{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:35:27Z","timestamp":1760060127285,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Charcot\u2013Marie\u2013Tooth (CMT) is a group of inherited diseases impairing the peripheral nervous system. CMT originates from genetic variants that affect proteins fundamental for the myelination of peripheral nerves and survival. Moreover, environmental and humoral factors can impact disease development and evolution. Currently, no therapy is available. Metabolomics is an emerging field of biomedical research that enables the development of novel biomarkers for neurodegenerative diseases by targeting metabolic pathways or metabolites. This study aimed to evaluate the metabolomics profile of CMT disease by comparing patients with healthy individuals. Methods: A total of 22 CMT patients (CMT) were included in this study and were demographically matched with 26 healthy individuals (C). Serum samples were analyzed through Nuclear Magnetic Resonance spectroscopy, and multivariate and univariate statistical analyses were subsequently applied. Results: A supervised model showed a clear separation (R2X = 0.3; R2Y = 0.7; Q2 = 0.4; p-value = 0.0004) between the two classes of subjects, and nine metabolites were found to be significantly different (2-hydroxybutyrate, 3-hydroxybutyrate, 3-methyl-2-oxovalerate, choline, citrate, glutamate, isoleucine, lysine, and methyl succinate). The combined ROC curve showed an AUC of 0.94 (CI: 0.9\u20131). Additional altered metabolic pathways were also identified within the disease context. Conclusion: This study represents a promising starting point, demonstrating the efficacy of metabolomics in evaluating CMT patients and identifying novel potential disease biomarkers.<\/jats:p>","DOI":"10.3390\/metabo15080520","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T07:49:58Z","timestamp":1754380198000},"page":"520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of the Metabolomics Profile in Charcot\u2013Marie\u2013Tooth (CMT) Patients: Novel Potential Biomarkers"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-9851","authenticated-orcid":false,"given":"Federica","family":"Murgia","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Clinical Metabolomics Unit, University of Cagliari, 09042 Cagliari, Italy"},{"name":"Toxicology Unit, Clinical Pathology and Microbiology Laboratory, S.S. Trinit\u00e0 Hospital, ASL Cagliari, 09121 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7159-3428","authenticated-orcid":false,"given":"Martina","family":"Cadeddu","sequence":"additional","affiliation":[{"name":"School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Frau","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Binaghi Hospital, ASL Cagliari, 09126 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo","family":"Coghe","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Binaghi Hospital, ASL Cagliari, 09126 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2050-2908","authenticated-orcid":false,"given":"Lorefice","family":"Lorena","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Binaghi Hospital, ASL Cagliari, 09126 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Vannelli","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Binaghi Hospital, ASL Cagliari, 09126 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Rita","family":"Murru","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Binaghi Hospital, ASL Cagliari, 09126 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9592-1178","authenticated-orcid":false,"given":"Martina","family":"Spada","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Clinical Metabolomics Unit, University of Cagliari, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3538-0050","authenticated-orcid":false,"given":"Antonio","family":"Noto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Clinical Metabolomics Unit, University of Cagliari, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0606-4959","authenticated-orcid":false,"given":"Luigi","family":"Atzori","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Clinical Metabolomics Unit, University of Cagliari, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Cocco","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Binaghi Hospital, ASL Cagliari, 09126 Cagliari, Italy"},{"name":"Department of Medical Science and Public Health, University of Cagliari, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1529-8027.2011.00324.x","article-title":"Charcot-Marie-Tooth disease","volume":"16","author":"Reilly","year":"2011","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1007\/s10072-017-2905-x","article-title":"Charcot-Marie-Tooth disease: Genetic subtypes in the Sardinian population","volume":"38","author":"Lorefice","year":"2017","journal-title":"Neurol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/S1474-4422(09)70110-3","article-title":"Diagnosis, natural history, and management of Charcot\u2013Marie\u2013Tooth disease","volume":"8","author":"Pareyson","year":"2009","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1136\/jnnp.70.4.548","article-title":"Disability and quality of life in Charcot-Marie-Tooth disease type 1","volume":"70","author":"Pfeiffer","year":"2001","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1111\/j.1469-1809.2007.00412.x","article-title":"Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation","volume":"72","author":"Barisic","year":"2008","journal-title":"Ann. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev.neuro.31.061307.090711","article-title":"Role of axonal transport in neurodegenerative diseases","volume":"31","author":"Grierson","year":"2008","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s11940-005-0003-5","article-title":"Current Therapy for Charcot-Marie-Tooth Disease","volume":"7","author":"Grandis","year":"2005","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pisciotta, C., Saveri, P., and Pareyson, D. (2021). Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives. Brain Sci., 11.","DOI":"10.3390\/brainsci11111447"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e321","DOI":"10.1212\/NXI.0000000000000321","article-title":"Metabolomic signatures associated with disease severity in multiple sclerosis","volume":"4","author":"Villoslada","year":"2017","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.1002\/pmic.200600106","article-title":"Metabolomics: Current technologies and future trends","volume":"17","author":"Hollywood","year":"2006","journal-title":"Proteomics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1177\/1352458515622827","article-title":"Metabolomics in multiple sclerosis","volume":"22","author":"Bhargava","year":"2016","journal-title":"Mult. Scler."