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The exact consequence of accumulating lcFAO\u2010intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO\u2010intermediates and to explore the presence of disease\u2010specific markers, we used tracer\u2010based lipidomics with deuterium\u2010labeled oleic acid (D9\u2010C18:1) in lcFAOD patient\u2010derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease\u2010specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1\u2010carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S\u2010(3\u2010hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3\u2010hydroxyacyl\u2010CoAs. S\u2010(3\u2010hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease\u2010specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.<\/jats:p>","DOI":"10.1096\/fj.202302163r","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T11:10:15Z","timestamp":1708341015000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Tracer\u2010based lipidomics enables the discovery of disease\u2010specific candidate biomarkers in mitochondrial \u03b2\u2010oxidation disorders"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4775-1760","authenticated-orcid":false,"given":"Marit","family":"Schwantje","sequence":"first","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Department of Metabolic Diseases Wilhelmina Children's Hospital, University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-1978","authenticated-orcid":false,"given":"Signe","family":"Mosegaard","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Amsterdam Gastroenterology, Endocrinology, and Metabolism  Amsterdam the Netherlands"},{"name":"Amsterdam Cardiovascular Sciences  Amsterdam the Netherlands"},{"name":"Emma Center for Personalized Medicine Amsterdam UMC  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzan J. 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