{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:23:03Z","timestamp":1789928583950,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,1,21]],"date-time":"2019-01-21T00:00:00Z","timestamp":1548028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic phenotyping is poised as a powerful and promising tool for biomarker discovery in inherited metabolic diseases. However, few studies applied this approach to mcopolysaccharidoses (MPS). Thus, this innovative functional approach may unveil comprehensive impairments in MPS biology. This study explores mcopolysaccharidosis VI (MPS VI) or Maroteaux\u2013Lamy syndrome (OMIM #253200) which is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulfatase B enzyme. Urine samples were collected from 16 MPS VI patients and 66 healthy control individuals. Untargeted metabolomics analysis was applied using ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Furthermore, dermatan sulfate, amino acids, carnitine, and acylcarnitine profiles were quantified using liquid chromatography coupled to tandem mass spectrometry. Univariate analysis and multivariate data modeling were used for integrative analysis and discriminant metabolites selection. Pathway analysis was done to unveil impaired metabolism. The study revealed significant differential biochemical patterns using multivariate data modeling. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS VI. Integrative analysis of targeted and untargeted metabolomics data with in silico results yielded arginine-proline, histidine, and glutathione metabolism being the most affected. This study is one of the first metabolic phenotyping studies of MPS VI. The findings might shed light on molecular understanding of MPS pathophysiology to develop further MPS studies to enhance diagnosis and treatments of this rare condition.<\/jats:p>","DOI":"10.3390\/ijms20020446","type":"journal-article","created":{"date-parts":[[2019,1,22]],"date-time":"2019-01-22T03:08:22Z","timestamp":1548126502000},"page":"446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Analysis of Mucopolysaccharidosis Type VI through Integrative Functional Metabolomics"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8901-2678","authenticated-orcid":false,"given":"Abdellah","family":"Tebani","sequence":"first","affiliation":[{"name":"Department of Metabolic Biochemistry, Rouen University Hospital, 76000 Rouen, France"},{"name":"Normandie University, UNIROUEN, CHU Rouen, INSERM U1245, 76000 Rouen, France"},{"name":"Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenaig","family":"Abily-Donval","sequence":"additional","affiliation":[{"name":"Normandie University, UNIROUEN, CHU Rouen, INSERM U1245, 76000 Rouen, France"},{"name":"Department of Neonatal Pediatrics, Intensive Care and Neuropediatrics, Rouen University Hospital, 76031 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Schmitz-Afonso","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2341-6514","authenticated-orcid":false,"given":"Monique","family":"Piraud","sequence":"additional","affiliation":[{"name":"Service de Biochimie et Biologie Mol\u00e9culaire Grand Est, Unit\u00e9 des Maladies H\u00e9r\u00e9ditaires du M\u00e9tabolisme et D\u00e9pistage N\u00e9onatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69002 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Ausseil","sequence":"additional","affiliation":[{"name":"INSERM U1088, Laboratoire de Biochimie M\u00e9tabolique, Centre de Biologie Humaine, CHU Sud, 80054 Amiens CEDEX, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid","family":"Zerimech","sequence":"additional","affiliation":[{"name":"Laboratoire de Biochimie et Biologie Mol\u00e9culaire, Universit\u00e9 de Lille et P\u00f4le de Biologie Pathologie G\u00e9n\u00e9tique du CHRU de Lille, 59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Pilon","sequence":"additional","affiliation":[{"name":"Department of Metabolic Biochemistry, Rouen University Hospital, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-0314","authenticated-orcid":false,"given":"Tony","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Rouen University Hospital, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Marret","sequence":"additional","affiliation":[{"name":"Normandie University, UNIROUEN, CHU Rouen, INSERM U1245, 76000 Rouen, France"},{"name":"Department of Neonatal Pediatrics, Intensive Care and Neuropediatrics, Rouen University Hospital, 76031 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2406-5664","authenticated-orcid":false,"given":"Carlos","family":"Afonso","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumeya","family":"Bekri","sequence":"additional","affiliation":[{"name":"Department of Metabolic Biochemistry, Rouen University Hospital, 76000 Rouen, France"},{"name":"Normandie University, UNIROUEN, CHU Rouen, INSERM U1245, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1080\/23808993.2016.1273067","article-title":"The role of metabolomics in precision medicine","volume":"1","author":"Bekri","year":"2016","journal-title":"Expert Rev. Precis. Med. Drug Dev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tebani, A., Afonso, C., Marret, S., and Bekri, S. (2016). Omics-based strategies in precision medicine: Toward a paradigm shift in inborn errors of metabolism investigations. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091555"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1080\/004982599238047","article-title":"\u2018Metabonomics\u2019: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological nmr spectroscopic data","volume":"29","author":"Nicholson","year":"1999","journal-title":"Xenobiotica Fate Foreign Compd. Biol. Syst."