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
{"title":"slc31a1相关发育性和癫痫性脑病的临床和分子特征:来自13例新病例的见解","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","doi":"10.1093/braincomms/fcaf348","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf348"},"PeriodicalIF":4.5000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484445/pdf/","citationCount":"0","resultStr":"{\"title\":\"Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases.\",\"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\",\"doi\":\"10.1093/braincomms/fcaf348\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":93915,\"journal\":{\"name\":\"Brain communications\",\"volume\":\"7 5\",\"pages\":\"fcaf348\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2025-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484445/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Brain communications\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/braincomms/fcaf348\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain communications","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/braincomms/fcaf348","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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 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.