analyzing baseline and last encounter biochemical, metabolic, and anthropometric parameters. Statistical analyses included Wilcoxon Signed Ranks tests and Generalized Estimated Equations to assess effects on thyroid and metabolic markers, and Receiver Operating Characteristics curves to predict optimal dose. Patients showed a significant reduction in serum total T3 (TT3) concentration and TT3/TT4 ratio, with increased serum TT4 and FT4 concentrations. The use of PTU effectively reduced TT3 concentration by 25% at an average dose of 6.8 mg/Kg/day, while LT4 increased FT4 concentration by 40% from baseline at an average dose of 4.3 μg/Kg/day. TSH concentration was undetectable on treatment. No statistical differences were observed in metabolic and physical parameters between baseline and last encounter overall for the group but 6 of 8 patients for whom this data was available had an increase in weight (z score). There were no adverse effects on liver function or granulocyte numbers noted throughout the period of observation. Combined treatment with PTU and LT4 normalized serum T3, FT4, TT4 in patients with MCT8 deficiency. Individualized dose adjustments were crucial for achieving therapeutic goals, indicating the need for personalized treatment plans.

Effect of the T3 analogue triac on patient-centered outcome measures in patients with MCT8 deficiency: post-hoc analysis of the international triac trial I

Effect of the T3 analogue triac on patient-centered outcome measures in patients with MCT8 deficiency: post-hoc analysis of the international triac trial I

T3 analogue triiodothyroacetic acid (TRIAC) treatment and survival in MCT8 deficiency: an international real-world cohort study

T3 analogue triiodothyroacetic acid (TRIAC) treatment and survival in MCT8 deficiency: an international real-world cohort study

Blood-brain barrier leakage and neurovascular unit ultrastructural alterations as new pathophysiological mechanisms for MCT8 deficiency

Blood-brain barrier leakage and neurovascular unit ultrastructural alterations as new pathophysiological mechanisms for MCT8 deficiency

Defective thyroid hormone transport to the brain leads to astroglial alterations

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 by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.

Identification of a novel nonsense SLC16A2 gene mutation in an infant with severe neurologic phenotype: A case report.

Allan-Herndon-Dudley syndrome (AHDS) results from a pathogenic variant in the hemizygous subunit of the SLC16A2 gene, which encodes monocarboxylate transporter 8 and follows an X-linked recessive pattern. AHDS manifests as neuropsychomotor developmental delay, intellectual disability, movement disorders, and thyroid hormone abnormalities. It is frequently misdiagnosed as cerebral palsy or hypothyroidism. A 9-month-old male infant exhibited poor head control, hypodynamia, motor retardation, hypertonic limbs, and thyroid abnormalities. Despite levothyroxine supplementation and rehabilitation therapy, no improvements were observed. Whole-exome sequencing identified a novel nonsense mutation in SLC16A2 (c.124G > T, p.E42X), which unequivocally established the diagnosis. AHDS was confirmed. Levothyroxine treatment commenced early in infancy, followed by 3 months of rehabilitation therapy, starting at 5 months of age. The combined administration of levothyroxine and methimazole was initiated at 1 year and 10 months of age, respectively. While improvements were noted in thyroid hormone levels, neurological developmental delays persisted. AHDS should be considered in patients presenting with atypical neurological features and thyroid hormone abnormalities such as elevated triiodothyronine and decreased thyroxine levels. The early utilization of exome sequencing aids in prompt diagnosis. The identified SLC16A2 nonsense mutation correlates with severe neurological phenotypes and adds to the spectrum of genetic variations associated with AHDS.

A Highly Selective Fluorescent Probe for Monitoring the Thyroid Hormone Transporter Activity in Mammalian Cells.