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1023\/A:1013713905833","article-title":"Metabolomics\u2014The link between genotypes and phenotypes","volume":"48","author":"Fiehn","year":"2002","journal-title":"Plant Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tebani, A., Abily-Donval, L., Afonso, C., Marret, S., and Bekri, S. (2016). Clinical metabolomics: The new metabolic window for inborn errors of metabolism investigations in the post-genomic era. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071167"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.cca.2014.05.024","article-title":"High-throughput tandem mass spectrometry multiplex analysis for newborn urinary screening of creatine synthesis and transport disorders, triple h syndrome and otc deficiency","volume":"436","author":"Maranda","year":"2014","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_7","first-page":"19","article-title":"Principles and applications of liquid chromatography-mass spectrometry in clinical biochemistry","volume":"30","author":"Pitt","year":"2009","journal-title":"Clin. Biochem. Rev. Aust. Assoc. Clin. Biochem."},{"key":"ref_8","first-page":"57","article-title":"Newborn screening","volume":"31","author":"Pitt","year":"2010","journal-title":"Clin. Biochem. Rev. Aust. Assoc. Clin. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1093\/clinchem\/48.11.1970","article-title":"Comprehensive screening of urine samples for inborn errors of metabolism by electrospray tandem mass spectrometry","volume":"48","author":"Pitt","year":"2002","journal-title":"Clin. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1373\/clinchem.2012.189936","article-title":"High-throughput assay of 9 lysosomal enzymes for newborn screening","volume":"59","author":"Spacil","year":"2013","journal-title":"Clin. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1053\/j.semperi.2015.03.002","article-title":"Current status of newborn screening worldwide: 2015","volume":"39","author":"Therrell","year":"2015","journal-title":"Semin. Perinatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s10545-017-0080-0","article-title":"Advances in metabolome information retrieval: Turning chemistry into biology. Part ii: Biological information recovery","volume":"41","author":"Tebani","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10545-017-0074-y","article-title":"Advances in metabolome information retrieval: Turning chemistry into biology. Part i: Analytical chemistry of the metabolome","volume":"41","author":"Tebani","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.bbamcr.2008.12.001","article-title":"Lysosomal disorders: From storage to cellular damage","volume":"1793","author":"Ballabio","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1136\/adc.72.3.263","article-title":"The mucopolysaccharidoses: A clinical review and guide to management","volume":"72","author":"Wraith","year":"1995","journal-title":"Arch. Dis. Child."},{"key":"ref_16","unstructured":"Scrive, C., Ballabio, A., Sly, W., and Vaele, D. (2001). The mucopolysaccharidoses. The Metabolic and Molecular Basis of Inherited Disease, Mc Graw-Hill."},{"key":"ref_17","first-page":"111","article-title":"Pregnancy in patients with mucopolysaccharidosis: A case series","volume":"8","author":"Stewart","year":"2016","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1136\/jmedgenet-2015-103322","article-title":"Clinical course of sly syndrome (mucopolysaccharidosis type vii)","volume":"53","author":"Montano","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1146\/annurev-med-122313-085916","article-title":"Lysosomal storage diseases: From pathophysiology to therapy","volume":"66","author":"Parenti","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"ref_20","first-page":"1849","article-title":"A new dysostosis with urinary elimination of chondroitin sulfate b","volume":"71","author":"Maroteaux","year":"1963","journal-title":"La Presse Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"v4","DOI":"10.1093\/rheumatology\/ker394","article-title":"Overview of the mucopolysaccharidoses","volume":"50","author":"Muenzer","year":"2011","journal-title":"Rheumatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1750-1172-5-5","article-title":"Mucopolysaccharidosis vi","volume":"5","author":"Valayannopoulos","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s10545-011-9410-9","article-title":"Design, baseline characteristics, and early findings of the MPS VI (mucopolysaccharidosis vi) clinical surveillance program (csp)","volume":"36","author":"Hendriksz","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-662-44863-2","article-title":"Growth charts for individuals with mucopolysaccharidosis vi (maroteaux\u2013lamy syndrome)","volume":"Volume 18","author":"Zschocke","year":"2015","journal-title":"JIMD Reports"},{"key":"ref_25","first-page":"71","article-title":"Difficulties in diagnosing slowly progressive mucopolysaccharidosis vi: A case series","volume":"3","author":"Scarpa","year":"2010","journal-title":"J. Pediatr. Rehabil. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ymgme.2017.03.008","article-title":"The effect of galsulfase enzyme replacement therapy on the growth of patients with mucopolysaccharidosis vi (maroteaux-lamy syndrome)","volume":"122","author":"Harmatz","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_27","first-page":"69","article-title":"Enzyme replacement therapy attenuates disease progression in two japanese siblings with mucopolysaccharidosis type vi: 10-year follow up","volume":"13","author":"Furujo","year":"2017","journal-title":"Mol. Genet. Metab Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/1750-1172-8-134","article-title":"Haploidentical stem cell transplantation in two children with mucopolysaccharidosis vi: Clinical and biochemical outcome","volume":"8","author":"Jester","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ymgme.2015.08.001","article-title":"Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network","volume":"117","author":"Salazar","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R119","DOI":"10.1093\/hmg\/ddy155","article-title":"The