{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T18:08:10Z","timestamp":1780078090219,"version":"3.54.0"},"reference-count":21,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013885","name":"Ministry of Health Malaysia","doi-asserted-by":"publisher","award":["NMRR-16-1469-31910"],"award-info":[{"award-number":["NMRR-16-1469-31910"]}],"id":[{"id":"10.13039\/501100013885","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Early detection of mitochondrial disorders remains challenging due to phenotypic heterogeneity and limited access to definitive molecular diagnostics. Circulating biomarkers such as growth differentiation factor-15 (GDF-15) and fibroblast growth factor-21 (FGF-21) have emerged as potential adjunct indicators. This study evaluated the screening and stratification utility of GDF-15 and FGF-21 in individuals assessed for suspected mitochondrial disease. Methods: Archived biological specimens collected between 2016 and 2017 were analysed from 221 individuals stratified into clinically high-risk, screen-positive non-high-risk, post-mortem unexplained death and healthy controls groups. Plasma and fibroblast lysate concentrations of GDF-15 and FGF-21 were quantified using enzyme-linked immunosorbent assays. Biomarker performance was assessed using receiver operating characteristic (ROC) analysis, comparative group analysis and correlation testing across clinically defined referral groups. Results: Both biomarkers were significantly elevated in clinically high-risk and screen-positive individuals compared with controls. GDF-15 demonstrated better discriminatory performance than FGF-21, with an area under the curve (AUC) of 0.7187 \u00b1 0.0556 versus 0.6301 \u00b1 0.0603. At a threshold of 300 pg\/mL, GDF-15 demonstrated high sensitivity with moderate specificity for differentiation between clinically defined high-risk individuals and controls. Correlation analysis showed weak associations between GDF-15 and lactate and ammonia, while FGF-21 correlated modestly with glucose and alkaline phosphatase. A moderate positive correlation was observed between GDF-15 and FGF-21 across the overall cohort. Conclusions: GDF-15 and, to a lesser extent, FGF-21 may support early screening and stratification of individuals evaluated for suspected mitochondrial disease and assist in prioritising cases for further diagnostic evaluation.<\/jats:p>","DOI":"10.3390\/metabo16060372","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:36:18Z","timestamp":1780076178000},"page":"372","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Screening and Stratification Utility of GDF-15 and FGF-21 in Individuals Evaluated for Suspected Mitochondrial Disease: A Malaysian Cohort Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5861-6607","authenticated-orcid":false,"given":"Affandi","family":"Omar","sequence":"first","affiliation":[{"name":"Inborn Errors of Metabolism & Genetics Unit, Nutrition, Metabolic & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No 1, Persiaran Setia Murni U13\/52, Bandar Setia Alam, Shah Alam 40170, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dyg Pertiwi","family":"Abg Kamaludin","sequence":"additional","affiliation":[{"name":"Inborn Errors of Metabolism & Genetics Unit, Nutrition, Metabolic & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No 1, Persiaran Setia Murni U13\/52, Bandar Setia Alam, Shah Alam 40170, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9242-8802","authenticated-orcid":false,"given":"Wan Ahmad Syazani","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Nutrition Unit, Nutrition, Metabolic & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No 1, Persiaran Setia Murni U13\/52, Bandar Setia Alam, Shah Alam 40170, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4797-7655","authenticated-orcid":false,"given":"Fatimah Diana Amin","family":"Nordin","sequence":"additional","affiliation":[{"name":"Inborn Errors of Metabolism & Genetics Unit, Nutrition, Metabolic & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No 1, Persiaran Setia Murni U13\/52, Bandar Setia Alam, Shah Alam 40170, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosnani","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Inborn Errors of Metabolism & Genetics Unit, Nutrition, Metabolic & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No 1, Persiaran Setia Murni U13\/52, Bandar Setia Alam, Shah Alam 40170, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badrul Hisyam","family":"Razali","sequence":"additional","affiliation":[{"name":"Institute of Medical Science Technology, Universiti Kuala Lumpur, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3701-4006","authenticated-orcid":false,"given":"Imilia","family":"Ismail","sequence":"additional","affiliation":[{"name":"School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin (UniSZA), Gong Badak Campus, Kuala Nerus 21300, Terengganu, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngu Lock","family":"Hock","sequence":"additional","affiliation":[{"name":"Genetics Department, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur 50586, Federal Territory of Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7542-2922","authenticated-orcid":false,"given":"Julaina Abdul","family":"Jalil","sequence":"additional","affiliation":[{"name":"Inborn Errors of Metabolism & Genetics Unit, Nutrition, Metabolic & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No 1, Persiaran Setia Murni U13\/52, Bandar Setia Alam, Shah Alam 40170, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/joim.13054","article-title":"Mitochondrial