{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T22:54:50Z","timestamp":1770591290519,"version":"3.49.0"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T00:00:00Z","timestamp":1634774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["1U54NS115198-01"],"award-info":[{"award-number":["1U54NS115198-01"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["1U54NS115198-01"],"award-info":[{"award-number":["1U54NS115198-01"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Research Foundation - Flanders","doi-asserted-by":"publisher","award":["18B4322N"],"award-info":[{"award-number":["18B4322N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>PMM2-CDG is a rare disease, causing hypoglycosylation of multiple proteins, hence preventing full functionality. So far, no direct genotype\u2013phenotype correlations have been identified. We carried out a retrospective cohort study on 26 PMM2-CDG patients. We collected the identified genotype, as well as continuous variables indicating the disease severity (based on Nijmegen Pediatric CDG Rating Score or NPCRS) and dichotomous variables reflecting the patients\u2019 phenotype. The phenotypic effects of patients\u2019 genotype were studied using non-parametric and Chi-Square tests. Seventeen different pathogenic variants have been studied. Variants with zero enzyme activity had no significant impact on the Nijmegen score. Pathogenic variants involving the stabilization\/folding domain have a significantly lower total NPCRS (p = 0.017): presence of the p.Cys241Ser mutation had a significantly lower subscore 1,3 and NPCRS (p = 0.04) and thus result in a less severe phenotype. On the other hand, variants involving the dimerization domain, p.Pro113Leu and p.Phe119Leu, resulted in a significantly higher NPCRS score (p = 0.002), which indicates a worse clinical course. These concepts give a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base.<\/jats:p>","DOI":"10.3390\/genes12111658","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:22:02Z","timestamp":1634862122000},"page":"1658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Genotype-Phenotype Correlations in PMM2-CDG"],"prefix":"10.3390","volume":"12","author":[{"given":"Laurien","family":"Vaes","sequence":"first","affiliation":[{"name":"Faculty of Medicine, KU Leuven, B3000 Leuven, Belgium"}]},{"given":"Daisy","family":"Rymen","sequence":"additional","affiliation":[{"name":"Center for Metabolic Diseases, Department of Paediatrics, University Hospitals Leuven, B3000 Leuven, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6154-0970","authenticated-orcid":false,"given":"David","family":"Cassiman","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology-Hepatology, University Hospitals Leuven, B3000 Leuven, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5183-3086","authenticated-orcid":false,"given":"Anna","family":"Ligezka","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA"}]},{"given":"Nele","family":"Vanhoutvin","sequence":"additional","affiliation":[{"name":"Center for Metabolic Diseases, Department of Paediatrics, University Hospitals Leuven, B3000 Leuven, Belgium"}]},{"given":"Dulce","family":"Quelhas","sequence":"additional","affiliation":[{"name":"Unidade de Bioqu\u00edmica Gen\u00e9tica, Centro de Gen\u00e9tica M\u00e9dica, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"},{"name":"Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, University of Porto, 4050-313 Porto, Portugal"},{"name":"Centro Refer\u00eancia Doen\u00e7as Heredit\u00e1rias do Metabolismo, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"}]},{"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9264-6153","authenticated-orcid":false,"given":"Peter","family":"Witters","sequence":"additional","affiliation":[{"name":"Center for Metabolic Diseases, Department of Paediatrics, University Hospitals Leuven, B3000 Leuven, Belgium"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1006\/mgme.1999.2914","article-title":"Phosphomannomutase deficiency: The molecular basis of the classical Jaeken syndrome (CDGS type Ia)","volume":"68","author":"Matthijs","year":"1999","journal-title":"Mol. Genet. Metab."},{"key":"ref_2","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J., Stephens, K., Mirzaa, G., and Amemiya, A. (2021, August 15). PMM2-CDG (CDG-Ia), GeneReviews\u00ae [Internet], Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1110\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1203\/00006450-200211000-00003","article-title":"Congenital Disorders of Glycosylation: A Review","volume":"52","author":"Grunewald","year":"2002","journal-title":"Pediatr. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/ng0597-88","article-title":"Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome)","volume":"16","author":"Matthijs","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Citro, V., Cimmaruta, C., Monticelli, M., Riccio, G., Hay Mele, B., Cubellis, M., and Andreotti, G. (2018). The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082218"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.ejmg.2017.10.012","article-title":"Congenital disorders of glycosylation (CDG): Quo vadis?","volume":"61","author":"Foulquier","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"477","DOI":"10.21037\/atm.2018.10.45","article-title":"Congenital disorders of glycosylation","volume":"6","author":"Chang","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/s41436-018-0301-4","article-title":"Long-term follow-up in PMM2-CDG: Are we ready to start treatment