The following white paper was written in collaboration with the MCT8 Foundation (https://www.mct8.info) with edits provided by Dr. Refetoff of the University of Chicago Medical School.
Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 Deficiency
MCT8 Deficiency is a rare X-chromosome-linked genetic disorder that manifests neurocognitive disabilities, severe muscle and fat wasting, early hypotonia, and later spasticity.1,2 It is a rare disease with less than 400 affected individuals identified since its initial description in 2004 (most references cite roughly 350 known, reported cases). It affects primarily genotypic males though there exists a single report of an affected genotypic female due to unusual translocation and non-random X-chromosome inactivation.1
Thyroid & Thyroid hormones
Thyroid hormone, otherwise referred to as thyroxine or T4, owing to its 4 iodine content, is a precursor to the 3 iodine, triiodothyronine (T3), the biologically active hormone. The latter acts primarily as endocrine signaling (transcription) factor with effects in nearly all body systems both during development and throughout all stages of life.3 During fetal development, thyroid hormone helps to guide development of the brain and body.4 This is accomplished by binding to a nuclear receptor which starts the transcription process of DNA and thus changing gene expression.5 Thyroid hormones are also capable of potentiating pre-existing cellular signaling pathways to have a more immediate biochemical effect. This has a wide range of effects within the body to maintain homeostasis including increasing heart rate, turning up the metabolic levels in target cells with increased thermogenesis and ATP generation, increased ventilatory drive, increased gut motility, skeletal maturation, and liver production of enzymes.6
The Thyroid gland, located on either side of the trachea within the neck, primarily secretes the thyroid hormones thyroxine and triiodothyronine (T4 and T3, respectively).5,6 The Thyroid gland responds to Thyroid Stimulating Hormone (TSH), which is released from the anterior pituitary, a small midline stricture which is itself located outside of the brain. The anterior pituitary releases TSH under the influence of Thyrotropin Releasing Hormone (TRH) from the hypothalamus, a structure which is located within the Brain. The hypothalamus determines the need for increased TSH secretion largely via detection of low circulating levels of T4 and T3. 5
The Thyroid gland secretes predominantly T4; with the amount of T3 depending on the dietary intake of iodine. representing only about 10% when iodine is plentiful and up to 70% in iodine deficiency.5 T4, it is converted to the active hormone T3 as well as to the inactive form, reverse T3, within the cells by specific enzymes (deiodinases). These enzymes are present in most cells with the liver and kidney contributing to most of the generated T3 in blood.
T4 and T3 are taken into the target cells via a variety of transporters. These are long chains of proteins woven in the cell membrane to form physical channels through which specific target proteins, hormones, or other substances are able to pass into the cell.[SRM3] There are thousands of these transporters that make up a complex system of cellular material management. Indeed, there are over 16 different thyroid transporters in the human body alone, across 5 separate protein families.3 One of these is called MCT8, or Monocarboxylate Transporter 8.
MCT8 (Monocarboxylate Transporter 8)
Encoded by the gene SLC16A2, MCT8 is a T4 and T3 transporter. Although present ubiquitously in many body cells it is the unique thyroid hormone transporter in the human brain and the Blood Brain Barrier.1 In patients with a deficiency of this transporter, the brain is unable to accumulate sufficient thyroid hormone into the cells, preventing their downstream effects on gene expression and synthesis of critical proteins and signaling pathways during development and throughout life. From a functional perspective, this leads to severe developmental and movement delay in those afflicted. There is evidence of the deleterious effects on the development of the central nervous system with MRIs taken of children with MCT8 deficiency demonstrating delayed myelin formation.7
Another key piece of this syndrome involves general thyroid hormone metabolism. Thyroid synthesis is controlled by the release of TRH from the brain which controls the production and release if thyroid stimulating hormone (TSH) from the pituitary, as outlined above. The lack of MCT8 prevents proper movement of T4 and T3 into and out of specific cells, thus leading to a central nervous system hypothyroid state. On the other hand, MCT8 deficiency increases the enzyme deiodinase 1 that converts T4 to T3 peripheral tissue, such as the liver, resulting in an increase in the circulating T3 and consumptive reduction in the level of T4. Ultimately, this leads to peripheral tissues ramping up metabolism under the influence of the high T3, thus leading to fat and muscle wasting, difficulty gaining weight, and increased heart rate, amongst other symptoms.1,5
Treatment and Further Study
