Year: 2025
Type: article
Study design: Case Report
Abstract: CONTEXT: Monocarboxylate transporter (MCT) 8 facilitates thyroid hormone (TH) transport across the blood-brain barrier. Pathogenic variants in SLC16A2 cause MCT8 deficiency (Allan-Herndon-Dudley syndrome), characterized by intellectual and motor disability and abnormal thyroid function tests. MCT8 deficiency typically affects males due to its X-linked inheritance. OBJECTIVE: Here, we report 8 female patients with heterozygous pathogenic variants in SLC16A2 who presented with variable neurocognitive impairment, behavioral problems, and TH function abnormalities. METHODS: We performed X-chromosome inactivation studies in female patients in whom heterozygous pathogenic variants in SLC16A2 were identified. The effect of SLC16A2 variants on TH transport was assessed in transfected cells and patient-derived fibroblasts. RESULTS: In all patients (mean age 8.6 years; range, 2.3-25 years) routine care genetic analyses identified heterozygous variants in SLC16A2 (p.(R445C), p.(N193I), p.(G276R), t(X;20), resulting in a breakpoint in intron 1, t(X;19), resulting in a breakpoint in SLC16A2, p.(I562Sfs566*), p.(G221R)). All missense variants showed substantially reduced MCT8-mediated TH uptake in transiently transfected cells. X-chromosome inactivation studies in patient cells showed skewed X-inactivation in all 7 evaluated individuals. In 5 out of 7 evaluated cases, MCT8-mediated 3,5,3'-triiodothyronine (T3) uptake in patient-derived fibroblasts was impaired to a similar degree as in fibroblasts derived from male patients with MCT8 deficiency. CONCLUSION: Female patients with heterozygous pathogenic variants in SLC16A2 and skewed X-chromosome inactivation may present with variable neuro(psycho)logical, behavioral, and thyroid function test abnormalities. Female patients presenting with neurocognitive impairment and abnormal TH function tests (low free thyroxine and/or high total T3 concentrations) should be tested for genetic variants in SLC16A2.
Authors: Stefan Groeneweg, Ferdy S van Geest, Floor van der Most, Lucia Abela, Paolo Alfieri, Andrew J Bauer, Enrico Bertini, Marco Cappa, Nurullah Çelik, Irenaeus F M de Coo, Anna Dolcetta-Capuzzo, Ilja Dubinski, Jorge L Granadillo, Lies H Hoefsloot, Vera M Kalscheuer, Marieke M van der Knoop, Heiko Krude, Kyle P McNerney, Laura Paone, Robin P Peeters, Catherine Peters, Markus Schuelke, Ulrich Schweizer, Jennifer E Sprague, A S Paul van Trotsenburg, Nina-Maria Wilpert, Ginevra Zanni, Laura J C M van Zutven, W Edward Visser
Institutions: Erasmus MC, Erasmus University Rotterdam, University of Zurich, University Children's Hospital Zurich, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Children's Hospital of Philadelphia, University of Pennsylvania, Sivas Cumhuriyet Üniversitesi, Maastricht University Medical Centre, IRCCS Ospedale San Raffaele, LMU Klinikum, Center for Pediatric Endocrinology Zurich, Ludwig-Maximilians-Universität München, Washington University in St. Louis, Max Planck Institute for Molecular Genetics, Charité - Universitätsmedizin Berlin, Great Ormond Street Hospital, University of Bonn, Emma Kinderziekenhuis, Amsterdam University Medical Centers, Amsterdam Reproduction Development, University of Amsterdam, Berlin Institute of Health at Charité - Universitätsmedizin Berlin
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,750
Funders: Sherman Fairchild Foundation, ZonMw, Eurostars
Awards: G4011161389, G4447810220
OpenAlex ID: W4410789167