{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:03:07Z","timestamp":1790352187155,"version":"4.1.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100030560","name":"Rose Fund","doi-asserted-by":"publisher","award":["U54 NS115198"],"award-info":[{"award-number":["U54 NS115198"]}],"id":[{"id":"10.13039\/100030560","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The most common congenital disorder of glycosylation (CDG) worldwide is phosphomannomutase 2\u200e (PMM2)-CDG, which presents with a highly variable, multisystem clinical spectrum that poses challenges for diagnosis and prognosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>We performed N-glycomics analysis on plasma and 3 plasma fractions: affinity-purified transferrin, IgG, and a triple-depleted fraction in which IgG, transferrin, and albumin were removed. A total of 103 samples from 71 PMM2-CDG patients were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Three major glycosylation abnormalities were identified in PMM2-CDG: (a) increases in intermediate glycans derived from high-mannose glycan assembly; (b) decreases in mature\/processed multi-antennary N-glycans; and (c) abnormal fucosylation and branching. Total plasma N-glycan analysis demonstrated high clinical sensitivity and specificity, with increased Man3GlcNAc2 (Man3)\/Man4\u20136, Man3\/8\u20139, and Man5\/8 ratios detected in all patients. Novel PMM2-CDG diagnostic biomarkers were also identified from this study, including increased Man4GlcNAc2 linkage isomers in plasma and novel hybrid glycans in the transferrin fraction. When correlated with the Nijmegen Progression CDG Rating Scale (NPCRS) in a diverse cohort age &amp;gt;2 years (n = 39; NPCRS 10\u201340), 11 glycans and 10 glycan ratios from total plasma and plasma fractions showed significant associations, providing strong candidates for use as disease biomarkers for PMM2-CDG.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified 35 plasma N-glycan biomarkers in a large cohort of patients with PMM2-CDG, identifying key glycans and glycan ratios that correlate with clinical severity. Utilizing fractionated N-glycan profiling enhanced these clinical correlations, demonstrating their strong prognostic value and promising application as surrogate biomarkers in clinical trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/clinchem\/hvag116","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:21:06Z","timestamp":1786706466000},"source":"Crossref","is-referenced-by-count":0,"title":["Biomarker Discovery for PMM2-CDG Using Fractionated N-Glycomics Analysis"],"prefix":"10.1093","author":[{"given":"Earnest J P","family":"Daniel","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C","family":"Edmondson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics and Genomics, The Children's Hospital of Philadelphia , Philadelphia, PA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Genetic and Genomic Medicine, Icahn School of Medicine at Mount Sinai , New York, NY ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Freeman","sequence":"additional","affiliation":[{"name":"Genetic and Genomic Medicine, Icahn School of Medicine at Mount Sinai , New York, NY ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayden","family":"Vreugdenhill","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, WA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seishu","family":"Horikoshi","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, WA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4705-6434","authenticated-orcid":false,"given":"Christina","family":"Lam","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, WA ,","place":["United States"]},{"name":"Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine , Seattle, WA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin H J","family":"Kemperman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6808-631X","authenticated-orcid":false,"given":"Stephen R","family":"Master","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudson H","family":"Freeze","sequence":"additional","affiliation":[{"name":"Sanford Children\u2019s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute , La Jolla, CA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6333-0918","authenticated-orcid":false,"given":"Miao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"2026092511101697500_hvag116-B1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1373\/clinchem.2015.243279","article-title":"A novel N-tetrasaccharide in patients with congenital disorders of glycosylation, including asparagine-ainked glycosylation protein 1, phosphomannomutase 2, and mannose phosphate isomerase deficiencies","volume":"62","author":"Zhang","year":"2016","journal-title":"Clin 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ALG3-CDG","volume":"47","author":"Daniel","year":"2024","journal-title":"J Inherit Metab Dis"},{"key":"2026092511101697500_hvag116-B5","author":"Edmondson"},{"key":"2026092511101697500_hvag116-B6","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1002\/jimd.12589","article-title":"Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association","volume":"46","author":"Alharbi","year":"2023","journal-title":"J Inherit Metab Dis"},{"key":"2026092511101697500_hvag116-B7","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1002\/jimd.12367","article-title":"Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG","volume":"44","author":"Alsharhan","year":"2021","journal-title":"J Inherit Metab Dis"},{"key":"2026092511101697500_hvag116-B8","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.ymgme.2022.04.002","article-title":"Patient-reported outcomes and quality of life in PMM2-CDG","volume":"136","author":"Ligezka","year":"2022","journal-title":"Mol Genet Metab"},{"key":"2026092511101697500_hvag116-B9","first-page":"55","article-title":"ALG9-CDG: new clinical case and review of the literature","volume":"13","author":"Davis","year":"2017","journal-title":"Mol Genet Metab Rep"},{"key":"2026092511101697500_hvag116-B10","doi-asserted-by":"crossref","first-page":"1363558","DOI":"10.3389\/fgene.2024.1363558","article-title":"Case report: novel genotype of ALG2-CDG and confirmation of the heptasaccharide glycan (NeuAc-Gal-GlcNAc-Man2-GlcNAc2) as a specific diagnostic biomarker","volume":"15","author":"Mart\u00ednez Duncker","year":"2024","journal-title":"Front Genet"},{"key":"2026092511101697500_hvag116-B11","doi-asserted-by":"crossref","first-page":"100882","DOI":"10.1016\/j.mam.2020.100882","article-title":"Structural and functional diversity of neutrophil glycosylation in innate immunity and related disorders","volume":"79","author":"Ugonotti","year":"2021","journal-title":"Mol Aspects Med"},{"key":"2026092511101697500_hvag116-B12","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ab.2013.07.037","article-title":"Serum N-glycan and O-glycan analysis by mass spectrometry for diagnosis of congenital disorders of glycosylation","volume":"442","author":"Xia","year":"2013","journal-title":"Anal Biochem"},{"key":"2026092511101697500_hvag116-B13","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1093\/clinchem\/hvac012","article-title":"A 6-month-old infant with severe failure to thrive during COVID-19 pandemic","volume":"68","author":"Hong","year":"2022","journal-title":"Clin Chem"},{"key":"2026092511101697500_hvag116-B14","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1074\/mcp.M116.066746","article-title":"Paucimannose-rich N-glycosylation of spatiotemporally regulated human neutrophil elastase modulates its immune functions","volume":"16","author":"Loke","year":"2017","journal-title":"Mol Cell Proteomics"},{"key":"2026092511101697500_hvag116-B15","doi-asserted-by":"crossref","first-page":"108531","DOI":"10.1016\/j.ymgme.2024.108531","article-title":"In vitro treatment with liposome-encapsulated mannose-1-phosphate restores N-glycosylation in PMM2-CDG patient-derived fibroblasts","volume":"143","author":"Shirakura","year":"2024","journal-title":"Mol Genet Metab"},{"key":"2026092511101697500_hvag116-B16","first-page":"e70043","article-title":"Treatment of single patient with PMM2-congenital disorder of glycosylation with govorestat (AT-007), an aldose reductase inhibitor","volume":"66","author":"Jalazo","year":"2025","journal-title":"J Inherit Metab Dis Rep"},{"key":"2026092511101697500_hvag116-B17","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/imr.13407","article-title":"The importance of IgG glycosylation-what did we learn after analyzing over 100,000 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