Monocarboxylate transporter 8 (MCT8) is a trans-membrane transporter, which mediates the cellular delivery of thyroid hormones, L-thyroxine (T4) and 3,5,3 '-triiodo-L-thyronine (T3). In humans, the MCT8 protein is encoded by the SLC16A2 gene and mutations in the transporter cause a genetic neurological disorder known as Allan-Herndon-Dudley syndrome (AHDS). MCT8 deficiency leads to impaired transport of thyroid hormones in the brain. Radiolabelled T4 and T3 or LC/MS-MS methods have been used to monitor the thyroid hormone uptake through MCT8. Herein, we developed a fluorescent based assay to monitor the thyroid hormone uptake through MCT8. A dansyl-based fluorescent probe having L-thyroxine moiety is found to be highly selective towards MCT8 in living cells. The high selectivity of the probe towards MCT8 can be attributed to the halogen bond-mediated recognition by the transporter protein. The presence of a free carboxylic acid group is essential for the specificity of the probe towards MCT8. Additionally, the selectivity of the probe for MCT8 is abolished upon esterification of the carboxylic group. Similarly, MCT8 does not recognize the probe when it contains a free amine group.

3,3',5-Triiodothyroacetic Acid Transporters.

Introduction: Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter (MCT) 8 is a key transporter and is expressed at the blood-brain barrier (BBB), in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays because of cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3',5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human BBB and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and Methods: Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate-buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. Results: In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (n = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n = 19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6, and SLC22A24 (in DMEM). The zebrafish and mouse orthologs of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but was reduced at P120. Conclusions: Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8, and SLC22A24 as well as their mouse and zebrafish orthologs are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.

Phenylbutyrate Treatment in a Boy with MCT8 Deficiency: Improvement of Thyroid Function Tests and Possible Livertoxicity.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations. The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G > T (p.V235L). During a treatment period of 13 months, PB led to a significant decrease of elevated TSH and T3 serum concentrations, while fT4 increased. Weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate (PAA) in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity. In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies towards body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation.

Identification of Iodotyrosines as Novel Substrates for the Thyroid Hormone Transporter MCT8.

Background: Monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date, deficiency of which has been associated with severe intellectual and motor disability and abnormal serum thyroid function tests. However, it is presently unknown if MCT8, similar to other thyroid hormone transporters, also accepts additional substrates, and if disruption of their transport may contribute to the observed phenotype. Methods: In this study, we aimed to identify such substrates by applying liquid chromatography-mass spectrometry-based metabolome analysis in lysates of control and MCT8-overexpressing Xenopus oocytes. A subset of identified candidate substrates were validated by direct transport studies in transiently transfected COS-1 cells and human fibroblasts, which endogenously express MCT8. Moreover, transport characteristics were determined, including transport saturation and cis-inhibition potency of thyroid hormone transport. Results: Metabolome analysis identified 21 m/z ratios, corresponding to 87 candidate metabolites, with a 2.0-times differential abundance in MCT8-injected oocytes compared with controls. These metabolites included 3,5-diiodotyrosine (DIT) and several amino acids, including glutamate and glutamine. In accordance, MCT8-expressing COS-1 cells had 2.2-times lower intracellular accumulation of [125I]-DIT compared with control cells. This effect was largely blocked in the presence of 3,3',5-triiodothyronine (T3) (IC50: 2.5 ± 1.5 µM) or thyroxine (T4) (IC50: 5.8 ± 1.3 µM). Conversely, increasing concentrations of DIT enhanced the accumulation of T3 and T4. The MCT8-specific inhibitor silychristin increased the intracellular accumulation of DIT in human fibroblasts. COS-1 cells expressing MCT8 also exhibited a 50% reduction in intracellular accumulation of [125I]-3-monoiodotyrosine (MIT). In contrast, COS-1 cells expressing MCT8 did not alter the intracellular accumulation of [3H]-glutamate or [3H]-glutamine. However, studies in human fibroblasts showed a 1.5-1.9 times higher glutamate uptake in control fibroblasts compared with fibroblasts derived from patients with MCT8 deficiency, which was not affected in the presence of silychristin. Conclusions: Taken together, our results suggest that the iodotyrosines DIT and MIT can be exported by MCT8. MIT and DIT interfere with MCT8-mediated transport of thyroid hormone in vitro and vice versa. Future studies should elucidate if MCT8, being highly expressed in thyroidal follicular cells, also transports iodotyrosines invivo.

