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While previous transcriptomic studies have uncovered disrupted cellular pathways, the functional consequences of these alterations remain poorly understood. To further investigate PMM2\u2010CDG pathophysiology, we integrated proteomic and metabolomic profiling of patient\u2010derived fibroblasts with previously published transcriptomic data. Proteomic analysis was performed using Tandem Mass Tag\u2010based mass spectrometry, while metabolomics was conducted via Nuclear Magnetic Resonance spectroscopy. Multi\u2010omics integration was performed using principal component analysis\u2013based dimensionality reduction, incorporating clinical metadata as supplementary variables. Proteomic analysis identified 43 significantly altered proteins, with enrichment in the retinoic acid synthesis pathway, wound healing, and cytoskeletal organization. Metabolomic profiling revealed altered amino acid levels and elevated concentrations of UDP\u2010GlcNAc, consistent with perturbation of the hexosamine biosynthesis pathway, and increased levels of\n                    <jats:italic>my<\/jats:italic>\n                    <jats:italic>o<\/jats:italic>\n                    \u2010inositol. Notably,\n                    <jats:italic>myo<\/jats:italic>\n                    \u2010inositol levels showed a strong association with disease severity in the integrated analysis. RT\u2010qPCR confirmed the upregulation of\n                    <jats:italic>GFPT2<\/jats:italic>\n                    . This integrative multi\u2010omics study identifies consistent alterations in the retinoic acid synthesis pathway and hexosamine biosynthesis in PMM2\u2010CDG patient\u2010derived fibroblasts and reveals an association between intracellular\n                    <jats:italic>myo<\/jats:italic>\n                    \u2010inositol levels and disease severity. These findings provide new insights into PMM2\u2010CDG\u2013associated molecular alterations and illustrate the value of multi\u2010omics integration for hypothesis generation in rare diseases.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70233","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:34:56Z","timestamp":1786628096000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Proteo\u2010Metabolomic Profiling of\n                    <scp>PMM2<\/scp>\n                    \u2010\n                    <scp>CDG<\/scp>\n                    Reveals Dysregulation of Retinoic Acid Synthesis,\n                    <i>Myo<\/i>\n                    \u2010Inositol, and the Hexosamine Pathway"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3866-7316","authenticated-orcid":false,"given":"Diana","family":"Gallego","sequence":"first","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares. Centro de Biolog\u00eda Molecular Universidad Aut\u00f3noma de Madrid. CIBERER. IdiPAZ  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1594-0156","authenticated-orcid":false,"given":"Giuseppina","family":"Andreotti","sequence":"additional","affiliation":[{"name":"Institute of Biomolecular Chemistry (ICB) National Research Council of Italy  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3136-2138","authenticated-orcid":false,"given":"Maria","family":"Monticelli","sequence":"additional","affiliation":[{"name":"Institute of Biomolecular Chemistry (ICB) National Research Council of Italy  Naples Italy"},{"name":"UniCamillus \u2010 Saint Camillus International University of Health Sciences  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4526-8353","authenticated-orcid":false,"given":"Debora","family":"Paris","sequence":"additional","affiliation":[{"name":"Institute of Biomolecular Chemistry (ICB) National Research Council of Italy  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo","family":"Mart\u00edn\u2010Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares. Centro de Biolog\u00eda Molecular Universidad Aut\u00f3noma de Madrid. CIBERER. IdiPAZ  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2414-2586","authenticated-orcid":false,"given":"Alejandra","family":"G\u00e1mez","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares. Centro de Biolog\u00eda Molecular Universidad Aut\u00f3noma de Madrid. CIBERER. IdiPAZ  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2056-2428","authenticated-orcid":false,"given":"Mercedes","family":"Serrano","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, Hospital Sant Joan de D\u00e9u Barcelona, Spain and Institut de Recerca Sant Joan de D\u00e9u, CIBERER  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"C\u00f3rdoba\u2010Caballero","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, University of Malaga, 29010, Malaga, Spain. CIBERER. Institute of Biomedical Research in Malaga and Platform of Nanomedicine, IBIMA Plataforma BIONAND, 29071, Malaga, Spain. Spanish National Bioinformatics Institute (INB\/ELIXIR\u2010ES) Instituto de Salud Carlos III (ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3020-1415","authenticated-orcid":false,"given":"Pedro","family":"Seoane","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, University of Malaga, 29010, Malaga, Spain. CIBERER. Institute of Biomedical Research in Malaga and Platform of Nanomedicine, IBIMA Plataforma BIONAND, 29071, Malaga, Spain. Spanish National Bioinformatics Institute (INB\/ELIXIR\u2010ES) Instituto de Salud Carlos III (ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A. G.","family":"Ranea","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, University of Malaga, 29010, Malaga, Spain. CIBERER. 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