Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases
Por:
Julià-Palacios NA, Muñoz-Pujol, G, Maroofian, R, Bertoli-Avella, AM, Gómez-Chiari M, Muchart-Lopez J, Paredes-Fuentes, AJ, O'Callaghan-Gordo M, Machado-Casas, IS, Cristian, I, Morrison, J, Garcia-Cazorla A, Codina-Bergadà A, Miryounesi, M, Zonic, E, Bauer, P, Cheema, H, Anjum, MN, Al-Sannaa, N, Abd Elmaksoud, M, Ababneh, F, Alijanpour, S, Tonekaboni, SH, Fayazi, A, Urbaniak, M, Barba, U, Hoenicka J, Palau F, Houlden, H, Ortigoza-Escobar JD, Ribes, A, Santos-Ocaña, C, Tyler, M, Gaffney, P, Carroll, CJ, Tort, F, Wierenga, KJ, Webb, BD, Artuch-Iriberri R, Baide HS and Urreizti R
Publicada:
1 ene 2025
Ahead of Print:
23 sep 2025
Resumen:
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.
Juli & aacute;-Palacios, Mu & ntilde;oz-Pujol et al. reported 13 cases with bi-allelic SLC31A1 mutations, presenting with early-onset epileptic encephalopathy, severe neurodevelopmental delay, and hypotonia, with high mortality. Preliminary functional studies showed impaired mitochondrial function in patient fibroblasts. These findings expand the clinical spectrum of SLC31A1-related disorder and suggest mitochondrial dysfunction as a possible underlying mechanism.
Filiaciones:
Julià-Palacios NA:
Hosp St Joan de Deu, Dept Pediat Neurol, Barcelona 08950, Spain
Muñoz-Pujol, G:
Hosp Clin Barcelona, Biochem & Mol Genet, Div Inborn Errors Metab IBC, Barcelona 08028, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona 08036, Spain
Maroofian, R:
UCL Queen Sq Inst Neurol, Dept Neuromuscular Disorders, London WC1N 3GB, England
Bertoli-Avella, AM:
CENTOGENE GmbH, Med Genet Reporting & Res, D-18055 Rostock, Germany
Gómez-Chiari M:
Hosp St Joan de Deu, Dept Diagnost Imaging, IRSJD, Barcelona 08950, Spain
Muchart-Lopez J:
Hosp St Joan de Deu, Dept Diagnost Imaging, IRSJD, Barcelona 08950, Spain
:
Hosp Clin Barcelona, Biochem & Mol Genet, Div Inborn Errors Metab IBC, Barcelona 08028, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona 08036, Spain
Hosp St Joan de Deu, Dept Clin Biochem, IRSJD, Barcelona 08950, Spain
O'Callaghan-Gordo M:
Hosp St Joan de Deu, Dept Pediat Neurol, Barcelona 08950, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Machado-Casas, IS:
Hosp Univ Clin San Cecilio, Neuropediat & Neurodev Unit, Granada 18007, Spain
Cristian, I:
Arnold Palmer Hosp Children, Div Genet, Orlando, FL 32806 USA
Morrison, J:
Arnold Palmer Hosp Children, Div Genet, Orlando, FL 32806 USA
Garcia-Cazorla A:
Hosp St Joan de Deu, Dept Pediat Neurol, Barcelona 08950, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Hosp St Joan de Deu, Dept Neurol & MetabERN, Neurometab & Synapt Metab Lab, Barcelona 08950, Spain
Codina-Bergadà A:
Hosp St Joan de Deu, Appl Res Neuromuscular Dis, IRSJD, Barcelona 08950, Spain
Miryounesi, M:
Shahid Beheshti Univ Med Sci, Fac Med, Dept Med Genet, Tehran 1985717413, Iran
Zonic, E:
CENTOGENE GmbH, Med Genet Reporting & Res, D-18055 Rostock, Germany
Bauer, P:
CENTOGENE GmbH, Med Genet Reporting & Res, D-18055 Rostock, Germany
Cheema, H:
Childrens Hosp Lahore, Pediat Dept Gastroenterol, Lahore 54000, Pakistan
Anjum, MN:
Childrens Hosp Lahore, Pediat Dept Gastroenterol, Lahore 54000, Pakistan
Al-Sannaa, N:
Johns Hopkins Aramco Hlth Care, Dhahran 34465, Saudi Arabia
Abd Elmaksoud, M:
Alexandria Univ, Fac Med, Dept Pediat, Neurol Unit, Alexandria 21526, Egypt
Ababneh, F:
King Abdullah Specialized Children Hosp, Dept Genet & Precis Med, King Abdulaziz Med City, MNGHA, Riyadh 11481, Saudi Arabia
King Saud Bin Abdulaziz Univ Hlth Sci, King Abdullah Int Med Res Ctr, Riyadh 11481, Saudi Arabia
Alijanpour, S:
Alborz Univ Med Sci, Fac Med, Dept Genet, Karaj 3149969415, Iran
Tonekaboni, SH:
Shahid Beheshti Univ Med Sci, Mofid Childrens Hosp, Sch Med, Dept Pediat Neurol, Tehran 15468, Iran
Fayazi, A:
Hamadan Univ Med Sci, Sch Med, Dept Pediat, Hamadan 6517838678, Iran
Urbaniak, M:
Hosp St Joan de Deu, Dept Clin Biochem, IRSJD, Barcelona 08950, Spain
:
Hosp St Joan de Deu, Dept Clin Biochem, IRSJD, Barcelona 08950, Spain
Hoenicka J:
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Hosp St Joan de Deu, Ctr Genom Sci Med, Lab Neurogenet & Mol Med, IRSJD, Barcelona 08950, Spain
Palau F:
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Hosp St Joan de Deu, Ctr Genom Sci Med, Lab Neurogenet & Mol Med, IRSJD, Barcelona 08950, Spain
Houlden, H:
UCL Queen Sq Inst Neurol, Dept Neuromuscular Disorders, London WC1N 3GB, England
Ortigoza-Escobar JD:
Hosp St Joan de Deu, Dept Pediat Neurol, Barcelona 08950, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Ribes, A:
Hosp Clin Barcelona, Biochem & Mol Genet, Div Inborn Errors Metab IBC, Barcelona 08028, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona 08036, Spain
Santos-Ocaña, C:
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Univ Pablo de Olavide, Ctr Andaluz Biol Desarrollo, Seville 41013, Spain
Tyler, M:
City St Georges Univ London, Cardiovasc & Genom Res Inst, London SW17 0RE, England
Gaffney, P:
Oklahoma Med Res Fdn, Genes & Human Dis Res Program, Oklahoma City, OK 73104 USA
Carroll, CJ:
City St Georges Univ London, Cardiovasc & Genom Res Inst, London SW17 0RE, England
Tort, F:
Hosp Clin Barcelona, Biochem & Mol Genet, Div Inborn Errors Metab IBC, Barcelona 08028, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona 08036, Spain
Wierenga, KJ:
Univ Florida, Dept Pediat, Div Genet & Metab, Gainesville, FL 32610 USA
Webb, BD:
Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI 53792 USA
Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
Artuch-Iriberri R:
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Hosp St Joan de Deu, Dept Clin Biochem, IRSJD, Barcelona 08950, Spain
Baide HS:
Hosp St Joan de Deu, Dept Pediat Neurol, Barcelona 08950, Spain
Hosp Gen Granollers, Dept Pediat, Barcelona 08402, Spain
Urreizti R:
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Hosp St Joan de Deu, Dept Clin Biochem, IRSJD, Barcelona 08950, Spain
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