Insights on the role of thyroid hormone transport in neurosensory organs and implication for the Allan-Herndon-Dudley syndrome.

Thyroid hormones play an important role during the development and functioning of the different sensory systems. In order to exert their actions, thyroid hormones need to access their target cells through transmembrane transporter proteins, among which the monocarboxylate transporter 8 (MCT8) stands out for its pathophysiological relevance. Mutations in the gene encoding for MCT8 lead to the Allan-Herndon-Dudley syndrome (AHDS), a rare disease characterised by severe neuromotor and cognitive impairments. The impact of MCT8 deficiency in the neurosensory capacity of AHDS patients is less clear, with only a few patients displaying visual and auditory impairments. In this review we aim to gather data from different animal models regarding thyroid hormone transport and action in the different neurosensory systems that could aid to identify potential neurosensorial alterations in MCT8-deficient patients.

Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie Allan-Herndon-Dudley syndrome.

Patients with mutations in the thyroid hormone (TH) cell transporter monocarboxylate transporter 8 (MCT8) gene develop severe neuropsychomotor retardation known as Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired triiodothyronine (T3) transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3 inducibility of TH-regulated genes. In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3',5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for patients with AHDS.

Diagnosis and Therapy in MCT8 Deficiency: Ongoing Challenges

Diagnosis and Therapy in MCT8 Deficiency: Ongoing Challenges

Generation of iPSC lines with SLC16A2:G401R or SLC16A2 knock out

The X-linked Allan-Herndon-Dudley syndrome (AHDS) is characterized by severely impaired psychomotor development and is caused by mutations in the SLC16A2 gene encoding the thyroid hormone transporter MCT8 (monocarboxylate transporter 8). By targeting exon 3 of SLC16A2 using CRISPR/Cas9 with single-stranded oligodeoxynucleotides as homology-directed repair templates, we introduced the AHDS patient missense variant G401R and a novel knock-out deletion variant (F400Sfs*17) into the male healthy donor hiPSC line BIHi001-B. We successfully generated cerebral organoids from these genome-edited lines, demonstrating the utility of the novel lines for modelling the effects of MCT8-deficency on human neurodevelopment.

Neurovascular unit disruption and blood–brain barrier leakage in MCT8 deficiency

BackgroundThe monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood–brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, and no effective treatments are available for the neurological symptoms of the disease.MethodsNeurovascular unit ultrastructure was studied by means of transmission electron microscopy. BBB permeability and integrity were evaluated by immunohistochemistry, non-permeable dye infiltration assays and histological staining techniques. Brain blood-vessel density was evaluated by immunofluorescence and magnetic resonance angiography. Finally, angiogenic-related factors expression was evaluated by qRT-PCR. The studies were carried out both in an MCT8 deficient subject and Mct8/Dio2KO mice, an AHDS murine model, and their respective controls.ResultsUltrastructural analysis of the BBB of Mct8/Dio2KO mice revealed significant alterations in neurovascular unit integrity and increased transcytotic flux. We also found functional alterations in the BBB permeability, as shown by an increased presence of peripheral IgG, Sodium Fluorescein and Evans Blue, along with increased brain microhemorrhages. We also observed alterations in the angiogenic process, with reduced blood vessel density in adult mice brain and altered expression of angiogenesis-related factors during brain development. Similarly, AHDS human brain samples showed increased BBB permeability to IgG and decreased blood vessel density.ConclusionsThese findings identify for the first time neurovascular alterations in the MCT8-deficient brain, including a disruption of the integrity of the BBB and alterations in the neurovascular unit ultrastructure as a new pathophysiological mechanism for AHDS. These results open a new field for potential therapeutic targets for the neurological symptoms of these patients and unveils magnetic resonance angiography as a new non-invasive in vivo technique for evaluating the progression of the disease.

