Xinying Hong1, Jessica Daiker1, Martin Sadilek1, Nicole Ruiz-Schultz2, Arun Babu Kumar1, Stevie Norcross2, Warunee Dansithong2, Teryn Suhr3, Maria L Escolar4, C Ronald Scott5, Andreas Rohrwasser2, Michael H Gelb6,7. 1. Department of Chemistry, University of Washington, Seattle, WA, USA. 2. Utah Public Health Laboratory, Salt Lake City, UT, USA. 3. MLD Foundation, West Linn, OR, USA. 4. The Program for the Study of Neurodevelopment in Rare Disorders, University of Pittsburgh, Pittsburgh, PA, USA. 5. Department of Pediatrics, University of Washington, Seattle, WA, USA. 6. Department of Chemistry, University of Washington, Seattle, WA, USA. gelb@uw.edu. 7. Department of Biochemistry, University of Washington, Seattle, WA, USA. gelb@uw.edu.
Abstract
PURPOSE: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns. METHODS: To minimize the false-positive rate, a two-tier screening algorithm was designed. The primary test was to quantify C16:0-sulfatide in DBS by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The screening cutoff was established based on the results from 15 MLD newborns to achieve 100% sensitivity. The secondary test was to measure the ARSA activity in DBS from newborns with abnormal C16:0-sulfatide levels. Only newborns that displayed both abnormal C16:0-sulfatide abundance and ARSA activity were considered screen positives. RESULTS: A total of 27,335 newborns were screened using this two-tier algorithm, and 2 high-risk cases were identified. ARSA gene sequencing identified these two high-risk subjects to be a MLD-affected patient and a heterozygote. CONCLUSION: Our study demonstrates that newborn screening for MLD is highly feasible in a real-world scenario with near 100% assay specificity.
PURPOSE: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns. METHODS: To minimize the false-positive rate, a two-tier screening algorithm was designed. The primary test was to quantify C16:0-sulfatide in DBS by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The screening cutoff was established based on the results from 15 MLD newborns to achieve 100% sensitivity. The secondary test was to measure the ARSA activity in DBS from newborns with abnormal C16:0-sulfatide levels. Only newborns that displayed both abnormal C16:0-sulfatide abundance and ARSA activity were considered screen positives. RESULTS: A total of 27,335 newborns were screened using this two-tier algorithm, and 2 high-risk cases were identified. ARSA gene sequencing identified these two high-risk subjects to be a MLD-affected patient and a heterozygote. CONCLUSION: Our study demonstrates that newborn screening for MLD is highly feasible in a real-world scenario with near 100% assay specificity.
Authors: Francyne Kubaski; Zackary M Herbst; Maira Graeff Burin; Kristiane Michelin-Tirelli; Franciele B Trapp; Rejane Gus; Alice B O Netto; Ana Carolina Brusius-Facchin; Sandra Leistner-Segal; Maria Teresa Sanseverino; Carolina Moura Fischinger de Souza; Matheus V M B Wilke; Thiago Oliveira; Jose A A Magalhães; Roberto Giugliani Journal: JIMD Rep Date: 2022-01-19
Authors: Francesca Fumagalli; Valeria Calbi; Maria Grazia Natali Sora; Maria Sessa; Cristina Baldoli; Paola Maria V Rancoita; Francesca Ciotti; Marina Sarzana; Maddalena Fraschini; Alberto Andrea Zambon; Serena Acquati; Daniela Redaelli; Vanessa Attanasio; Simona Miglietta; Fabiola De Mattia; Federica Barzaghi; Francesca Ferrua; Maddalena Migliavacca; Francesca Tucci; Vera Gallo; Ubaldo Del Carro; Sabrina Canale; Ivana Spiga; Laura Lorioli; Salvatore Recupero; Elena Sophia Fratini; Francesco Morena; Paolo Silvani; Maria Rosa Calvi; Marcella Facchini; Sara Locatelli; Ambra Corti; Stefano Zancan; Gigliola Antonioli; Giada Farinelli; Michela Gabaldo; Jesus Garcia-Segovia; Laetitia C Schwab; Gerald F Downey; Massimo Filippi; Maria Pia Cicalese; Sabata Martino; Clelia Di Serio; Fabio Ciceri; Maria Ester Bernardo; Luigi Naldini; Alessandra Biffi; Alessandro Aiuti Journal: Lancet Date: 2022-01-22 Impact factor: 79.321