{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:44:03Z","timestamp":1773078243454,"version":"3.50.1"},"reference-count":15,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\u2019s National Center for Advancing Translational Sciences","award":["UM1TR004405"],"award-info":[{"award-number":["UM1TR004405"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJNS"],"abstract":"<jats:p>Mucopolysaccharidosis type I (MPS I) results in the accumulation of glycosaminoglycans (GAG) and, for the purposes of newborn screening, is differentiated into two forms: severe (Hurler syndrome) versus attenuated (encompassing Scheie and Hurler-Scheie syndromes). MPS I was added to the federal Recommended Uniform Screening Panel for newborn screening (NBS) in 2016, and as of December 2025, 45 of 54 programs in the United States (US) screen for MPS I. Within the newborn screening program, a second-tier analysis of GAG is thought to reduce false-positive rates, particularly through mitigating the detection of pseudodeficiency. However, there have been some concerns that the use of second-tier GAG analysis might inadvertently result in missed detection of attenuated cases. A survey of all US NBS programs was conducted requesting data on the total number of screen-positive NBS results for MPS I as well as the final diagnostic outcome from these results. Diagnostic outcomes after screening were classified as false-positive, pseudodeficiency, severe MPS I, attenuated MPS I, and MPS I of undetermined phenotype. Additionally, information on testing methodologies and dates of MPS I NBS implementation was collected. Responses were obtained from 32 NBS programs. The cohort of screening programs utilizing second-tier blood spot GAG determinations detected a higher proportion of severe cases than those not using this second-tier test (48% vs. 29%). The proportion of attenuated cases remained consistent between both groups (13% vs. 14%). The proportion of pseudodeficiency detection was only slightly lower in the cohort using second-tier GAG analysis (85% vs. 91%). Second-tier GAG analysis appears to reduce the detection of false-positive cases and improves the resolution of severe MPS I cases, though the proportion of pseudodeficiency was only slightly lower compared to the programs that do not use second-tier GAG analysis. Currently, the proportion of attenuated cases is comparable between the two cohorts, but the higher number of \u201cundetermined phenotype\u201d cases may eventually shift the balance toward states not using GAG analysis once the type is determined.<\/jats:p>","DOI":"10.3390\/ijns12010015","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:48:56Z","timestamp":1772542136000},"page":"15","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Detection: Comparing State-Based Newborn Screening Methods for Effective Mucopolysaccharidosis I Diagnosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Rithika","family":"Thampy","sequence":"first","affiliation":[{"name":"Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76706, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2943-2136","authenticated-orcid":false,"given":"Nishitha R.","family":"Pillai","sequence":"additional","affiliation":[{"name":"Advanced Therapies Program, Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7449-3993","authenticated-orcid":false,"given":"Michael","family":"Evans","sequence":"additional","affiliation":[{"name":"Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8895-6485","authenticated-orcid":false,"given":"Chester B.","family":"Whitley","sequence":"additional","affiliation":[{"name":"Advanced Therapies Program, Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9426-1292","authenticated-orcid":false,"given":"Paul J.","family":"Orchard","sequence":"additional","affiliation":[{"name":"Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1701-5052","authenticated-orcid":false,"given":"Matthew","family":"Ellinwood","sequence":"additional","affiliation":[{"name":"National MPS Society USA, P.O. Box 14686, Durham, NC 27709-4686, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7598-3820","authenticated-orcid":false,"given":"Amy","family":"Gaviglio","sequence":"additional","affiliation":[{"name":"Connetics Consulting, LLC., Minneapolis, MN 55417, USA"},{"name":"Association of Public Health Laboratories, 7700 Wisconsin Avenue, Suite 1000, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). GeneReviews(\u00ae), University of Washington."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/ajmg.1320460222","article-title":"Long-term outcome of Hurler syndrome following bone marrow transplantation","volume":"46","author":"Whitley","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6023","DOI":"10.1182\/bloodadvances.2022007212","article-title":"Hematopoietic stem cell transplant for Hurler syndrome: Does using bone marrow or umbilical cord blood make a difference?","volume":"6","author":"Orchard","year":"2022","journal-title":"Blood Adv."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ojodu, J., Singh, S., Kellar-Guenther, Y., Yusuf, C., Jones, E., Wood, T., Baker, M., and Sontag, M.K. (2018). NewSTEPs: The Establishment of a National Newborn Screening Technical Assistance Resource Center. Int. J. Neonatal Screen., 4.","DOI":"10.3390\/ijns4010001"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hall, P.L., Sanchez, R., Hagar, A.F., Jerris, S.C., Wittenauer, A., and Wilcox, W.R. (2020). Two-Tiered Newborn Screening with Post-Analytical Tools for Pompe Disease and Mucopolysaccharidosis Type I Results in Performance Improvement and Future Direction. Int. J. Neonatal Screen., 6.","DOI":"10.3390\/ijns6010002"},{"key":"ref_6","first-page":"75","article-title":"Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency","volume":"58","author":"Aronovich","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Herbst, Z.M., Urdaneta, L., Klein, T., Burton, B.K., Basheeruddin, K., Liao, H.-C., Fuller, M., and Gelb, M.H. (2022). Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis Type II. Int. J. Neonatal Screen., 8.","DOI":"10.3390\/ijns8010009"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1002\/ajmg.a.61930","article-title":"Mucopolysaccharidosis type I newborn screening: Importance of second tier testing for ethnically diverse populations","volume":"185","author":"Bosfield","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e63940","DOI":"10.1002\/ajmg.a.63940","article-title":"Long-Term Health Outcomes of Individuals With Pseudodeficiency Alleles in IDUA May Inform Newborn Screening Practices for Mucopolysaccharidosis Type I","volume":"197","author":"Grady","year":"2025","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Herbst, Z.M., Urdaneta, L., Klein, T., Fuller, M., and Gelb, M.H. (2020). Evaluation of Multiple Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis-I. Int. J. Neonatal Screen., 6.","DOI":"10.3390\/ijns6030069"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s10545-009-9036-3","article-title":"Dermatan sulfate and heparan sulfate as a biomarker for mucopolysaccharidosis I","volume":"33","author":"Tomatsu","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Peck, D.S., Lacey, J.M., White, A.L., Pino, G., Studinski, A.L., Fisher, R., Ahmad, A., Spencer, L., Viall, S., and Shallow, N. (2020). Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I. Int. J. Neonatal Screen., 6.","DOI":"10.3390\/ijns6010010"},{"key":"ref_13","first-page":"103","article-title":"Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment","volume":"5","author":"Hendriksz","year":"2015","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108612","DOI":"10.1016\/j.ymgme.2024.108612","article-title":"High precision newborn screening for mucopolysaccharidosis type I by enzymatic activity followed by endogenous, non-reducing end glycosaminoglycan analysis","volume":"144","author":"Herbst","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107685","DOI":"10.1016\/j.ymgme.2023.107685","article-title":"Endogenous, non-reducing end glycosaminoglycan biomarkers for the mucopolysaccharidoses: Accurate diagnosis and elimination of false positive newborn screening results","volume":"140","author":"Saville","year":"2023","journal-title":"Mol. Genet. Metab."}],"container-title":["International Journal of Neonatal Screening"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2409-515X\/12\/1\/15\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:54:25Z","timestamp":1773053665000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2409-515X\/12\/1\/15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":15,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijns12010015"],"URL":"https:\/\/doi.org\/10.3390\/ijns12010015","relation":{},"ISSN":["2409-515X"],"issn-type":[{"value":"2409-515X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]}}}