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A total of 213 biosamples (urine, plasma, and CSF) from 153 treatment-na\u00efve patients with SMA across five German centers were analyzed using 1H-NMR spectroscopy. Prediction models were developed using machine learning algorithms which enabled the patients with SMA to be grouped according to disease severity. A quantitative enrichment analysis was employed to identify metabolic pathways associated with disease progression. The results demonstrate high sensitivity (84\u201391%) and specificity (91\u201394%) in distinguishing treatment-na\u00efve patients with SMA from controls across all biofluids. The urinary and plasma profiles differentiated between early-onset (type I) and later-onset (type II\/III) SMA with over 80% accuracy. Key metabolic differences involved alterations in energy and amino acid metabolism. This study suggests that 1H-NMR spectroscopy based metabolic profiling may be a promising, non-invasive tool to identify patients with SMA and for severity stratification, potentially complementing current diagnostic and prognostic strategies in SMA management.<\/jats:p>","DOI":"10.3390\/ijms252212123","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T05:21:59Z","timestamp":1731388919000},"page":"12123","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of Biochemical Determinants for Diagnosis and Prediction of Severity in 5q Spinal Muscular Atrophy Using 1H-Nuclear Magnetic Resonance Metabolic Profiling in Patient-Derived Biofluids"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4119-7519","authenticated-orcid":false,"given":"Afshin","family":"Saffari","sequence":"first","affiliation":[{"name":"Division of Child Neurology and Metabolic Medicine, Department of Pediatrics I, Center for Pediatrics and Adolescent Medicine, Medical Faculty Heidelberg, University Hospital Heidelberg, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2873-0032","authenticated-orcid":false,"given":"Moritz","family":"Niesert","sequence":"additional","affiliation":[{"name":"Department of Pediatrics I, Center for Pediatrics and Adolescent Medicine, Medical Faculty Heidelberg, University Hospital Heidelberg, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Cannet","sequence":"additional","affiliation":[{"name":"Bruker BioSpin GmbH & Co. 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Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3233\/JND-180315","article-title":"Evaluation of Children with SMA Type 1 Under Treatment with Nusinersen within the Expanded Access Program in Germany","volume":"5","author":"Pechmann","year":"2018","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1038\/s41591-022-01867-3","article-title":"Onasemnogene Abeparvovec for Presymptomatic Infants with Three Copies of SMN2 at Risk for Spinal Muscular Atrophy: The Phase III SPR1NT Trial","volume":"28","author":"Strauss","year":"2022","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"503","DOI":"10.3233\/JND-190428","article-title":"One Year of Newborn Screening for SMA\u2014Results of a German Pilot Project","volume":"6","author":"Vill","year":"2019","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s13023-021-01783-8","article-title":"Newborn Screening for Spinal Muscular Atrophy in Germany: Clinical Results after 2 Years","volume":"16","author":"Vill","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1001\/jamapediatrics.2024.0492","article-title":"Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy: A Nonrandomized Controlled Trial","volume":"178","author":"Schwartz","year":"2024","journal-title":"JAMA Pediatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"597","DOI":"10.3233\/JND-221510","article-title":"Newborn Screening for SMA\u2014Can a Wait-and-See Strategy Be Responsibly Justified in Patients with Four SMN2 Copies?","volume":"9","author":"Blaschek","year":"2022","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.expneurol.2003.07.008","article-title":"Counting Motor Units in Chronic Motor Neuropathies","volume":"184","author":"Bromberg","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1002\/mus.1128","article-title":"Depletion and Sizes of Motor Units in Spinal Muscular Atrophy","volume":"24","author":"Galea","year":"2001","journal-title":"Muscle Nerve"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1002\/ana.25101","article-title":"Natural History of Infantile-Onset Spinal Muscular