disease in children","volume":"287","author":"Rahman","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Burow, P., Haselier, M., Naegel, S., Scholle, L.M., Gaul, C., and Kraya, T. (2021). The mitochondrial biomarkers FGF-21 and GDF-15 in patients with episodic and chronic migraine. Cells, 10.","DOI":"10.3390\/cells10092471"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/acn3.51104","article-title":"Accuracy of FGF-21 and GDF-15 for the diagnosis of mitochondrial disorders: A meta-analysis","volume":"7","author":"Lin","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e00325","DOI":"10.1016\/j.neurot.2024.e00325","article-title":"Biomarkers of mitochondrial disorders","volume":"21","author":"Shayota","year":"2024","journal-title":"Neurotherapeutics"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Li, Y., Li, S., Qiu, Y., Zhou, M., Chen, M., Hu, Y., Hong, S., Jiang, L., and Guo, Y. (2022). Circulating FGF21 and GDF15 as Biomarkers for Screening, Diagnosis, and Severity Assessment of Primary Mitochondrial Disorders in Children. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.851534"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"36017","DOI":"10.1038\/s41598-025-20005-w","article-title":"Evaluating the utility of growth differentiation factor 15 and fibroblast growth factor 21 as blood biomarkers for Rett syndrome","volume":"15","author":"Hertzog","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Therrell, B.L., Padilla, C.D., Borrajo, G.J.C., Khneisser, I., Schielen, P.C.J.I., Knight-Madden, J., Malherbe, H.L., and Kase, M. (2024). Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020\u20132023). Int. J. Neonatal Screen., 10.","DOI":"10.3390\/ijns10020038"},{"key":"ref_8","first-page":"101094","article-title":"Whole exome sequencing in energy deficiency inborn errors of metabolism: A systematic review","volume":"40","author":"Omar","year":"2024","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1007\/s10545-015-9843-7","article-title":"Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism","volume":"38","author":"Miller","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e066288","DOI":"10.1136\/bmj-2021-066288","article-title":"Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: Cohort study","volume":"375","author":"Schon","year":"2021","journal-title":"BMJ"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.mito.2021.10.007","article-title":"Mitochondrial diseases in South Asia\u2014A systematic review","volume":"62","author":"Hettiarachchi","year":"2022","journal-title":"Mitochondrion"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13023-023-02632-6","article-title":"Mitochondrial diseases in Hong Kong: Prevalence, clinical characteristics and genetic landscape","volume":"18","author":"Wong","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.4103\/0971-5916.154489","article-title":"Mitochondrial disorders: Challenges in diagnosis & treatment","volume":"141","author":"Khan","year":"2015","journal-title":"Indian J. Med. Res."},{"key":"ref_14","first-page":"1","article-title":"Diagnostic Advances for Inborn Errors of Metabolism (IEM) and Screening Interventions in Selected Asian Countries","volume":"6","author":"Olalere","year":"2021","journal-title":"J. Biomed. Clin. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Shafie, A.A., Supian, A., Hassali, M.A.A., Ngu, L.-H., Thong, M.-K., Ayob, H., and Chaiyakunapruk, N. (2020). Rare disease in Malaysia: Challenges and solutions. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0230850"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1212\/WNL.0000000000003374","article-title":"FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)","volume":"87","author":"Lehtonen","year":"2016","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.mito.2021.08.011","article-title":"Serum fibroblast growth factor 21 and growth differentiation factor 15: Two sensitive biomarkers in the diagnosis of mitochondrial disorders","volume":"60","author":"Huddar","year":"2021","journal-title":"Mitochondrion"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lu, H., Wang, X., Li, M., Ji, D., Liang, D., Liang, C., Liu, Y., Zhang, Z., Cao, Y., and Zou, W. (2023). Mitochondrial Unfolded Protein Response and Integrated Stress Response as Promising Therapeutic Targets for Mitochondrial Diseases. Cells, 12.","DOI":"10.3390\/cells12010020"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eabn7105","DOI":"10.1126\/sciadv.abn7105","article-title":"FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction","volume":"8","author":"Croon","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4093\/dmj.2023.0115","article-title":"Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases","volume":"48","author":"Zhang","year":"2024","journal-title":"Diabetes Metab. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.semcdb.2022.02.011","article-title":"Implications of mitochondrial fusion and fission in skeletal muscle mass and health","volume":"143","author":"Romanello","year":"2023","journal-title":"Semin. Cell Dev. Biol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/6\/372\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:57:16Z","timestamp":1780077436000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/6\/372"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":21,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["metabo16060372"],"URL":"https:\/\/doi.org\/10.3390\/metabo16060372","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]}}}