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.cmet.2007.10.005","article-title":"Metabolomics","volume":"6","author":"Idle","year":"2007","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.biocel.2017.07.004","article-title":"Metabolomic analysis identifies altered metabolic pathways in Multiple Sclerosis","volume":"93","author":"Poddighe","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Murgia, F., Lorefice, L., Poddighe, S., Fenu, G., Secci, M.A., Marrosu, M.G., Cocco, E., and Atzori, L. (2020). Multi-Platform Characterization of Cerebrospinal Fluid and Serum Metabolome of Patients Affected by Relapsing-Remitting and Primary Progressive Multiple Sclerosis. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030863"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Giudetti, A.M., Guerra, F., Longo, S., Beli, R., Romano, R., Manganelli, F., Nolano, M., Mangini, V., Santoro, L., and Bucci, C. (2020). An altered lipid metabolism characterizes Charcot-Marie-Tooth type 2B peripheral neuropathy. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1865.","DOI":"10.1016\/j.bbalip.2020.158805"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Soldevilla, B., Cuevas-Mart\u00edn, C., Ib\u00e1\u00f1ez, C., Santacatterina, F., Alberti, M.A., Sim\u00f3, C., Casasnovas, C., M\u00e1rquez-Infante, C., Sevilla, T., and Pascual, S.I. (2017). Plasma metabolome and skin proteins in Charcot-Marie-Tooth 1A patients. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178376"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Setlere, S., Schiemer, T., Vaska, A., Gailite, L., Rots, D., Kenina, V., and Klavins, K. (2025). Metabolomics insights into Charcot\u2013Marie\u2013Tooth disease: Toward biomarker discovery. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1543547"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e185","DOI":"10.1212\/NXI.0000000000000185","article-title":"(1)H-NMR analysis provides a metabolomic profile of patients with multiple sclerosis","volume":"3","author":"Cocco","year":"2015","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gagliano, A., Murgia, F., Capodiferro, A.M., Tanca, M.G., Hendren, A., Falqui, S.G., Aresti, M., Comini, M., Carucci, S., and Cocco, E. (2022). 1H-NMR-Based Metabolomics in Autism Spectrum Disorder and Pediatric Acute-Onset Neuropsychiatric Syndrome. J. Clin. Med., 11.","DOI":"10.3390\/jcm11216493"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1007\/s13311-019-00721-8","article-title":"Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by 1H-NMR Spectroscopy","volume":"16","author":"Lorefice","year":"2019","journal-title":"Neurotherapeutics."},{"key":"ref_21","first-page":"109","article-title":"PLS_regression: A basic tool of chemometrics","volume":"58","author":"Wold","year":"2001","journal-title":"J. Chemom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4430","DOI":"10.1021\/ac060209g","article-title":"Targeted profiling: Quantitative analysis of 1H NMR metabolomics data","volume":"78","author":"Weljie","year":"2006","journal-title":"Anal. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14.10.1","DOI":"10.1002\/cpbi.11","article-title":"Using MetaboAnalyst 3.0 for Comprehensive Metabolomics Data Analysis","volume":"55","author":"Xia","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, R.J., Liu, Y., Liu, H.Q., and Li, J. (2020). Ketogenic diets and protective mechanisms in epilepsy, metabolic disorders, cancer, neuronal loss, and muscle and nerve degeneration. J. Food Biochem., 44.","DOI":"10.1111\/jfbc.13140"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.plefa.2003.05.001","article-title":"Ketone body synthesis in the brain: Possible neuroprotective effects","volume":"70","year":"2004","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","article-title":"Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics","volume":"25","author":"Puchalska","year":"2017","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, L., Chen, P., and Xiao, W. (2021). \u03b2-hydroxybutyrate as an Anti-Aging Metabolite. Nutrients, 28.","DOI":"10.3390\/nu13103420"},{"key":"ref_28","first-page":"97","article-title":"Effects of ketone bodies on the brain","volume":"3","author":"Toprak","year":"2022","journal-title":"J. Exp. Basic Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Jensen, N.J., Wodschow, H.Z., Nilsson, M., and Rungby, J. (2020). Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228767"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yang, H., Shan, W., Zhu, F., Wu, J., and Wang, Q. (2019). Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00585"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1097\/FBP.0000000000000505","article-title":"Mitochondrial metabolism: A common link between neuroinflammation and neurodegeneration","volume":"30","author":"Garabadu","year":"2019","journal-title":"Behav. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/978-981-32-9636-7_2","article-title":"Regulatory Mechanism of Peripheral Nerve Myelination by Glutamate-Induced Signaling","volume":"1190","author":"Araki","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1523\/JNEUROSCI.3591-09.2010","article-title":"Proteasomal degradation of glutamine synthetase regulates schwann cell differentiation","volume":"30","author":"Saitoh","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/S0387-7604(03)00071-8","article-title":"2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: Impaired catabolism of isoleucine presenting as neurodegenerative disease","volume":"26","author":"Sass","year":"2004","journal-title":"Brain Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1203\/00006450-200012000-00025","article-title":"Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: A novel inborn error of branched-chain fatty acid and isoleucine metabolism","volume":"48","author":"Zschocke","year":"2000","journal-title":"Pediatr. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/978-3-319-28383-8_21","article-title":"Choline and the Brain: An Epigenetic Perspective","volume":"12","author":"Bekdash","year":"2016","journal-title":"Adv. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.ajhg.2012.09.019","article-title":"Defective presynaptic choline transport underlies hereditary motor neuropathy","volume":"91","author":"Barwick","year":"2012","journal-title":"Am. J. Hum. Genet."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/8\/520\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:21:03Z","timestamp":1760034063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/8\/520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,1]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["metabo15080520"],"URL":"https:\/\/doi.org\/10.3390\/metabo15080520","relation":{},"ISSN":["2218-1989"],"issn-type":[{"type":"electronic","value":"2218-1989"}],"subject":[],"published":{"date-parts":[[2025,8,1]]}}}