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Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1\u20134]), 4\u2032\u2010phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except <jats:italic>PPCDC<\/jats:italic>, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of <jats:italic>PPCDC<\/jats:italic>. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 4\u2032\u2010phosphopantothenoylcysteine to 4\u2032\u2010phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient\u2010derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra\u2010rare, severe inborn error of metabolism due to pathogenic variants of <jats:italic>PPCDC<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/jimd.12584","type":"journal-article","created":{"date-parts":[[2022,12,24]],"date-time":"2022-12-24T05:12:20Z","timestamp":1671858740000},"page":"261-272","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pathogenic variants of the coenzyme A biosynthesis\u2010associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal\u2010recessive dilated cardiomyopathy"],"prefix":"10.1002","volume":"46","author":[{"given":"Irene","family":"Bravo\u2010Alonso","sequence":"first","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Centro de Biolog\u00eda Molecular Universidad Aut\u00f3noma de Madrid, CIBERER, IdiPAZ  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mat\u00edas","family":"Morin","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica Hospital Universitario Ram\u00f3n y Cajal, IRYCIS  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras Instituto de Salud Carlos III (CB06\/07\/0048; CIBERER\u2010ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Arribas\u2010Carreira","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Centro de Biolog\u00eda Molecular Universidad Aut\u00f3noma de Madrid, CIBERER, IdiPAZ  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Centro de Biolog\u00eda Molecular Universidad Aut\u00f3noma de Madrid, CIBERER, IdiPAZ  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consuelo","family":"Pedr\u00f3n\u2010Giner","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Gastroenterolog\u00eda y Nutrici\u00f3n Hospital Infantil Universitario Ni\u00f1o Jes\u00fas  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Soletto","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica Hospital Universitario Ram\u00f3n y Cajal, IRYCIS  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Santolaria","sequence":"additional","affiliation":[{"name":"Institut de Biotecnologia i Biomedicina &amp; Departament de Bioqu\u00edmica i Biologia Molecular Universitat Aut\u00f2noma de Barcelona  Cerdanyola del Vall\u00e8s Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Ram\u00f3n\u2010Maiques","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Valencia (IBV) CSIC. 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