Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder: evidence from patients and models of the disease

Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder: evidence from patients and models of the disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder: evidence from patients and models of the disease Arcangela Iuso, Fangfang Zhang, Tatjana Dorn, Barbara Gnutti, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4582436/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jul, 2025 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract Background PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS , which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified. In this study, we report on six additional patients. We shed light on the functional aspects of DCM in PPCS DD and evaluate therapeutic approaches to boost CoA levels both in vitro and in vivo. Methods and Results Whole-exome sequencing identified causative variants in PPCS in six additional individuals presenting with DCM and a spectrum of phenotypes, including neuromuscular signs and neurologic deterioration. Western blotting analyses demonstrated destabilizing effects of identified variants on the PPCS protein. Microplate-based assessment of CoA showed reduced levels of the coenzyme in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional investigation of DCM in cardiac cells and heart patches revealed defects in contractile function and arrhythmic events, which were partially rescued by pantethine. Long-term clinical assessment showed encouraging benefits in pantethine-treated patients. Conclusion Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals. Health sciences/Diseases/Metabolic disorders Health sciences/Cardiology/Cardiovascular biology Phosphopantothenoylcysteine synthetase (PPCS) PPCS deficiency disorder (PPCS DD) Dilated cardiomyopathy (DCM) Coenzyme A (CoA) Pantethine 4'-P-pantetheine Pantothenate Kinase-Associated Neurodegeneration (PKAN) COASY protein-associated neurodegeneration (COPAN) Phosphopantothenoylcysteine decarboxylase deficiency disorder (PPCDC DD) Metabolic disease Full Text Additional Declarations Yes there is potential Competing Interest. Sibon is co-inventor on two patent application for 4'-phosphopantetheine for use in disorders exclusive and inclusive of PKAN. Sibon is a co-inventor on a patent application for acetyl-4'-phosphopantetheine for use in PKAN and in related disorders. Sibon serves as non-compensated executive for the Spoonbill Foundation, a not-for-profit organization that may benefit from the results of this research. Cite Share Download PDF Status: Published Journal Publication published 31 Jul, 2025 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4582436","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":318448266,"identity":"1a2e07b4-856f-4a6e-8df0-f46057006d42","order_by":0,"name":"Arcangela 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München","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Moretti","suffix":""}],"badges":[],"createdAt":"2024-06-14 13:40:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4582436/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4582436/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-025-01017-z","type":"published","date":"2025-07-31T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88075650,"identity":"864b144f-d96b-4173-b48d-b46a4fbca8c1","added_by":"auto","created_at":"2025-08-01 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Sibon is a co-inventor on a patent application for acetyl-4'-phosphopantetheine for use in PKAN and in related disorders. Sibon serves as non-compensated executive for the Spoonbill Foundation, a not-for-profit organization that may benefit from the results of this research.","formattedTitle":"Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder: evidence from patients and models of the disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Phosphopantothenoylcysteine synthetase (PPCS), PPCS deficiency disorder (PPCS DD), Dilated cardiomyopathy (DCM), Coenzyme A (CoA), Pantethine, 4'-P-pantetheine, Pantothenate Kinase-Associated Neurodegeneration (PKAN), COASY protein-associated neurodegeneration (COPAN), Phosphopantothenoylcysteine decarboxylase deficiency disorder (PPCDC DD), Metabolic disease","lastPublishedDoi":"10.21203/rs.3.rs-4582436/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4582436/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in \u003cem\u003ePPCS\u003c/em\u003e, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified. In this study, we report on six additional patients. We shed light on the functional aspects of DCM in PPCS DD and evaluate therapeutic approaches to boost CoA levels both in vitro and in vivo.\u003c/p\u003e\u003ch2\u003eMethods and Results\u003c/h2\u003e \u003cp\u003eWhole-exome sequencing identified causative variants in PPCS in six additional individuals presenting with DCM and a spectrum of phenotypes, including neuromuscular signs and neurologic deterioration. Western blotting analyses demonstrated destabilizing effects of identified variants on the PPCS protein. Microplate-based assessment of CoA showed reduced levels of the coenzyme in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional investigation of DCM in cardiac cells and heart patches revealed defects in contractile function and arrhythmic events, which were partially rescued by pantethine. Long-term clinical assessment showed encouraging benefits in pantethine-treated patients.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals.\u003c/p\u003e","manuscriptTitle":"Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder: evidence from patients and models of the disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-22 03:48:40","doi":"10.21203/rs.3.rs-4582436/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"21a8f012-aedc-40c8-b18c-0417a70cc68e","owner":[],"postedDate":"August 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33672059,"name":"Health sciences/Diseases/Metabolic disorders"},{"id":33672060,"name":"Health sciences/Cardiology/Cardiovascular biology"}],"tags":[],"updatedAt":"2025-08-01T07:05:48+00:00","versionOfRecord":{"articleIdentity":"rs-4582436","link":"https://doi.org/10.1038/s43856-025-01017-z","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2025-07-31 04:00:00","publishedOnDateReadable":"July 31st, 2025"},"versionCreatedAt":"2024-08-22 03:48:40","video":"","vorDoi":"10.1038/s43856-025-01017-z","vorDoiUrl":"https://doi.org/10.1038/s43856-025-01017-z","workflowStages":[]},"version":"v1","identity":"rs-4582436","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4582436","identity":"rs-4582436","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}