{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:03:59Z","timestamp":1789473839983,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T00:00:00Z","timestamp":1759536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Precision Medicine Laboratory Department, Genome Medicine Center of Excellence, at King Faisal Specialist Hospital and Research Center"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Maple syrup urine disease (MSUD) is a genetic disorder caused by mutations in the branched-chain \u03b1-ketoacid dehydrogenase (BCKDH) complex, leading to toxic buildup of branched-chain amino acids (BCAAs) and their ketoacid derivatives. While newborn screening (NBS) and molecular testing are standard diagnostic tools, they face challenges such as delayed results and false positives. Untargeted metabolomics has emerged as a complementary approach, offering comprehensive metabolic profiling and potential for novel biomarker discovery. We previously applied untargeted metabolomics to neonates with MSUD, identifying distinct metabolic signatures. Objective: This follow-up study investigates metabolic changes and biomarkers in pediatric MSUD patients and explores shared dysregulated metabolites between neonatal and pediatric MSUD. Methods: Dried blood spot (DBS) samples from pediatric MSUD patients (n = 14) and matched healthy controls (n = 14) were analyzed using LC\/MS-based untargeted metabolomics. Results: In pediatric MSUD, 3716 metabolites were upregulated and 4038 downregulated relative to controls. Among 1080 dysregulated endogenous metabolites, notable biomarkers included uric acid, hypoxanthine, and bilirubin diglucuronide. Affected pathways included sphingolipid, glycerophospholipid, purine, pyrimidine, nicotinate, and nicotinamide metabolism, and steroid hormone biosynthesis. Seventy-two metabolites overlapped with neonatal MSUD cases, some exhibiting inverse trends between age groups. Conclusion: Untargeted metabolomics reveals that the metabolic profiling of MCUD pediatric patients different from that of their controls. Also, there are valuable age-specific and shared metabolic alterations in MSUD, enhancing the understanding of disease progression in MSUD patients. This supports its utility in improving diagnostic precision and developing personalized treatment strategies across developmental stages.<\/jats:p>","DOI":"10.3390\/metabo15100658","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T13:33:41Z","timestamp":1759757621000},"page":"658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Insights from Metabolomics Profiling of MSUD in Pediatrics Toward Disease Progression"],"prefix":"10.3390","volume":"15","author":[{"given":"Abeer Z.","family":"Alotaibi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, College of Science, King Saud University, Riyadh 11652, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem H.","family":"AlMalki","sequence":"additional","affiliation":[{"name":"Metabolomics Section, Precision Medicine Laboratory Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3638-8716","authenticated-orcid":false,"given":"Rajaa","family":"Sebaa","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra 11961, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2244-6842","authenticated-orcid":false,"given":"Maha","family":"Al Mogren","sequence":"additional","affiliation":[{"name":"Metabolomics Section, Precision Medicine Laboratory Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Alanazi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Science, King Saud University, Riyadh 11652, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9595-8649","authenticated-orcid":false,"given":"Khalid M.","family":"Sumaily","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Alodaib","sequence":"additional","affiliation":[{"name":"Metabolomics Section, Precision Medicine Laboratory Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-8281","authenticated-orcid":false,"given":"Ahmed H.","family":"Mujamammi","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minnie","family":"Jacob","sequence":"additional","affiliation":[{"name":"Metabolomics Section, Precision Medicine Laboratory Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8266-5177","authenticated-orcid":false,"given":"Essa M.","family":"Sabi","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4222-0952","authenticated-orcid":false,"given":"Ahmad","family":"Alfares","sequence":"additional","affiliation":[{"name":"Metabolomics Section, Precision Medicine Laboratory Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-9424","authenticated-orcid":false,"given":"Anas M.","family":"Abdel Rahman","sequence":"additional","affiliation":[{"name":"Metabolomics Section, Precision Medicine Laboratory Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia"},{"name":"Department of Biochemistry and Molecular Medicine, College of Medicine, AlFaisal University, Riyadh 12846, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dimou, A., Tsimihodimos, V., and Bairaktari, E. 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