MINI REVIEW published: 28 April 2020 doi: 10.3389/fnins.2020.00380 MCT8 Deficiency: The Road to Therapies for a Rare Disease Carmen Grijota-Martínez 1,2,3* , Soledad Bárez-López 2,4 , David Gómez-Andrés 5 and Ana Guadaño-Ferraz 1,2* 1 Department of Endocrine and Nervous System Pathophysiology, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain, 2 Center for Biomedical Research on Rare Diseases (Ciberer), Instituto de Salud Carlos III, Madrid, Spain, 3 Department of Cell Biology, Faculty of Biology, Universidad Complutense de Madrid, Madrid, Spain, 4 Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, United Kingdom, 5 Pediatric Neurology, Vall d’Hebron University Hospital and VHIR (Euro-NMD, ERN-RND), Barcelona, Spain Allan-Herndon-Dudley syndrome is a rare disease caused by inactivating mutations in the SLC16A2 gene, which encodes the monocarboxylate transporter 8 (MCT8), a transmembrane transporter specific for thyroid hormones (T3 and T4). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development resulting in severe brain hypothyroidism. Patients also suffer from thyrotoxicity in other organs due to the presence of a high concentration of T3 in the serum. An effective therapeutic strategy should restore thyroid hormone serum levels (both T3 and T4) Edited by: and should address MCT8 transporter deficiency in brain barriers and neural cells, to Riccarda Granata, enable the access of thyroid hormones to target neural cells. Unfortunately, targeted University of Turin, Italy therapeutic options are currently scarce and their effect is limited to an improvement Reviewed by: Ulrich E. M. Schweizer, in the thyrotoxic state, with no sign of any neurological improvement. The use of University of Bonn, Germany thyroid hormone analogs such as TRIAC, DITPA, or sobetirome, that do not require Lior Appelbaum, MCT8 to cross cell membranes and whose controlled thyromimetic activity could Bar-Ilan University, Israel potentially restore the normal function of the affected organs, are being explored to *Correspondence: Carmen Grijota-Martínez improve the cerebral availability of these analogs. Other strategies aiming to restore cgrijota@iib.uam.es the transport of THs through MCT8 at the brain barriers and the cellular membranes Ana Guadaño-Ferraz aguadano@iib.uam.es include gene replacement therapy and the use of pharmacological chaperones. The design of an appropriate therapeutic strategy in combination with an early diagnosis Specialty section: (at prenatal stages), will be key aspects to improve the devastating alterations present This article was submitted to Neuroendocrine Science, in these patients. a section of the journal Keywords: thyroid hormones, brain, neurodevelopment, MCT8, DITPA, sobetirome, TRIAC Frontiers in Neuroscience Received: 28 January 2020 Accepted: 27 March 2020 Published: 28 April 2020 INTRODUCTION Citation: Thyroid hormones (THs; T4 or thyroxine and T3 or triiodothyronine) are essential for the Grijota-Martínez C, Bárez-López development and function of the CNS. An insufficient supply of THs during development can S, Gómez-Andrés D and hinder essential processes such as neurogenesis, cell migration, synaptogenesis or myelinization. Guadaño-Ferraz A (2020) MCT8 Deficiency: The Road to Therapies These neurological alterations range from very mild to very severe, and can be even irreversible, for a Rare Disease. depending on the time and duration of the hormonal deficiency. Front. Neurosci. 14:380. THs are synthesized in the thyroid gland, mostly as T4, and released by follicular cells to doi: 10.3389/fnins.2020.00380 the circulation, reaching the different target tissues. Both genomic and non-genomic actions of Frontiers in Neuroscience | www.frontiersin.org 1 April 2020 | Volume 14 | Article 380 Grijota-Martínez et al. Therapies in AHDS-MCT8 Deficiency THs have been described. The latter are carried out in the Indeed, brain tissue necropsies of MCT8-deficient patients cytoplasm or plasma membrane by binding to receptors such have revealed alterations compatible with brain hypothyroidism as integrin αvβ3 (Davis et al., 2016). On the other hand, in the with anomalies in neuronal differentiation, myelinization and genomic actions T3 binds to nuclear receptors (TR), regulating synaptogenesis present already from prenatal stages (López- the transcription of target genes. The main isoforms of these Espíndola et al., 2014). Consistent with this, MCT8 has been TR are TRα1, TRα2, TRβ1, and TRβ2, which mediate different found to be very abundant at the brain barriers in the human actions and whose expression varies throughout ontogeny and fetal brain (Wirth et al., 2009; López-Espíndola et al., 2019; different tissues. The amount of the nuclear active hormone T3 Wilpert et al., 2020). is mainly regulated locally in the target tissues by the action The rapid diagnosis is a key factor for the patients’ of different deiodinase enzymes which activate (converting T4 wellbeing. For instance, unlike other similar diseases, there is a into T3) or inactivate (deiodinating T4 and T3 into inactive marked prevalence of respiratory problems and kyphoscoliosis, metabolites) THs. so intensive monitoring and an adequate care is important THs use transporter proteins located in cell membranes to to improve the survival and quality of life of patients. reach the inside the cells (Hennemann et al., 2001). Some of Moreover, due to the fact that brain alterations start during the major transporters of THs include the monocarboxylate development, an early treatment, including prenatal treatment, transporter 8 (MCT8), MCT10 and the solute carrier organic takes special importance. Currently, targeted therapies to anion transporter 1C1 (OATP1C1), but only MCT8 has been improve the neurological picture of patients are not available. identified as being specific to transport THs. MCT8 is encoded by As MCT8-deficient patients suffer from brain hypothyroidism in the SLC16A2 gene (Friesema et al., 2003) and the mutations that combination with peripheral hyperthyroidism, the design of an cause the inactivation of this transporter result in a rare X-linked effective treatment is challenging. The aim of this manuscript is to disease known as Allan-Herndon-Dudley Syndrome (AHDS or critically review therapeutic approaches attempted so far both at MCT8 deficiency). AHDS (ORPHA:59) is an ultra-rare disorder the clinical level in patients and at the preclinical level in models with an estimated prevalence lower than 1 case per million. of the disease to contribute to the development of future solutions Orphanet suggested that 320 patients had been diagnosed within for AHDS patients (summarized in Table 1). more than 130 families but these numbers are prone to raise given the increasing access to new generation sequencing technologies and the expanding spectrum of severity attributed to the disease MURINE MODELS OF THE DISEASE (Remerand et al., 2019). AHDS was described in 1944 (Allan et al., 1944) but its The development of targeted therapies in rare diseases depends association to mutations in the SLC16A2 gene was established on the availability of good animal models, both to unravel the in 2004 (Dumitrescu et al., 2004; Friesema et al., 2004). AHDS mechanisms of disease and to carry out preclinical studies to patients have a characteristic thyroid profile with elevated plasma evaluate therapeutic strategies. In the case of MCT8 deficiency, T3 levels (peripheral hyperthyroidism), low T4 and normal or most of the knowledge about the mechanisms underlying the slightly elevated TSH with a free T3/T4 ratio greater than 0.75 disease as well as the preclinical studies considered so far has (Dumitrescu et al., 2004; Friesema et al., 2004; Groeneweg et al., arisen from using murine models of the syndrome. However, 2019; Remerand et al., 2019). it has not been straightforward to obtain a suitable model and In addition, the phenotype of AHDS is characterized by severe there is still ongoing work focused on the characterization of paraparesis with hypotonia (with poor cephalic control being different animal models. an early symptom), bradykinesia, spasticity and extrapyramidal Initially, mice deficient of the MCT8 transporter (Mct8KO manifestations (dystonia or dystonia with choreoathetosis) mice) were proposed as a disease model. Although these mice and moderate to severe intellectual disability with absence of showed a thyroid profile similar to that of the patients and language, associated with low weight and/or low muscle mass and relatively low levels of T3 in different brain areas (Dumitrescu in some cases, epilepsy (Remerand et al., 2019). In recent years, et al., 2006; Trajkovic et al., 2007), brain histopathology studies the increasing knowledge about this condition have promoted a did not reveal major defects and only subtle behavioral changes growing number of patients that have defined a much broader were found (Wirth et al., 2009). It was therefore suggested phenotype, with the appearance of milder forms with motor that these animals present some compensatory mechanism that and cognitive disability of lesser severity (Masnada et al., 2019; prevents neurological damage. This compensatory mechanism is Remerand et al., 2019). due to the complementary action of two proteins: the organic These alterations occur as a consequence of two phenomena. anion transporter OATP1C1 and the deiodinase type 2 (DIO2) On the one hand, the excess of T3 in serum produces enzyme. OATP1C1 transporter is codified by the Slco1c1 gene, it peripheral hyperthyroidism with muscle thyrotoxicosis that transports mainly T4 and is expressed abundantly in rodent brain causes a generalized loss of muscle volume. On the other hand, barriers, but to a much lesser extent in humans (Roberts et al., the absence of MCT8 impairs the effective transport of THs to 2008; López-Espíndola et al., 2019). The entry of T4 to the brain the CNS, most probably due to the lack of functional MCT8 through this transporter and the subsequent action of DIO2, in brain barriers (Ceballos et al., 2009; Iwayama et al., 2016; which converts T4 into T3 in astrocytes and whose expression Vatine et al., 2017) leading to brain hypothyroidism (Dumitrescu is increased in these mice, would provide a sufficient amount et al., 2006; Trajkovic et al., 2007; López-Espíndola et al., 2014). of the nuclear active hormone T3 in the mouse brain, exerting Frontiers in Neuroscience | www.frontiersin.org 2 April 2020 | Volume 14 | Article 380 Grijota-Martínez et al. Therapies in AHDS-MCT8 Deficiency TABLE 1 | Summary of the existing clinical and preclinical therapeutic approaches for AHDS. Effects on Effects on Effects on Effects on Treatment Model serum TSH serum T4 serum T3 brain References TH replacement LT4 Human ↓ ↑ ↑ Not observed Namba et al., 2008; therapies Papadimitriou et al., 2008 LT4 + T3 Human ↓ ↑ ↑ Not observed Biebermann et al., 2005; Zung et al., 2011 LT4 + PTU Human ↓ ↑ ↓ Not observed Wemeau et al., 2008; Visser et al., 2013 TH analogs DITPA Zebrafish N/R N/R N/R Prevents Zada et al., 2014, 2016 treatments hypomyelination Mouse ↓ ↓ ↓ Only at high doses Di Cosmo et al., 2009; (0.01 mg/g BW) Ferrara et al., 2015 Human ↓ ↑ ↓ Not observed Verge et al., 2012 TRIAC Zebrafish N/R N/R N/R Prevents and Zada et al., 2014, 2016 rescues hypomyelination Mouse ↓ ↓ ↓ Only at high doses Kersseboom et al., 2015; (200–400 ng/g BW) Bárez-López et al., 2016 and early treatment Human ↓ ↓ ↓ Under Investigation Groeneweg et al., 2019 Sobetirome Mice ↓ ↓ ↓ Modulation of Bárez-López et al., 2018 TH-target genes Other therapies Gene replacement Zebrafish N/R N/R N/R Rescues Zada et al., 2016 therapy hypomyelination Mice N/R N/R = Modulation of Iwayama et al., 2016 TH-target genes when MCT8 is replaced at brain barriers Pharmacological In vitro ex vivo N/A N/A N/A N/A Braun and Schweizer, chaperones 2015, 2017; Groeneweg et al., 2018 ↑, ↓, = : increased, decreased or not modified, respectively, versus non-treated patients or mouse model; N/R: not reported; N/A: not applicable. a compensatory mechanism for the lack of MCT8 (Figure 1). THYROID HORMONE REPLACEMENT For this reason, two alternative models are currently being THERAPIES used; MCT8 and DIO2 (Mct8/Dio2KO) or MCT8 and OATP1C1 (Mct8/Slc1c1KO) -deficient mice, in which this compensatory As soon as it was found that the syndrome was due to mechanism is suppressed. These models present a thyroid profile mutations in a transporter of THs, and that it had an endocrine similar to that of the patients in addition to several neuromotor component with altered THs levels, treatments to intervene alterations, offering a more suitable model (Mayerl et al., 2014; on the thyroid axis were considered. In Mct8KO mice, Bárez-López et al., 2019a). the injection of supraphysiological doses of levothyroxine In addition, other alternative models currently available (LT4) was able to reduce the increased expression