Allan-Herndon-Dudley syndrome in Hong Kong: Implication for newborn screening

BackgroundAllan-Herndon-Dudley syndrome (MCT 8 deficiency) is an X-linked recessive condition caused by hemizygous pathogenic variants in SLC16A2 encoding the monocarboxylate transporter 8 (MCT8). Patients present with global developmental delay and neurological impairment, and abnormal serum thyroid function tests. The drug, 3,3′,5 triiodothyroacetic acid (TRIAC), was recently demonstrated to improve the endocrinological profile. Improvement in diagnostic approach is key to earlier start of treatment. Patient findingsWe described four Chinese patients with MCT8 deficiency undergoing different diagnostic odysseys. Their initial presentation included global developmental delay and dystonia. Patient 2 also had epilepsy. Patients 1 and 2 presented with two novel variants: (1)hemizygous NM_006517.4(SLC16A2):c.1170 + 2 T > A; p.(?), and (2)hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17) respectively. Patients 3 and 4 were biological brothers harboring hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17), which was first reported in 2004. We obtained the measurement of triiodothyronine (T3) and reverse T3 (rT3) from dried blood spot samples collected on Day 1 of life from Patient 1 and studied the biomarkers (rT3 and T3/rT3 ratio) proposed by Iwayama et al. for the detection of MCT8 deficiency at birth. Our data verified the significantly reduced rT3 level in Patient 1, compared with healthy newborns, although low T3 level and comparable T3/rT3 ratio with controls were detected. SummaryPatients with MCT8 deficiency often undergo diagnostic odysseys. An early diagnosis could be missed by a normal newborn thyroid function screening result based on biochemical measurement of TSH and/or T4/fT4. Early detection of rT3 is key to improving current diagnostic approach. ConclusionWe recommend that full thyroid function profile (TSH, T4/fT4, T3/fT3, rT3) be considered early for all pediatric patients presenting with unexplained developmental delay and/or dystonia. The potential inclusion of rT3 measurement in newborn screening may prove promising.

Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function.

Thyroid hormone (TH) transporter MCT8 deficiency causes severe locomotor disabilities likely due to insufficient TH transport across brain barriers and, consequently, compromised neural TH action. As an established animal model for this disease, Mct8/Oatp1c1 double knockout (DKO) mice exhibit strong central TH deprivation, locomotor impairments and similar histo-morphological features as seen in MCT8 patients. The pathways that cause these neuro-motor symptoms are poorly understood. In this paper, we performed proteome analysis of brain sections comprising cortical and striatal areas of 21-day-old WT and DKO mice. We detected over 2900 proteins by liquid chromatography mass spectrometry, 67 of which were significantly different between the genotypes. The comparison of the proteomic and published RNA-sequencing data showed a significant overlap between alterations in both datasets. In line with previous observations, DKO animals exhibited decreased myelin-associated protein expression and altered protein levels of well-established neuronal TH-regulated targets. As one intriguing new candidate, we unraveled and confirmed the reduced protein and mRNA expression of Pde10a, a striatal enzyme critically involved in dopamine receptor signaling, in DKO mice. As altered PDE10A activities are linked to dystonia, reduced basal ganglia PDE10A expression may represent a key pathogenic pathway underlying human MCT8 deficiency.

OR14-02 The Thyroid Hormone Analogs DITPA And TRIAC Triggered T3-signalling In Human MCT8-deficient Brain Organoids