As of now, no cure exists for this condition. There are a number of ongoing clinical trials examining the efficacy of treatment modalities, but no standard of care has been established. Treatment is currently limited to a few options. One of these is exogenous T4 with PTU (propylthiouracil, a medication which reduces the conversion of T4 to T3) which has been shown to improve some of the symptoms of elevated T3 (improves heart rate, modest improvement in weight gain), but does little to improve neurologic or developmental delay.1 DITPA (diiodothyropropionic acid) is a T3 analogue that does not require the MCT8 channel to be carried into cells and has been shown to normalize T4/T3 blood levels as well as improve weight gain, though again, long term neurologic improvements have not been demonstrated to date.1,8 Of note, DITPA is able to cross the placental barrier during pregnancy and an open trial is currently enrolling unborn patients affected by MCT8 to determine if prenatal treatment is an option (Clinical Trial NCT04143295).1 Triac (triiodothyroacetic acid) is another T3 analogue that relies on a different transporter for entrance to the cell which, like DITPA, shows improvement in thyroid labs and peripheral hyperthyroidism symptoms, but notably also improves neurocognitive outcomes in children when treated before the age of 4.1,9
Sobetirome and Sob-AM2 (a prodrug form of Sobetirome) are currently under study as possible thyroid hormone analogues. Early data suggests that these two substances are able to increase T3-dependent gene expression in the brains of mice as well as decrease circulating T3 and T4, thus addressing the hallmark MCT8 peripheral hyperthyroidism.1,10 A recent study on a murine (mouse) model demonstrated that administration of Sobetirome to a pregnant mouse led to spontaneous loss of the fetus, but administration of Sob-AM2 did not lead to fetal loss and demonstrated ability to effect expression of T3 dependent genes in the absence of MCT8.11
Sodium Phenylbutyrate (NaPB) is a chemical chaperone (substance that assists in stability or folding of proteins) that has previously been used to treat patients with cystic fibrosis by stabilizing protein channels and allowing them to function appropriately. A recent study was performed in murine and canine models utilizing NaPB which demonstrated recovery of MCT8 function in mice with SLC16A2 gene defects leading to protein misfolding.12,13
Work continues to define the disease, develop treatment modalities, and improve the quality of life and life expectancy of those individuals affected by MCT8 deficiency. An excited new area of study is gene therapy, which can involve changing genetic expression of a corrected MCT8 protein or another protein with similar function, but this field remains in its infancy.
Works Cited
1. van Geest FS, Gunhanlar N, Groeneweg S, Visser WE. Monocarboxylate Transporter 8 Deficiency: From Pathophysiological Understanding to Therapy Development. Front Endocrinol (Lausanne). 2021;12. doi:10.3389/fendo.2021.723750
2. Vancamp P, Demeneix BA, Remaud S. Monocarboxylate Transporter 8 Deficiency: Delayed or Permanent Hypomyelination? Front Endocrinol (Lausanne). 2020;11. doi:10.3389/fendo.2020.00283
3. Groeneweg S, van Geest FS, Peeters RP, Heuer H, Visser WE. Thyroid Hormone Transporters. Endocr Rev. 2019;41(2). doi:10.1210/endrev/bnz008
4. de Escobar GM, Obregón MJ, del Rey FE. Role of thyroid hormone during early brain development. In: European Journal of Endocrinology, Supplement. Vol 151. ; 2004. doi:10.1530/eje.0.151u025
5. Hall J, Hall M. Thyroid Metabolic Hormones. In: Guyton and Hall Textbook of Medical Physiology. 14th ed. ; 2021:941953.
6. Jonklaas J, Cooper D. Thyroid in Goldman-Cecil Medicine. In: Goldman-Cecil Medicine. 26th ed. ; 2020:1462-1476.
7. Lee JY, Kim MJ, Deliyanti D, et al. Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination. EBioMedicine. 2017;25:122-135. doi:10.1016/j.ebiom.2017.10.016
8. Verge CF, Konrad D, Cohen M, et al. Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. Journal of Clinical Endocrinology and Metabolism. 2012;97(12):4515-4523. doi:10.1210/jc.2012-2556
9. Groeneweg S, Peeters RP, Moran C, et al. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(9):695-706. doi:10.1016/S2213-8587(19)30155-X
10. Bárez-López S, Hartley MD, Grijota-Martínez C, Scanlan TS, Guadaño-Ferraz A. Sobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain. Thyroid. 2018;28(9):1211-1220. doi:10.1089/thy.2018.0008
11. Valcárcel-Hernández V, Guillén-Yunta M, Scanlan TS, Bárez-López S, Guadaño-Ferraz A. Maternal Administration of the CNS-Selective Sobetirome Prodrug Sob-AM2 Exerts Thyromimetic Effects in Murine MCT8-Deficient Fetuses. Thyroid. Published online March 17, 2023. doi:10.1089/thy.2022.0612
12. Braun D, Schweizer U. The chemical chaperone phenylbutyrate rescues MCT8 mutations associated with milder phenotypes in patients with Allan-Herndon-Dudley syndrome. Endocrinology. 2017;158(3):678-691. doi:10.1210/en.2016-1530
13. Braun D, Schweizer U. The Protein Translocation Defect of MCT8L291RIs Rescued by Sodium Phenylbutyrate. Eur Thyroid J. 2020;9(5):269-280. doi:10.1159/000507439