{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:03:42Z","timestamp":1792789422466,"version":"4.5.0"},"reference-count":21,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Voa Voa! Amici di Sofia\u2013Onlus patient advocacy organization","award":["cdc 775"],"award-info":[{"award-number":["cdc 775"]}]},{"name":"Fondazione dell\u2019Ospedale Pediatrico Anna Meyer","award":["cdc 775"],"award-info":[{"award-number":["cdc 775"]}]},{"name":"Current Research of the Meyer University Children\u2019s Hospital IRCCS, 2024 of the Italian Ministry of Health","award":["cdc 775"],"award-info":[{"award-number":["cdc 775"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJNS"],"abstract":"<jats:p>Metachromatic leukodystrophy (MLD) is a rare inherited disorder of lysosomal storage, caused by a deficiency in the arylsulfatase A (ARSA) enzyme, leading to toxic accumulation of sulfatides, which progressively impair motor and cognitive function. MLD is a candidate for inclusion in newborn screening (NBS) programs, due to the narrow pre-symptomatic window for effective therapeutic intervention. We set up a prospective pilot NBS program for MLD in Tuscany, based on a two-step approach. The first-tier test quantified four sulfatides; if levels exceeded the cut-off, we performed the second-tier test by measuring ARSA activity on the same neonatal dried blood spot (DBS). We performed the first-tier test on 42,262 newborns over two years and the second-tier test on residual neonatal DBS from 90 of them (0.21%). We recalled 10 newborns (0.02%) for an additional DBS, due to insufficient residual material for a second-tier test (n = 4) or to low ARSA activity (n = 6). We found normal ARSA activity in all new DBS and identified no new cases of MLD. Retrospective analysis of eight neonatal and fifteen non-neonatal DBS from patients with genetically confirmed MLD showed that the algorithm accurately identified MLD patients. This diagnostic algorithm proved feasible and accurate for early detection of MLD in prospective NBS.<\/jats:p>","DOI":"10.3390\/ijns11020030","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T06:18:02Z","timestamp":1745475482000},"page":"30","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Newborn Screening for Metachromatic Leukodystrophy in Tuscany: The Paradigm of a Successful Preventive Medicine Program"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3968-0264","authenticated-orcid":false,"given":"Sabrina","family":"Malvagia","sequence":"first","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Bettiol","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6232-3123","authenticated-orcid":false,"given":"Margherita","family":"Porcaro","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Mura","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Funghini","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Ombrone","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3158-0348","authenticated-orcid":false,"given":"Giulia","family":"Forni","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Scolamiero","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Coppi","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Damiano","sequence":"additional","affiliation":[{"name":"Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Laboratory, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9571-0862","authenticated-orcid":false,"given":"Cristina","family":"Cereda","sequence":"additional","affiliation":[{"name":"Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9675-7965","authenticated-orcid":false,"given":"Simonetta","family":"Simonetti","sequence":"additional","affiliation":[{"name":"Clinical Pathology and Neonatal Screening, Pediatric Hospital Giovanni XXIII, Azienda Ospedaliera Policlinico Giovanni XXIII, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3944-3090","authenticated-orcid":false,"given":"Annalisa","family":"Lonetti","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Daniotti","sequence":"additional","affiliation":[{"name":"Metabolic and Muscular Unit, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-2624","authenticated-orcid":false,"given":"Anna","family":"Caciotti","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics of Neurometabolic Diseases, Neuroscience and Human Genetics Department, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Morrone","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics of Neurometabolic Diseases, Neuroscience and Human Genetics Department, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"},{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Calbi","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7476-4087","authenticated-orcid":false,"given":"Francesca","family":"Fumagalli","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Neurology Unit and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Aiuti","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Medical School, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8534-9951","authenticated-orcid":false,"given":"Elena","family":"Procopio","sequence":"additional","affiliation":[{"name":"Metabolic and Muscular Unit, Meyer Children\u2019s Hospital IRCCS, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug 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