{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T15:42:05Z","timestamp":1787326925894,"version":"build-2736575974"},"reference-count":22,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016062","name":"Metakids","doi-asserted-by":"publisher","award":["2024-104"],"award-info":[{"award-number":["2024-104"]}],"id":[{"id":"10.13039\/100016062","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024-104"],"award-info":[{"award-number":["2024-104"]}],"id":[{"id":"https:\/\/ror.org\/028jnma48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Neonatal Screen.","IJNS"],"abstract":"<jats:p>Since October 2019, screening for methylmalonic acidemia (MMA) has been implemented in the Dutch Newborn Screening (NBS) program. Since implementation, most referrals for MMA have been the result of (maternal) vitamin B12 deficiency. Although vitamin B12 deficiency is an important condition and early detection can confer health benefits, its identification was not the original objective of the screening. We therefore examined whether genetic forms of MMA can be distinguished from acquired forms. Early distinction between these forms is essential for guiding clinical management, informing prognosis, and enabling appropriate genetic counseling. Specifically, we tested whether the use of Collaborative Laboratory Integrated Reports (CLIR) to complement NBS results improved specificity of the test for genetic MMAs. We found that with the use of CLIR, genetic conditions including methylmalonyl-CoA mutase (mut) deficiency and cobalamin (cbl) A, B, C and D deficiency can be partially differentiated from acquired causes. This results in a significant reduction in the number of second-tier tests required. However, this approach may also exclude certain other genetic causes. Based on all findings, we provide considerations and implications for MMA screening that may inform decision-makers in (other) NBS programs.<\/jats:p>","DOI":"10.3390\/ijns12030069","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:20:36Z","timestamp":1787322036000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Refining MMA Screening in the Dutch Newborn Screening Program: Lessons from Vitamin B12 Deficiency and Genetic Cases"],"prefix":"10.3390","volume":"12","author":[{"given":"Nils W. F.","family":"Meijer","sequence":"first","affiliation":[{"name":"Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4027-9723","authenticated-orcid":false,"given":"Klaas","family":"Koop","sequence":"additional","affiliation":[{"name":"Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose E.","family":"Maase","sequence":"additional","affiliation":[{"name":"Reference Laboratory for Neonatal Screening, Center for Health Protection, National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia L.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter F.","family":"Visser","sequence":"additional","affiliation":[{"name":"Reference Laboratory for Neonatal Screening, Center for Health Protection, National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda","family":"Oussoren","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5027-5916","authenticated-orcid":false,"given":"Annet M.","family":"Bosch","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases, Department of Pediatrics, Emma Children\u2019s Hospital, Amsterdam Gastroenterology Endocrinology and Metabolism, University of Amsterdam, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-0770","authenticated-orcid":false,"given":"M. Rebecca","family":"Heiner-Fokkema","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3033-4397","authenticated-orcid":false,"given":"Monique G. M.","family":"de Sain-van der Velden","sequence":"additional","affiliation":[{"name":"Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41390-024-03687-2","article-title":"Mutation spectrum and genotype-phenotype correlation of pediatric patients with methylmalonic acidemia","volume":"98","author":"Lu","year":"2025","journal-title":"Pediatr. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1515\/jpem-2022-0340","article-title":"Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns","volume":"35","year":"2022","journal-title":"J. Pediatr. Endocrinol. 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