{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:08:24Z","timestamp":1785146904865,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201023\u2010CE17\u20100066"],"award-info":[{"award-number":["ANR\u201023\u2010CE17\u20100066"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_192505"],"award-info":[{"award-number":["310030_192505"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030E_219127"],"award-info":[{"award-number":["320030E_219127"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cobalamin (vitamin B12) is an essential cofactor for two human enzymes, methionine synthase and methylmalonyl\u2010CoA mutase. Inborn errors of cobalamin metabolism (IECMs) are inherited genetic defects resulting in improper transport, modification, or utilization of cobalamin and include inherited methylmalonic acidurias, a group of IECMs most frequently caused by a defect in the methylmalonyl\u2010CoA mutase enzyme. Here, we performed genome\u2010scale modeling of IECMs to gain insight into their metabolic perturbations. First, we simulated deficiencies in 11 IECM\u2010related genes and demonstrated that they cluster based on impaired metabolic pathways. Next, we leveraged RNA sequencing data from fibroblasts of 202 individuals with methylmalonic aciduria and 19 unaffected controls to construct and interrogate personalized metabolic models. Finally, we analyzed fluxes differing between patients depending on reported symptom presentation. Our findings reveal that (i) metabolic pathways including fatty acid metabolism and heme biosynthesis have reduced flux in IECMs, (ii) in personalized simulations, succinate and fumarate production and heme biosynthesis are impaired, especially in methylmalonyl\u2010CoA mutase deficiency, (iii) one\u2010carbon metabolism reactions such as serine hydroxymethyltransferase and folylglutamate synthase have reduced flux in all individuals with methylmalonic aciduria, and (iv) specific metabolic pathways are up\u2010 or down\u2010regulated according to symptoms, including failure to thrive and hematological abnormalities, and treatments, such as antibiotics and protein restriction. Overall, our study delineates metabolic pathways perturbed in IECMs. In future applications, our modeling framework could be applied to other rare genetic diseases or used to predict personalized therapeutic or dietary interventions.<\/jats:p>","DOI":"10.1002\/jimd.70077","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T04:30:08Z","timestamp":1754973008000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Personalized Genome\u2010Scale Modeling Reveals Metabolic Perturbations in Fibroblasts of Methylmalonic Aciduria Patients"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6938-8072","authenticated-orcid":false,"given":"Almut","family":"Heinken","sequence":"first","affiliation":[{"name":"UMRS Inserm 1256 nGERE (Nutrition\u2010Genetics\u2010Environmental Risks), Institute of Medical Research (P\u00f4le BMS) University of Lorraine  Nancy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussein","family":"Awada","sequence":"additional","affiliation":[{"name":"UMRS Inserm 1256 nGERE (Nutrition\u2010Genetics\u2010Environmental Risks), Institute of Medical Research (P\u00f4le BMS) University of Lorraine  Nancy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito R. T.","family":"Zanotelli","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center, University Children's Hospital Z\u00fcrich University of Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1557-3517","authenticated-orcid":false,"given":"D. Sean","family":"Froese","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center, University Children's Hospital Z\u00fcrich University of Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa\u2010Maria","family":"Gu\u00e9ant\u2010Rodriguez","sequence":"additional","affiliation":[{"name":"UMRS Inserm 1256 nGERE (Nutrition\u2010Genetics\u2010Environmental Risks), Institute of Medical Research (P\u00f4le BMS) University of Lorraine  Nancy France"},{"name":"National Reference Medical Biology Laboratory (LBMR) for Inherited Metabolic Diseases, Biochemistry\u2010Molecular Biology\u2010Nutrition Laboratory University Regional Hospital of Nancy  Nancy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Louis","family":"Gu\u00e9ant","sequence":"additional","affiliation":[{"name":"UMRS Inserm 1256 nGERE (Nutrition\u2010Genetics\u2010Environmental Risks), Institute of Medical Research (P\u00f4le BMS) University of Lorraine  Nancy France"},{"name":"Department of Hepato\u2010Gastroenterology, National Reference Center for Inherited Metabolic Diseases University Regional Hospital of Nancy  Nancy France"},{"name":"Joan Klein Jacobs Center for Precision Nutrition and Health Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409238.2021.1979459"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12009"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12348"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100670"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104911"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010008\u20100839\u20104"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010022\u201000720\u20108"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.11.012"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306\u2010016\u20101094\u20106"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17091555"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9781139854610"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4072"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102796.2011.02494.x"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2023.155738"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12575"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201900282"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.03641"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.104949"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010018\u20100098\u20102"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky992"},{"key":"e_1_2_12_22_1","volume-title":"GeneReviews","author":"Sloan J. 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