of include the use of pluripotent stem cells induced from human TRH mRNA in hypothalamic neurons, indicating that in patients (Vatine et al., 2017) or the use of other organisms such the absence of MCT8 these neurons can respond to T4 as zebrafish (Vatine et al., 2013), chicken (Delbaere et al., 2017) or treatment. In contrast, only a high dose of T3 was able to even Xenopus (Mughal et al., 2017). For the first time, this rich downregulate TSH levels in plasma with a modest reduction cataloge of models is providing the possibility of testing drugs in of TRH, suggesting an impaired uptake of circulating T3 a fast and accurate way in preclinical stages in AHDS. (Trajkovic et al., 2007). Frontiers in Neuroscience | www.frontiersin.org 3 April 2020 | Volume 14 | Article 380 Grijota-Martínez et al. Therapies in AHDS-MCT8 Deficiency FIGURE 1 | Proposed model illustrating the differences between MCT8-deficient mice and humans in thyroid hormone availability to neural cells. The model for T3 availability to the brain under normal conditions supports that brain T3 can access the target neural cells though two different routes: (1) directly from the circulation, with T3 crossing the BBB mainly via the MCT8 transporter into the extracellular fluid where it directly reaches the target neural cells, or (2) T3 can also be produced locally by DIO2 activity in the astrocytes from T4, which crosses the BBB directly into the astrocytes mainly through MCT8 in humans and through MCT8 and OATP1C1 in mice. In MCT8-deficient mice, the elevated DIO2 activity in the astrocytes converts the T4 available through OATP1C1 into T3, that is subsequently available to target neural cells, compensating for the lack of MCT8. In MCT8-deficient humans, this compensatory mechanism cannot take place as OATP1C1 is hardly present in the human BBB, preventing T4 entry to the brain and its subsequent conversion into T3. Based on this, in patients, a LT4 supplement alone TREATMENT WITH THYROID HORMONE or in combination with T3 was initially considered. This ANALOGS treatment suppressed TSH and restored T4; however, it further increased T3 serum levels, worsening the hyperthyroidism The search for T3 analogs that do not require MCT8 to cross the in extracerebral tissues, and did not improve the patient’s cell membranes is one of the main strategies in the search for neurological impairments (Namba et al., 2008; Papadimitriou an effective therapy. 3,5-diiodo-thyropropionic acid (DITPA) is et al., 2008). After this first approximation, a block-replacement a T3 analog that binds with similar affinity to the different TR therapy consisting of the administration of propylthiouracil isoforms, although with much lower affinity than T3 (Pennock (PTU; an antithyroid drug that also inhibits type 1 deiodinase et al., 1992). Despite this, it has been shown to have inotropic (DIO1), which transforms T4 into T3) together with LT4, thyromimetic actions but maintaining a low metabolic activity decreased endogenous production of THs and prevented the (Pennock et al., 1992; Moreno et al., 2008). In zebrafish, treatment conversion of LT4 into T3. This therapy normalized TSH levels with DITPA was able to prevent hypomyelination in Mct8- and significantly decreased serum T3, which was reflected in an deficient embryos but did not fully recovered hypomyelination improvement in body mass index and a reduction in heart rate. present in the larvae (Zada et al., 2014, 2016). The administration However, none of the patients experienced any improvement at of this compound to MCT8-deficient mice was able to the psychomotor level (Wemeau et al., 2008; Visser et al., 2013). normalize T3 and TSH while it further decreased T4 levels Frontiers in Neuroscience | www.frontiersin.org 4 April 2020 | Volume 14 | Article 380 Grijota-Martínez et al. Therapies in AHDS-MCT8 Deficiency in serum, ameliorating metabolic parameters related to the importance of considering therapeutic approaches that do not hypermetabolism of Mct8KO mice. However, improvements in further decrease serum T4. brain hypothyroidism could only be observed when using high Currently, alternative delivery pathways are being explored doses of DITPA (Di Cosmo et al., 2009; Ferrara et al., 2015). The in order to increase TRIAC content in the brain with the administration