{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T19:41:30Z","timestamp":1786822890219,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR\u20102018\u201012365610"],"award-info":[{"award-number":["GR\u20102018\u201012365610"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF\u20102021\u201012373111"],"award-info":[{"award-number":["RF\u20102021\u201012373111"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:italic>COASY<\/jats:italic>, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular <jats:italic>de novo<\/jats:italic> coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein\u2010associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of <jats:italic>COASY<\/jats:italic>\u2010related disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified five new individuals harboring novel <jats:italic>COASY<\/jats:italic> variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in <jats:italic>COASY<\/jats:italic>\u2010related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in <jats:italic>COASY<\/jats:italic> fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4\u2032\u2010phosphopantetheinylated proteins were significantly reduced in <jats:italic>COASY<\/jats:italic> patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These results not only extend the clinical phenotype associated with <jats:italic>COASY<\/jats:italic> variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of <jats:italic>COASY<\/jats:italic>\u2010associated diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52079","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T03:03:54Z","timestamp":1715828634000},"page":"1615-1629","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of <scp><i>COASY<\/i><\/scp>\u2010associated diseases"],"prefix":"10.1002","volume":"11","author":[{"given":"Chiara","family":"Cavestro","sequence":"first","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Morra","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Legati","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"D'Amato","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Nasca","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arcangela","family":"Iuso","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine Technical University of Munich  Munich Germany"},{"name":"Institute of Neurogenomics Helmholtz Zentrum M\u00fcnchen  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Lubarr","sequence":"additional","affiliation":[{"name":"Department of Neurology Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Division of Genetics, Arnold Palmer Hospital  Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia G.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Division of Genetics, Arnold Palmer Hospital  Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Serra\u2010Juh\u00e9","sequence":"additional","affiliation":[{"name":"Genetics Department Hospital de la Santa Creu i Sant Pau  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjam\u00edn","family":"Rodr\u00edguez\u2010Santiago","sequence":"additional","affiliation":[{"name":"Genetics Department Hospital de la Santa Creu i Sant Pau  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER)  Madrid Spain"},{"name":"Genomic Instability Syndromes and DNA Repair Group and Join Research Unit on Genomic Medicine UAB\u2010Sant Pau Biomedical Research Institute Hospital de la Santa Creu i Sant Pau  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eulalia","family":"Tur\u00f3n\u2010Vi\u00f1as","sequence":"additional","affiliation":[{"name":"Child Neurology Unit, Pediatrics Service Hospital de la Santa Creu i Sant Pau  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clement","family":"Prouteau","sequence":"additional","affiliation":[{"name":"Department of Genetics University Hospital of Angers  Angers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magalie","family":"Barth","sequence":"additional","affiliation":[{"name":"Department of Genetics University Hospital of Angers  Angers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan J.","family":"Hayflick","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics Oregon Health &amp; 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