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This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of <jats:sup>13<\/jats:sup>C\u2010propionate (exhaled <jats:sup>13<\/jats:sup>CO<jats:sub>2<\/jats:sub>), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.<\/jats:p>","DOI":"10.1002\/jimd.12478","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T16:37:54Z","timestamp":1642437474000},"page":"132-143","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Biomarkers for drug development in propionic and methylmalonic acidemias"],"prefix":"10.1002","volume":"45","author":[{"given":"Nicola","family":"Longo","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn Oliver","family":"Sass","sequence":"additional","affiliation":[{"name":"Research Group Inborn Errors of Metabolism, Department of Natural Sciences &amp; Institute for Functional Gene Analytics (IFGA) 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