Allan-Herndon-Dudley Syndrome (AHDS)

Central hypothyroidism and the Allan-Herndon Dudley Syndrome (AHDS)

The Allan-Herndon Dudley Syndrome (AHDS) is a rare disease caused by dysfunctional monocarboxylate transporter 8 (MCT8) (1-3). In patients with AHDS, the absence of functional MCT8 impairs transport of T3/T4 through the brain barriers (BB), leading to a central state of TH deficiency. Consequential to the MCT8 deficiency, patients with AHDS show severe cognitive and motor defects associated with decreased myelination of CNS neurons (4). Reflecting the severity of the disease, patients with AHDS are typically unable to speak or to otherwise communicate, and the accompanying motor deficits and hypotonia often preclude affected individuals from eating, walking or even sitting upright without assistance (1). Pharmacotherapies capable of bypassing MCT8 deficiency are urgently required. 

In mice, the AHDS is mimicked by concomitant deletion of the thyroid hormone transporters MCT8 and the solute carrier organic anion transporter family member 1c1 (OATP1C1) (5). Similar to AHDS patients, MCT8/OATP1C1 double knock out (dKO) mice show impaired central T3/T4 transport with peripheral hyperthyroidism and central TH deficiency (5). Like AHDS patients, MCT8/OATP1C1 dKO mice further show locomotor deficits and brain maldevelopment, making these mice a valuable model organism to evaluate novel drugs to treat the AHDS (5).  

Novel pharmacotherapies for the treatment of central TH deprivation associated with Mct8/Oatp1c1 deficiency

In the framework of our interdisciplinary Collaborative Research Centre / Transregio 296 consortium "Local Control of Thyroid Hormone Action" (LOCOTACT), we will evaluate a series of novel thyroid hormone peptide chimeras for their ability to improve brain TH deficiency associated with the AHDS. Studies will include LSFM and MS-based assessment of drug BBB permeability, advanced in vitro and in vivo approaches to delineate proof-of-concept and drugability of central MCT8 deficiency and state-of-the art genetic, microscopic, transcriptomic and proteomic approaches to further advance our knowledge on the neuronal and behavioral underpinnings underlying disturbed MCT8 expression and function.

Chemical hybridization (I), visualization and quantification of CNS transport (II), and characterization of CNS action of novel peptide-TH chimera (III) in a murine model of AHDS.

References:

  1. Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, et al. Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am J Hum Genet. 2005 Jul;77(1):41–53. 
  2. Friesema ECH, Jansen J, Heuer H, Trajkovic M, Bauer K, Visser TJ. Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8. Nature clinical practice Endocrinology & metabolism. Nature Publishing Group; 2006 Sep;2(9):512–23. 
  3. Maranduba CMC, Friesema ECH, Kok F, Kester MHA, Jansen J, Sertié AL, et al. Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter. J Med Genet. BMJ Publishing Group Ltd; 2006 May;43(5):457–60. 
  4. La Piana R, Vanasse M, Brais B, Bernard G. Myelination Delay and Allan-Herndon-Dudley Syndrome Caused by a Novel Mutation in the SLC16A2 Gene. J Child Neurol. SAGE PublicationsSage CA: Los Angeles, CA; 2015 Sep;30(10):1371–4. 
  5. Mayerl S, Müller J, Bauer R, Richert S, Kassmann CM, Darras VM, et al. Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. J Clin Invest. American Society for Clinical Investigation; 2014 May;124(5):1987–99. 

https://www.uni-due.de/crctr296/project-p05.php