Abstract Disclosure: F. Salas Lucia: None. A.M. Dumitrescu: None. S. Refetoff: None. Patients with mutations in the X chromosome-linked thyroid hormone (TH) cell transporter MCT8 gene have brain hypothyroidism, resulting in severe neuro-psychomotor retardation for which treatment remains very challenging. Potential new treatments using the TH-analogues 3,5-diiodothyropropionic acid (DITPA) and 3,3’,5-triiodothyroacetic acid (TRIAC) have been explored in Mct8-deficient mice. However, given species differences in brain TH transporters, in vitro models using human cells are needed. Here, we generated human brain organoids (BOs) from 4 lines of human induced pluripotent stem cells (hiPSCs). Two lines were derived from MCT8-deficient patients. The other two lines were used as controls: one isogenic line in which the MCT8 mutation has been corrected using CRISPR/Cas9, and a line derived from the unaffected father. Control BOs showed multiple large and continuous neuroepithelia surrounding a ventricle and expressed forebrain markers (FOXG1, and LHX2) at 10-fold higher levels than the hiPSCs. After 20 days in culture, BOs expressed TH transporters; the most abundant being MCT8, trailed by LAT2, LAT1, and MCT10. In contrast, the MCT8-deficient BOs exhibit a 3-fold decrease in the relative expression of LAT2, compared to controls. All BOs showed a similar expression of the deiodinase type 3 (DIO3), and the TH nuclear receptor beta (THRB) genes; the DIO2 and THRA expression were undetectable. Additionally, all four BOs expressed the neuronal and glial markers NEUN and GFAP (5.1±2.0, and 7.3±3.8-fold expression, respectively). Immunohistochemistry using fluorescent antibodies confirmed the presence of postmitotic neurons (TUJ1+) expressing MCT8 in the BOs. Next, we measured the D3 activity. BOs were incubated with T3I125, which resulted in a prominent peak of T2I125 measured using an ultra-high-performance liquid chromatography linked to a gamma counter. The peak of T2I125 indicates the uptake of T3I125 into the neural cells residing in the BOs, its metabolism, and the release of T2I125 in the medium. MCT8-deficient BOs exhibited a D3 activity of 5.3±3.1 pmol/mg/h, a 70% less when compared to the 18.4±7.7 pmol/mg/h of controls. When control BOs were incubated with the MCT8 inhibitor Silychristin 2µM, they exhibited 4.4±3.0 pmol/mg/h D3 activity, like MCT8-deficient BOs. Next, BOs were incubated for 24h with either 10nM L-T3, 10nM TRIAC, or 3.5μM DITPA and T3-responsive genes were studied. Treatment with L-T3 upregulated by 2-fold the gene KLF9 in all four BOs, suggesting that the T3-signalling in the MCT8-deficient BOs might not be compromised. The genes HAIRLESS and DIO3 were unresponsive. In parallel, incubation with DITPA and TRIAC also upregulated KLF9 by 1.5-fold, representing a proof of concept for these thyromimetic molecules to act in human neural cells. This human cell model may be used as a platform to screen therapeutic drugs for MCT8 deficiency. Presentation: Friday, June 16, 2023

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review.

The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life. We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials. We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints. We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.

Parent Perspectives on Complex Needs in Patients With MCT8 Deficiency: An International, Prospective, Registry Study.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare neurodevelopmental and metabolic disorder, with daily care posing a heavy burden on caregivers. A comprehensive overview of these complex needs and daily care challenges is lacking. We established an international prospective registry to systemically capture data from parents and physicians caring for patients with MCT8 deficiency. Parent-reported data on complex needs and daily care challenges were extracted. Between July 17, 2018, and May 16, 2022, 51 patients were registered. Difficulties in daily life care were mostly related to feeding and nutritional status (17/33 patients), limited motor skills (12/33 patients), and sleeping (11/33 patients). Dietary advice was provided for 11/36 patients. Two of 32 patients were under care of a cardiologist. Common difficulties in the diagnostic trajectory included late diagnosis (20/35 patients) and visiting a multitude of specialists (15/35 patients). Median diagnostic delay was significantly shorter in patients born in or after 2017 vs before 2017 (8 vs 19 months, P < .0001). Feeding and sleeping problems and limited motor skills mostly contribute to difficulties in daily care. The majority of patients did not receive professional dietary advice, although being underweight is a key disease feature, strongly linked with poor survival. Despite sudden death being a prominent cause of death, potentially related to the cardiovascular abnormalities frequently observed, patients were hardly seen by cardiologists. These findings can directly improve patient-centered multidisciplinary care and define patient-centered outcome measures for intervention studies in patients with MCT8 deficiency.