pathogenesis of lysosomal storage disorders: Beyond the engorgement of lysosomes to abnormal development and neuroinflammation","volume":"27","author":"Fiorenza","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1242\/dev.083691","article-title":"Roles for hedgehog signaling in adult organ homeostasis and repair","volume":"141","author":"Petrova","year":"2014","journal-title":"Development"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16420","DOI":"10.1073\/pnas.1310097110","article-title":"Structural insights into proteoglycan-shaped hedgehog signaling","volume":"110","author":"Whalen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44391","DOI":"10.1074\/jbc.M111.285361","article-title":"Two distinct sites in sonic hedgehog combine for heparan sulfate interactions and cell signaling functions","volume":"286","author":"Chang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cca.2017.01.007","article-title":"Oxidative damage and redox in lysosomal storage disorders: Biochemical markers","volume":"466","author":"Donida","year":"2017","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cca.2017.09.024","article-title":"Urinary metabolic phenotyping of mucopolysaccharidosis type i combining untargeted and targeted strategies with data modeling","volume":"475","author":"Tebani","year":"2017","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1186\/s12967-018-1625-1","article-title":"Unveiling metabolic remodeling in mucopolysaccharidosis type iii through integrative metabolomics and pathway analysis","volume":"16","author":"Tebani","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.cca.2018.02.022","article-title":"Serum metabolomics study in a group of parkinson\u2019s disease patients from northern india","volume":"480","author":"Gupta","year":"2018","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.mam.2011.10.009","article-title":"Neuroprotective features of carnosine in oxidative driven diseases","volume":"32","author":"Bellia","year":"2011","journal-title":"Mol. Aspects Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4701275","DOI":"10.1155\/2018\/4701275","article-title":"Till death do us part: The marriage of autophagy and apoptosis","volume":"2018","author":"Cooper","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_40","first-page":"46","article-title":"Oxidative profile exhibited by mucopolysaccharidosis type iva patients at diagnosis: Increased keratan urinary levels","volume":"11","author":"Donida","year":"2017","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1021\/ac503715v","article-title":"Ion mobility-derived collision cross section as an additional measure for lipid fingerprinting and identification","volume":"87","author":"Paglia","year":"2015","journal-title":"Anal. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.aca.2016.06.054","article-title":"Uplc-ms\/ms detection of disaccharides derived from glycosaminoglycans as biomarkers of mucopolysaccharidoses","volume":"936","author":"Lavoie","year":"2016","journal-title":"Anal. Chim. Acta"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s11306-016-1026-5","article-title":"Normalization and integration of large-scale metabolomics data using support vector regression","volume":"12","author":"Shen","year":"2016","journal-title":"Metabolomics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/cem.2581","article-title":"A chemometrics toolbox based on projections and latent variables","volume":"28","author":"Eriksson","year":"2014","journal-title":"J. Chemom."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/cem.1187","article-title":"Cv-anova for significance testing of pls and opls\u00ae models","volume":"22","author":"Eriksson","year":"2008","journal-title":"J. Chemom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for rna-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1148\/radiology.143.1.7063747","article-title":"The meaning and use of the area under a receiver operating characteristic (roc) curve","volume":"143","author":"Hanley","year":"1982","journal-title":"Radiology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/cem.2627","article-title":"Variable influence on projection (vip) for orthogonal projections to latent structures (opls)","volume":"28","author":"Eriksson","year":"2014","journal-title":"J. Chemom."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1093\/bioinformatics\/btx140","article-title":"Metccs predictor: A web server for predicting collision cross-section values of metabolites in ion mobility-mass spectrometry based metabolomics","volume":"33","author":"Zhou","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Li, S., Park, Y., Duraisingham, S., Strobel, F.H., Khan, N., Soltow, Q.A., Jones, D.P., and Pulendran, B. (2013). Predicting network activity from high throughput metabolomics. PLoS Comput. Biol., 9.","DOI":"10.1371\/journal.pcbi.1003123"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"W251","DOI":"10.1093\/nar\/gkv380","article-title":"Metaboanalyst 3.0-making metabolomics more meaningful","volume":"43","author":"Xia","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.matbio.2018.02.019","article-title":"A role for proteoglycans in vascular disease","volume":"71\u201372","author":"Wight","year":"2018","journal-title":"Matrix Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/2\/446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:27:35Z","timestamp":1760185655000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/2\/446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,21]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,1]]}},"alternative-id":["ijms20020446"],"URL":"https:\/\/doi.org\/10.3390\/ijms20020446","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,21]]}}}