Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases
Year: 2025
Type: article
Study design: Observational Study
Abstract: Copper is indispensable for various metabolic processes, notably mitochondrial respiration. In humans, copper homeostasis hinges on transporters such as copper transporter 1 (CTR1), encoded by the SLC31A1 gene. Recently, bi-allelic mutations in SLC31A1 have been associated with a new neurodevelopmental disorder. This study presents clinical, genetic, and biochemical findings from 13 new cases across 10 families worldwide. RNA sequencing evaluated gene expression, and Western blotting assessed copper transporter 1 protein levels. Additionally, mitochondrial respiratory capacity was measured via high-resolution respirometry. Affected individuals exhibited a distinct clinical phenotype characterized by early-onset epileptic encephalopathy, severe neurodevelopmental delay and hypotonia, with high mortality. Neuroimaging revealed significant brain atrophy and white matter abnormalities. Genetic analysis identified bi-allelic SLC31A1 variants, predominantly p.His120Gln in six cases and p.(Arg102Cys/His) in three cases. Functional studies in patient fibroblasts demonstrated impaired mitochondrial respiration. This study significantly broadens the clinical spectrum of this recently described syndrome, presenting as a severe developmental encephalopathy with high mortality risk, and suggests mitochondrial dysfunction as a potential pathomechanism. These findings contribute to the mounting evidence linking copper transporter 1 dysfunction to neurodegeneration, underscoring the urgency for further therapeutic investigations.
Source: Brain Communications
Authors: Natalia Juliá-Palacios, Gerard Muñoz-Pujol, Reza Maroofian, Aida M Bertoli-Avella, Marta Gómez-Chiari, Jordi Muchart-López, Abraham J Paredes-Fuentes, Mar O’Callaghan, Irene S Machado-Casas, Ingrid Cristian, Jennifer Morrison, Angels Garcia-Cazorla, Anna Codina, Mohammad Miryounesi, Emir Zonic, Peter Bauer, Huma Cheema, Muhammad Nadeem Anjum, Nouriya Al-Sannaa, Marwa Abd Elmaksoud, Faroug Ababneh, Sahar Alijanpour, Seyed Hassan Tonekaboni, Afshin Fayazi, Maria Urbaniak, Uxía Barba, Janet Hoenicka, Francesc Palau, Henry Houlden, Juan Darío Ortigoza-Escobar, Antonia Ribes, Carlos Santos-Ocaña, Millie Tyler, Patrick Gaffney, Christopher J Carroll, Frederic Tort, Klaas J Wierenga, Bryn D Webb, Rafael Artuch, Heidy Baide-Mairena, Roser Urreizti
Institutions: Hospital Sant Joan de Déu Barcelona, Institut de Recerca Sant Joan de Déu, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, UCL Queen Square Institute of Neurology, University College London, Centogene (Germany), Complejo Hospitalario Universitario de Granada, Arnold Palmer Hospital for Children, Shahid Beheshti University, Shahid Beheshti University of Medical Sciences, Saudi Aramco Medical Services Organization, Alexandria University, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, King Abdullah International Medical Research Center, National Guard Health Affairs, Alborz University of Medical Sciences, Hamedan University of Medical Sciences, Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, City St George's, University of London, Oklahoma Medical Research Foundation, University of Florida, University of Wisconsin–Madison, Icahn School of Medicine at Mount Sinai, Hospital General de Granollers
Language: English
Topic: Trace Elements in Health
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,024
Awards: Desarrollo de una estrategia multiómica y de biología funcional para mejorar el flujo diagnóstico de las enfermedades del metabolismo energético mitocondrial, Diagnóstico molecular de los defectos de la fosforilación oxidativa mitocondrial: patogénesis de las deficiencias de CoQ10, G1845787663, G2496428145, G4509608868, Pipeline para el diagnóstico y seguimiento de pacientes con enfermedades mitocondriales basado en un análisis multiómico: Mitoverso., Desarrollo de una plataforma para demostrar patogenicidad de variantes de significado incierto y nuevos genes causantes de enfermedad en pacientes con trastornos del metabolismo energético mitocondrial., G570868066, G8725658324
OpenAlex ID: W4414435669