trials?","volume":"21","author":"Witters","year":"2018","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/jimd.12024","article-title":"International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up","volume":"42","author":"Altassan","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14918","DOI":"10.1074\/jbc.M601505200","article-title":"The X-ray crystal structures of human alpha-phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a","volume":"281","author":"Silvaggi","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"34900","DOI":"10.1074\/jbc.M114.586362","article-title":"Conformational Response to Ligand Binding in Phosphomannomutase2: Insights into Inborn Glycosylation Disorder","volume":"289","author":"Andreotti","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_12","unstructured":"Cooper, D.N., Ball, E.V., Stenson, P.D., Phillips, A.D., Evans, K., Heywood, S., Hayden, M.J., Chapman, M.M., Mort, M.E., and Azevedo, L. (2021, August 15). Humane Gene Mutation Database (HGMD) [Internet]. Available online: http:\/\/www.hgmd.cf.ac.uk\/ac\/index.Php."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Monticelli, M., Liguori, L., Allocca, M., Andreotti, G., and Cubellis, M.V. (2019). \u03b2-Glucose-1,6-Bisphosphate Stabilizes Pathological Phophomannomutase2 Mutants In Vitro and Represents a Lead Compound to Develop Pharmacological Chaperones for the Most Common Disorder of Glycosylation, PMM2-CDG. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174164"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/sj.ejhg.5200470","article-title":"Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia)","volume":"8","author":"Schollen","year":"2000","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s10545-011-9328-2","article-title":"Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2-CDG): Expression analysis of PMM2-CDG mutations","volume":"34","author":"Vega","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1136\/jmedgenet-2018-105588","article-title":"From gestalt to gene: Early predictive dysmorphic features of PMM2-CDG","volume":"56","author":"Cuadras","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/8904_2011_114","article-title":"Expanding the Spectrum of PMM2-CDG Phenotype","volume":"5","author":"SSIEM","year":"2011","journal-title":"JIMD Reports\u2014Case and Research Reports, 2012\/2 [Internet]"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/ajmg.a.38235","article-title":"Three families with mild PMM2-CDG and normal cognitive development","volume":"173","author":"Vals","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ligezka, A.N., Radenkovic, S., Saraswat, M., Garapati, K., Ranatunga, W., Krzysciak, W., Yanaihara, H., Preston, G., Brucker, W., and McGovern, R.M. (2021, October 15). Sorbitol is a Severity Biomarker for PMM2-CDG with Therapeutic Implications. Available online: https:\/\/onlinelibrary.wiley.com\/doi\/abs\/10.1002\/ana.26245.","DOI":"10.1002\/ana.26245"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1002\/1098-1004(200011)16:5<386::AID-HUMU2>3.0.CO;2-Y","article-title":"Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia)","volume":"16","author":"Matthijs","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1086\/301763","article-title":"Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A","volume":"62","author":"Matthijs","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13023-015-0358-y","article-title":"Phosphomannomutase deficiency (PMM2-CDG): Ataxia and cerebellar assessment","volume":"10","author":"Serrano","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1086\/318199","article-title":"High residual activity of PMM2 in patients\u2019 fibroblasts: Possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency)","volume":"68","author":"Schollen","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1136\/adc.85.3.236","article-title":"Congenital disorder of glycosylation type Ia (CDG-Ia): Phenotypic spectrum of the R141H\/F119L genotype","volume":"85","author":"Kjaergaard","year":"2001","journal-title":"Arch. Dis. Child."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1007\/s10545-011-9325-5","article-title":"Nijmegen paediatric CDG rating scale: A novel tool to assess disease progression","volume":"34","author":"Achouitar","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0014-5793(99)00673-0","article-title":"Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2","volume":"452","author":"Pirard","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_27","unstructured":"Griffiths, A.J.F. (2000). An Introduction to Genetic Analysis, W.H. Freeman. [7th ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Francisco, R., Pascoal, C., Marques-Da-Silva, D., Brasil, S., Pimentel-Santos, F.M., Altassan, R., Jaeken, J., Grosso, A.R., Ferreira, V.D.R., and Videira, P.A. (2020). New Insights into Immunological Involvement in Congenital Disorders of Glycosylation (CDG) from a People-Centric Approach. J. Clin. Med., 9.","DOI":"10.3390\/jcm9072092"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/(SICI)1098-1004(199912)14:6<543::AID-HUMU17>3.0.CO;2-S","article-title":"Characterization of the 415G>A (E139K) PMM2 mutation in carbohydrate-deficient glycoprotein syndrome type Ia disrupting a splicing enhancer resulting in exon 5 skipping","volume":"14","author":"Barnier","year":"1999","journal-title":"Hum. Mutat."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/11\/1658\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:20:08Z","timestamp":1760167208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/11\/1658"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,21]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["genes12111658"],"URL":"https:\/\/doi.org\/10.3390\/genes12111658","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,21]]}}}