Atrophy","volume":"82","author":"Kolb","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1212\/01.wnl.0000252934.70676.ab","article-title":"Preclinical Validation of a Multiplex Real-Time Assay to Quantify SMN MRNA in Patients with SMA","volume":"68","author":"Simard","year":"2007","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1212\/01.wnl.0000201929.56928.13","article-title":"SMN MRNA and Protein Levels in Peripheral Blood: Biomarkers for SMA Clinical Trials","volume":"66","author":"Sumner","year":"2006","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chabanon, A., Seferian, A.M., Daron, A., Pereon, Y., Cances, C., Vuillerot, C., De Waele, L., Cuisset, J.M., Laugel, V., and Schara, U. (2018). Prospective and Longitudinal Natural History Study of Patients with Type 2 and 3 Spinal Muscular Atrophy: Baseline Data NatHis-SMA Study. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201004"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e921","DOI":"10.1212\/WNL.0000000000008762","article-title":"Serum Creatinine Is a Biomarker of Progressive Denervation in Spinal Muscular Atrophy","volume":"94","author":"Alves","year":"2020","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/mus.26995","article-title":"Whole Blood Survival Motor Neuron Protein Levels Correlate with Severity of Denervation in Spinal Muscular Atrophy","volume":"62","author":"Alves","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/acn3.779","article-title":"Neurofilament as a Potential Biomarker for Spinal Muscular Atrophy","volume":"6","author":"Darras","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1186\/s13023-021-02075-x","article-title":"1H-NMR-Based Metabolic Profiling Identifies Non-Invasive Diagnostic and Predictive Urinary Fingerprints in 5q Spinal Muscular Atrophy","volume":"16","author":"Saffari","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3233\/JND-190468","article-title":"Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2","volume":"7","author":"Glascock","year":"2020","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_25","first-page":"114","article-title":"270th ENMC International Workshop: Consensus for SMN2 Genetic Analysis in SMA Patients","volume":"34","author":"Abiusia","year":"2024","journal-title":"Neuromuscul. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Dosi, C., and Masson, R. (2024). The Impact of Three SMN2 Gene Copies on Clinical Characteristics and Effect of Disease-Modifying Treatment in Patients with Spinal Muscular Atrophy: A Systematic Literature Review. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1308296"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41436-020-00987-w","article-title":"CMAP Changes upon Symptom Onset and during Treatment in Spinal Muscular Atrophy Patients: Lessons Learned from Newborn Screening","volume":"23","author":"Weng","year":"2021","journal-title":"Genet. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104937","DOI":"10.1016\/j.earlhumdev.2019.104937","article-title":"Neuromuscular Maturation in the Neonate: Combined Electroneurographic and Ultrasonographic Study","volume":"141","author":"Lori","year":"2020","journal-title":"Early Hum. Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pnmrs.2017.01.001","article-title":"Beyond the Paradigm: Combining Mass Spectrometry and Nuclear Magnetic Resonance for Metabolomics","volume":"100","author":"Marshall","year":"2017","journal-title":"Prog. Nucl. Magn. Reson. Spectrosc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1021\/ac504075g","article-title":"NMR Spectroscopy for Metabolomics and Metabolic Profiling","volume":"87","author":"Larive","year":"2015","journal-title":"Anal. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wishart, D.S., Cheng, L.L., Copi\u00e9, V., Edison, A.S., Eghbalnia, H.R., Hoch, J.C., Gouveia, G.J., Pathmasiri, W., Powers, R., and Schock, T.B. (2022). NMR and Metabolomics\u2014A Roadmap for the Future. Metabolites, 12.","DOI":"10.3390\/metabo12080678"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lu, Y., Pang, Z., and Xia, J. (2023). Comprehensive Investigation of Pathway Enrichment Methods for Functional Interpretation of LC-MS Global Metabolomics Data. Brief. Bioinform., 24.","DOI":"10.1093\/bib\/bbac553"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Tissue-Based Map of the Human Proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tapken, I., Schweitzer, T., Paganin, M., Sch\u00fcning, T., Detering, N.T., Sharma, G., Niesert, M., Saffari, A., Kuhn, D., and