Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases

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 <i>SLC31A1</i> gene. Recently, bi-allelic mutations in <i>SLC31A1</i> 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 <i>SLC31A1</i> 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.

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Journal
Brain Communications
Published
2025-01-01
DOI
https://doi.org/10.1093/braincomms/fcaf348
Citations
2
Primary Topic
Trace Elements in Health
Type
article
Field-Weighted Citation Impact
2.24

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article

Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases

Afshin Fayazi, Marta Gómez‐Chiari, Christopher J. Carroll, Mar O’Callaghan et al.
2 citations
Brain Communications
Trace Elements in Health
2.24
article

Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases

Afshin Fayazi, Marta Gómez‐Chiari, Christopher J. Carroll, Mar O’Callaghan, Klaas J. Wierenga, Jordi Muchart-López, Janet Hoenicka, Natalia Juliá‐Palacios, Ingrid Cristian, Rafael Artuch, Seyed Hassan Tonekaboni, Frederic Tort, Huma Arshad Cheema, Gerard Muñoz‐Pujol, Roser Urreizti, Patrick M. Gaffney, Abraham J. Paredes‐Fuentes, Bryn D. Webb, Juan Darío Ortigoza‐Escobar, Irene Machado-Casas, Marwa Abd Elmaksoud, Jennifer Morrison, Nouriya Al‐Sannaa, Àngels García‐Cazorla, Antònia Ribes, Aida M. Bertoli‐Avella, Mohammad Miryounesi, Henry Houlden, Reza Maroofian, Carlos Santos‐Ocaña, Francesc Palau, Heidy Baide‐Mairena, Sahar Alijanpour, Emir Zonic, Peter Bauer, Muhammad Nadeem Anjum, Anna Codina, Faroug Ababneh, Mary W. Tyler, Maria Urbaniak, Uxía Barba
article en
2 citations

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 <i>SLC31A1</i> gene. Recently, bi-allelic mutations in <i>SLC31A1</i> 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 <i>SLC31A1</i> 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.

Brain CommunicationsVol. 7(5)
Hamedan University of Medical Sciences (IR), Hospital Sant Joan de Déu Barcelona (ES), University of Wisconsin–Madison (US), St George's, University of London (GB), King Saud bin Abdulaziz University for Health Sciences (SA), Lahore General Hospital (PK), Arnold Palmer Hospital for Children (US), Saudi Aramco Medical Services Organization (SA), King Abdulaziz Medical City (SA), Oklahoma Medical Research Foundation (US), University of Florida (US), Jahrom University of Medical Sciences (IR), Hospital General de Granollers (ES), Centro Andaluz de Biología del Desarrollo (ES), Instituto de Investigación Biosanitaria de Granada (ES), Hospital Clínic de Barcelona (ES), Synaptic Research (United States) (US), King Abdulaziz Hospital (SA), Centogene (Germany) (DE), Genomics England (GB), Mayo Hospital (PK), National Hospital for Neurology and Neurosurgery (GB), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Instituto de Investigación de Enfermedades Raras (ES), University College London (GB), Shahid Beheshti University of Medical Sciences (IR), Alexandria University (EG), Icahn School of Medicine at Mount Sinai (US)
Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, Universitat de Barcelona, Asociación de Enfermos de Patologías Mitocondriales, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III
Openalex Percentile: Top 11%
Trace Elements in Health
2.24
DOIOpen Access PDFOpenAlex
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