of DITPA in four patients normalized T3 and TSH final aim of ameliorating the brain hypothyroidism. In a recent and, unlike in mice, increased the levels of T4 to the lower normal study we administered TRIAC directly into the brain of MCT8- range in serum, decreasing also the cardiac rhythm. However, deficient animals through a catheter inserted into the brain no improvement, or very small, was found in the neurological lateral ventricle (Bárez-López et al., 2019b).We found that this performance of these patients when they were assessed with the treatment did not affect T3 or T4 levels in the serum, thus Bayley-III scale (Verge et al., 2012). did not aggravate the brain hypothyroidism. Moreover, even Another T3 analog that has received special attention is though TRIAC content increased in the brain after treatment, sobetirome (also called GC-1), a compound that has been this increase was not enough to mediate the expression of T3 used in numerous animal studies (Hartley et al., 2017) as target genes. Further studies will be necessary to finally determine well as in clinical trials for patients with dyslipidemias. if TRIAC serves as a T3 analog mediating brain effects of Sobetirome binds to TRs with the same affinity for TRβ1 as THs in vivo. T3 but 4–10 times less affinity than T3 for TRα1 (Chiellini Due to the extensive clinical experience with TRIAC, that has et al., 1998). In 2018 we published the first study evaluating demonstrated its ability to inhibit TSH secretion and therefore its action in the absence of MCT8 after intraperitoneal decrease the production of endogenous THs, TRIAC has been administration to Mct8/Dio2KO mice (Bárez-López et al., used in a phase I clinical trial evaluating its effectiveness and 2018). An increase in the content of sobetirome was detected safety for treatment of peripheral thyrotoxicosis in MCT8- in the brain of the treated animals, demonstrating that it deficient patients, both pediatric and adult (Groeneweg et al., was able to cross the blood-brain barrier of mice in the 2019). In accordance with the results found in the animal model, absence of MCT8. Most importantly, we provided evidence of treatment with 38.3 µg of TRIAC per kg of body weight per sobetirome action in brain, regulating the expression of T3 day reduced serum T3 levels to the normal range and further target genes, since it was able to partially recover and even decreased serum T4 levels. This study has shown that TRIAC normalize the expression of some genes that are altered in is safe and effective in controlling peripheral thyrotoxicosis Mct8/Dio2KO animals. improving the altered weight, heart rate and blood pressure. A third and promising alternative is 3,5,3’-triiodothyroacetic However, it is important to point out that reduced plasma T4 acid (TRIAC), a natural metabolite of THs. This compound arises levels could have potential adverse consequences on the brain, as as one of the potential options for the treatment of patients was found in systemically TRIAC-treated Mct8KO mice. Having since in vitro studies have shown that it can bind the TR with evaluated the effects of TRIAC on peripheral thyrotoxicosis and the same affinity as T3 for the isoform TRα and with greater showing encouraging effects (a trend toward improvement) in affinity for TRβ (Takeda et al., 1995; Messier and Langlois, 2000), gross motor function when children are treated before 4 year of that it can exert thyromimetic actions, and that can access the age, the clinical study is currently in phase II to evaluate the action inside of the cell in the absence of MCT8 (Horn et al., 2013; of this analog on neurological symptoms in pediatric patients Kersseboom et al., 2015). Moreover, treatment with TRIAC in (NCT02396459). zebrafish was able to prevent and rescue hypomyelination in Mct8-deficient embryos and larvae, respectively (Zada et al., 2014, 2016). The first study evaluating the in vivo action of OTHER THERAPIES FOR MCT8 TRIAC in MCT8 deficiency was carried out in Mct8/Slco1c1KO DEFICIENCY mice treated with high doses of TRIAC (200-400 ng per gram of weight per day) during early postnatal stages (from postnatal In parallel to the use of T3 analogs, other possibilities such as gene day 1 (P1) to P12). These studies revealed that at high doses replacement therapy and the