Glynn, A. (2024). The Systemic Complexity of a Monogenic Disease: The Molecular Network of Spinal Muscular Atrophy. Brain, online ahead of print.","DOI":"10.1093\/brain\/awae272"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/ana.23582","article-title":"Glucose Metabolism and Pancreatic Defects in Spinal Muscular Atrophy","volume":"72","author":"Bowerman","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.nmd.2021.02.002","article-title":"Glucose and Lipid Metabolism Disorders in Children and Adolescents with Spinal Muscular Atrophy Types 2 and 3","volume":"31","author":"Djordjevic","year":"2021","journal-title":"Neuromuscul. Disord."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Errico, F., Marino, C., Grimaldi, M., Nuzzo, T., Bassareo, V., Valsecchi, V., Panicucci, C., Di Schiavi, E., Mazza, T., and Bruno, C. (2022). Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy. Biomolecules, 12.","DOI":"10.3390\/biom12101431"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1586\/14789450.2015.1094380","article-title":"Physiological Conditions Can Be Reflected in Human Urine Proteome and Metabolome","volume":"12","author":"Wu","year":"2015","journal-title":"Expert Rev. Proteom."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Deutsch, L., Osredkar, D., Plavec, J., and Stres, B. (2021). Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort. Metabolites, 11.","DOI":"10.3390\/metabo11040206"},{"key":"ref_40","unstructured":"Federal Institute for Drugs and Medical Devices (BfArM), on behalf of the Federal Ministry of Health (BMG), and ICD Working Group of the Board of Trustees for Questions of Classification in Health Care (KKG) (2022). ICD-10-GM: International Statistical Classification of Diseases and Related Health Problems, Federal Institute for Drugs and Medical Devices (BfArM)."},{"key":"ref_41","unstructured":"(2016). Molecular In Vitro Diagnostic Examinations\u2014Specivifaction for Pre-examination Processes for Metabolomics in Urine, Venous Blood Serum and Plasma (Standard No. CEN\/TS 16945:2016)."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9887","DOI":"10.1021\/ac5025039","article-title":"Precision High-Throughput Proton NMR Spectroscopy of Human Urine, Serum, and Plasma for Large-Scale Metabolic Phenotyping","volume":"86","author":"Dona","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Berezhnoy, G., Laske, C., and Trautwein, C. (2023). Metabolomic Profiling of CSF and Blood Serum Elucidates General and Sex-Specific Patterns for Mild Cognitive Impairment and Alzheimer\u2019s Disease Patients. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1219718"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1021\/ja055336t","article-title":"Measuring Protein Concentrations by NMR Spectroscopy","volume":"128","author":"Wider","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1073\/pnas.0705685105","article-title":"Evidence of Different Metabolic Phenotypes in Humans","volume":"105","author":"Assfalg","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4264","DOI":"10.1021\/pr900344m","article-title":"Individual Human Phenotypes in Metabolic Space and Time","volume":"8","author":"Bernini","year":"2009","journal-title":"J. Proteome Res."},{"key":"ref_47","first-page":"14.10.1","article-title":"Metabolomic Data Processing, Analysis, and Interpretation Using MetaboAnalyst","volume":"14","author":"Xia","year":"2011","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12505","DOI":"10.1021\/acs.analchem.3c02246","article-title":"Differential Correlations Informed Metabolite Set Enrichment Analysis to Decipher Metabolic Heterogeneity of Disease","volume":"95","author":"Lin","year":"2023","journal-title":"Anal. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/bioinformatics\/btg382","article-title":"A Global Test for Groups of Genes: Testing Association with a Clinical Outcome","volume":"20","author":"Goeman","year":"2004","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/12123\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:30:34Z","timestamp":1760113834000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/12123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,12]]},"references-count":49,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252212123"],"URL":"https:\/\/doi.org\/10.3390\/ijms252212123","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,12]]}}}