Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment

How to cite: Wilpert, N.-M.; Hewitt, A. L.; Pons, R.; Henke, M.-T.; Dell’Orco, A.; Bauer, M.; Grolik, C.; Menz, S.; Wahle, M.; Zink, A.; Prigione, A.; Reinauer, C.; Lange, C.; Furth, C.; Brockmann, K.; Jung-Klawitter, S.; Christ, S.; Kaindl, A. M.; Tietze, A.; Krude, H.; Opladen, T.; Schuelke, M. Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment. Preprints 2024, 2024090435. https://doi.org/10.20944/preprints202409.0435.v1 Wilpert, N.-M.; Hewitt, A. L.; Pons, R.; Henke, M.-T.; Dell’Orco, A.; Bauer, M.; Grolik, C.; Menz, S.; Wahle, M.; Zink, A.; Prigione, A.; Reinauer, C.; Lange, C.; Furth, C.; Brockmann, K.; Jung-Klawitter, S.; Christ, S.; Kaindl, A. M.; Tietze, A.; Krude, H.; Opladen, T.; Schuelke, M. Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment. Preprints 2024, 2024090435. https://doi.org/10.20944/preprints202409.0435.v1

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MDPI and ACS Style

Wilpert, N.-M.; Hewitt, A. L.; Pons, R.; Henke, M.-T.; Dell’Orco, A.; Bauer, M.; Grolik, C.; Menz, S.; Wahle, M.; Zink, A.; Prigione, A.; Reinauer, C.; Lange, C.; Furth, C.; Brockmann, K.; Jung-Klawitter, S.; Christ, S.; Kaindl, A. M.; Tietze, A.; Krude, H.; Opladen, T.; Schuelke, M. Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment. Preprints 2024, 2024090435. https://doi.org/10.20944/preprints202409.0435.v1

APA Style

Wilpert, N. M., Hewitt, A. L., Pons, R., Henke, M. T., Dell’Orco, A., Bauer, M., Grolik, C., Menz, S., Wahle, M., Zink, A., Prigione, A., Reinauer, C., Lange, C., Furth, C., Brockmann, K., Jung-Klawitter, S., Christ, S., Kaindl, A. M., Tietze, A., Krude, H., Opladen, T., & Schuelke, M. (2024). Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment. Preprints. https://doi.org/10.20944/preprints202409.0435.v1

Chicago/Turabian Style

Wilpert, N., Thomas Opladen and Markus Schuelke. 2024 "Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment" Preprints. https://doi.org/10.20944/preprints202409.0435.v1

Abstract

Background: Patients with mutations in the monocarboxylate transporter 8 (MCT8) suffer from Allan-Herndon-Dudley syndrome (AHDS), characterized by developmental delay and a highly disabling movement disorder. Despite the potential of thyroid hormone derivatives to overcome the transporter defect, current trials did not achieve patient-oriented therapeutic goals. Objectives: Since most neurological symptoms are related to the dopaminergic system, we investigated the role of dopamine and its metabolites in MCT8 deficiency with regard to pathophysiology and potential therapeutic strategies in an observational cohort study. Methods: We present longitudinal data from the DEEPTYPE registry of ten patients with video-documentation, standardized phenotyping, cerebrospinal fluid analysis, treatment response to levodopa/carbidopa supplementation, and neuroimaging data. To establish a cell-based model for pathophysiological studies, we differentiated healthy human induced pluripotent stem cells (hiPSCs) into dopaminergic neurons. Results: Children presented with signs of parkinsonism in childhood, including hypokinesia, hypomimia, inability to sit or stand, rigidity, dystonia, and autonomic dysfunction along the classification of Leuzzi and colleagues. Cerebrospinal fluid homovanillic acid concentrations were decreased (n=11), suggesting isolated dopamine pathway impairment. Six out of seven patients responded favorably to levodopa/carbidopa supplementation and we did not see any adverse drug reactions. Our cell-based studies showed that hiPSC-derived dopaminergic neurons expressed MCT8 and produced quantifiable levels of biogenic amines. Conclusions: Parkinsonism is part of AHDS's clinical presentation and may be amenable to treatment. The precise impact of MCT8 deficiency on the dopamine metabolism needs to be further elucidated, e.g. by using patient iPSC-derived dopaminergic neurons in future studies.

Keywords

MCT8; SLC16A2; movement disorder; parkinsonism; dopamine; iPSC cell model

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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