use of chemical chaperones are also TRIAC is able to prevent brain alterations in the absence of currently being explored. In order to improve brain alterations MCT8 (Kersseboom et al., 2015). To get a better understanding by gene therapy in mice, MCT8 was administered using adeno- on the potential of this analog in the clinical practice, we assessed associated virus (AAV) as a vector with the intention of restoring the effects of therapeutic doses of TRIAC at juvenile stages. MCT8 expression in the brain. For this purpose, AAV9 (which Mct8KO mice were treated with of 30 ng of TRIAC per gram is transduced in the brain with high efficiency) expressing of weight per day (similar to the dose used in patients) in MCT8 was injected to MCT8-deficient mice at day P1 either the drinking water from P21 to P30. This treatment decreased intravenously or directly into the brain intracerebroventricularly. serum levels of both T3 and T4, improving the peripheral The results showed that intravenous administration increased hyperthyroidism. However, TRIAC content in the brain did not the content of T3 in the brain and recovered the expression increase after treatment, and therefore no thyromimetic actions of T3 target genes altered in MCT8 deficiency. Although could be observed in this organ. Moreover, we also found that intracerebroventricular administration drove higher expression the decrease in T4 plasma levels worsened brain hypothyroidism of MCT8 in the brain than the intravenous delivery, there by further decreasing the brain T3 content and the expression of was no increase in the content of T3 or in the expression of some target genes (Bárez-López et al., 2016). This highlights the T3 target genes. This could be explained because, unlike the Frontiers in Neuroscience | www.frontiersin.org 5 April 2020 | Volume 14 | Article 380 Grijota-Martínez et al. Therapies in AHDS-MCT8 Deficiency intracerebroventricular route, the intravenous delivery was able approaches that aim to overcome the limitation of the brain to restore MCT8 expression in the choroid plexus demonstrating barriers are currently being explored. The use of alternative that for a successful gene replacement therapy, it is essential delivery pathways that can increase the content of T3 analogs to restore MCT8 in brain barriers to allow entry of THs into in the brain offers the possibility of enhancing the potential the brain (Iwayama et al., 2016). In zebrafish, the injection action of these analogs in the brain, as long as they are indeed of a genetic construct driving Mct8 expression in vascular effective in mediating TH-like actions in vivo. The use of endothelial cells into Mct8-deficient embryos was able to recover the sobetirome, gene replacement therapy and pharmaceutical hypomyelination in 10 days post fertilization larvae but not chaperones offers promising alternative therapies that require in 3 days post fertilization embryos. This suggests that genetic further characterization. Moreover, as an early treatment is treatment can be beneficial even after brain damage has occurred crucial, the use of T3 analogs that can cross the placental and offers a potential treatment for MCT8-deficient patients barrier such as TRIAC (Nicolini et al., 1996) or DITPA (Ferrara (Zada et al., 2016). et al., 2014) or the direct in utero administration of potential A different approximation is the use of pharmacological therapeutic agents, must be considered. chaperones that allow the conformational stabilization of Due to the great advances in preclinical stages of potential mutated proteins and assist in their translocation to the therapies for AHDS, we believe that studies devoted to enhance plasma membrane. It is believed that this approach would be our understanding about the role of MCT8 in development more effective for those mutations in SLC16A2 that affect the and the complex changes in the CNS related with this disorder stability of the protein and its intracellular traffic. A recent are particularly urgent in order to proceed with an optimal work using stable overexpression cell models demonstrated that translation of the different therapeutic approaches to patients. the use of pharmacological chaperones can restore MCT8 in cell membranes and mediate T3 transport in certain types of SLC16A2 mutations (Braun and Schweizer, 2015, 2017). AUTHOR CONTRIBUTIONS However, similar studies have subsequently been carried out ex vivo on fibroblasts derived from MCT8-deficient patients CG-M, SB-L, DG-A, and AG-F have contributed in the drafting of without functionally restoring MCT8 in cell membranes, the article and have revised it critically for important intellectual and thus demonstrating that the ability of pharmacological content and for the final approval of the submitted version. chaperones to rescue MCT8 function depends on the cell type CG-M and SB-L have designed the figures. used for the assays (Groeneweg et al., 2018). FUNDING CONCLUSION This work was supported by the Spanish Ministry of The complex nature of MCT8 deficiency presents certain Economy and Competitiveness, grant number SAF2017-86342-R difficulties when designing appropriate therapeutic strategies. (MINECO/AEI/FEDER, UE) to AG-F, the Sherman Foundation A suitable therapy should ameliorate the peripheral (Grant Number OTR02211) to AG-F and SB-L, and the BBSRC hyperthyroidism while improving the neurological defects. So far, (Grant Number BB/R016879/1) to SB-L. CG-M is a recipient several therapeutic approaches have been successful in improving of a contract from the Center for Biomedical Research on Rare the peripheral hyperthyroidism in patients. These include a Diseases (CIBERER), Instituto de Salud Carlos III, Madrid. The block-replacement therapy with LT4 in combination with PTU cost of this publication has been paid in part by FEDER funds. and the T3 analogs DITPA and TRIAC. Treatment with TRIAC further decreases T4 serum levels unlike DITPA and LT4 + PTU treatments. Due to the potential effects that T4 (through local ACKNOWLEDGMENTS conversion into T3) might be mediating in the brain, an ultimate therapeutic approach should not further decrease but restore We acknowledge support of the publication fee by the CSIC serum T4 levels. Open Access Publication Support Initiative through its Unit of The big challenge ahead of us is the improvement of the Information Resources for Research (URICI). We also thank neurological alterations in patients. To tackle this, several Javier Pérez García for the artwork. REFERENCES Bárez-López, S., Grijota-Martínez, C., Liao, X. H., Refetoff, S., and Guadaño-Ferraz, A. (2019b). Intracerebroventricular administration of the thyroid hormone Allan, W., Herndon, C. N., and Dudley, F. C. (1944). Some examples of analog TRIAC increases its brain content in the absence of MCT8. PLoS One the inheritance of mental deficiency: apparently sex-linked idiocy and 14:e0226017. doi: 10.1371/journal.pone.0226017 microcephaly. Am. J. 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E., Vrijmoeth, P., Visser, F. E., Arts, W. F., Van Toor, H., and Visser, Conflict of Interest: The authors declare that the research was conducted in the T. J. (2013). Identification, functional analysis, prevalence and treatment of absence of any commercial or financial relationships that could be construed as a monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients potential conflict of interest. with mental retardation. Clin. Endocrinol. 78, 310–315. doi: 10.1111/cen.12023 Wemeau, J. L., Pigeyre, M., Proust-Lemoine, E., D’herbomez, M., Gottrand, F., Copyright © 2020 Grijota-Martínez, Bárez-López, Gómez-Andrés and Guadaño- Jansen, J., et al. (2008). Beneficial effects of propylthiouracil plus L-thyroxine Ferraz. This is an open-access article distributed under the terms of the Creative treatment in a patient with a mutation in MCT8. J. Clin. Endocrinol. Metab. 93, Commons Attribution License (CC BY). The use, distribution or reproduction in 2084–2088. doi: 10.1210/jc.2007-2719 other forums is permitted, provided the original author(s) and the copyright owner(s) Wilpert, N. M., Krueger, M., Opitz, R., Sebinger, D., Paisdzior, S., Mages, B., are credited and that the original publication in this journal is cited, in accordance et al. (2020). Spatiotemporal changes of cerebral monocarboxylate transporter with accepted academic practice. No use, distribution or reproduction is permitted 8 expression. Thyroid doi: 10.1089/thy.2019.0544 [Epub ahead of print]. which does not comply with these terms. Frontiers in Neuroscience | www.frontiersin.org 8 April 2020 | Volume 14 | Article 380