Newborn Screening for Lysosomal Storage Diseases: A Concise Review of the Literature on Screening Methods, Therapeutic Possibilities and Regional Programs
Abstract
:1. Introduction
2. What Are Lysosomal Storage Diseases
3. Treatments for LSDs in Place and under Development
3.1. Enzyme Replacement Therapy (ERT)
3.2. Hematopoietic Stem Cell Transplantation (HSCT)
3.3. Substrate Reduction Therapy (SRT)
3.4. Gene Therapy
4. Measuring Lysosomal Enzymatic Activities and Biomarkers in DBS
5. Large Scale Pilot Studies of Newborn Screening of LSDs in DBS by Direct Enzymatic Activity Measurement Using MS/MS or Fluorimetry
6. Additional Comparison of MS/MS and Fluorimetric Methods for LSD Newborn Screening
7. Biomarkers for LSDs
8. Status of LSDs in Current Screening Programs
9. Conclusions
Author Contributions
Conflicts of Interest
References
- Parenti, G.; Andria, G.; Ballabio, A. Lysosomal storage diseases: From pathophysiology to therapy. Annu. Rev. Med. 2015, 66, 471–486. [Google Scholar] [CrossRef] [PubMed]
- Boustany, R.M. Lysosomal storage diseases—The horizon expands. Nat. Rev. Neurol. 2013, 9, 583–598. [Google Scholar] [CrossRef] [PubMed]
- Kingma, S.D.; Bodamer, O.A.; Wijburg, F.A. Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening. Best Pract. Res. Clin. Endocrinol. Metab. 2015, 29, 145–157. [Google Scholar] [CrossRef] [PubMed]
- Kelly, J.M.; Bradbury, A.; Martin, D.R.; Byrne, M.E. Emerging therapies for neuropathic lysosomal storage disorders. Prog. Neurobiol. 2016. [Google Scholar] [CrossRef] [PubMed]
- Lachmann, R.H. Enzyme replacement therapy for lysosomal storage diseases. Curr. Opin. Pediatr. 2011, 23, 588–593. [Google Scholar] [CrossRef] [PubMed]
- Wyatt, K.; Henley, W.; Anderson, L.; Anderson, R.; Nikolaou, V.; Stein, K.; Klinger, L.; Hughes, D.; Waldek, S.; Lachmann, R.; et al. The effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: A longitudinal cohort study of people with lysosomal storage disorders. Health Technol. Assess. 2012, 16, 1–543. [Google Scholar] [CrossRef] [PubMed]
- Munoz-Rojas, M.V.; Vieira, T.; Costa, R.; Fagondes, S.; John, A.; Jardim, L.B.; Vedolin, L.M.; Raymundo, M.; Dickson, P.I.; Kakkis, E.; et al. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am. J. Med. Genet. A 2008, 146, 2538–2544. [Google Scholar] [CrossRef] [PubMed]
- Muenzer, J.; Hendriksz, C.J.; Fan, Z.; Vijayaraghavan, S.; Perry, V.; Santra, S.; Solanki, G.A.; Mascelli, M.A.; Pan, L.; Wang, N.; et al. A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. Genet. Med. 2016, 18, 73–81. [Google Scholar] [CrossRef] [PubMed]
- Aldenhoven, M.; Jones, S.A.; Bonney, D.; Borrill, R.E.; Coussons, M.; Mercer, J.; Bierings, M.B.; Versluys, B.; van Hasselt, P.M.; Wijburg, F.A.; et al. Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: Results after implementation of international guidelines. Biol. Blood Marrow Transplant. 2015, 21, 1106–1109. [Google Scholar] [CrossRef] [PubMed]
- Biffi, A.; Montini, E.; Lorioli, L.; Cesani, M.; Fumagalli, F.; Plati, T.; Baldoli, C.; Martino, S.; Calabria, A.; Canale, S.; et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013, 341, 1233158. [Google Scholar] [CrossRef] [PubMed]
- Wasserstein, M.P.; Andriola, M.; Arnold, G.; Aron, A.; Duffner, P.; Erbe, R.W.; Escolar, M.L.; Estrella, L.; Galvin-Parton, P.; Iglesias, A.; et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet. Med. 2016, 18, 1235–1243. [Google Scholar] [CrossRef] [PubMed]
- Chamoles, N.A.; Blanco, M.; Gaggioli, D. Fabry disease: Enzymatic diagnosis in DBS on filter paper. Clin. Chim. Acta 2001, 308, 195–196. [Google Scholar] [CrossRef]
- Chamoles, N.A.; Niizawa, G.; Blanco, M.; Gaggioli, D.; Casentini, C. Glycogen storage disease type II: Enzymatic screening in DBS on filter paper. Clin. Chim. Acta 2004, 347, 97–102. [Google Scholar] [CrossRef] [PubMed]
- Niizawa, G.; Levin, C.; Aranda, C.; Blanco, M.; Chamoles, N.A. Retrospective diagnosis of glycogen storage disease type II by use of a newborn-screening card. Clin. Chim. Acta 2005, 359, 205–206. [Google Scholar] [CrossRef] [PubMed]
- Civallero, G.; Michelin, K.; de Mari, J.; Viapiana, M.; Burin, M.; Coelho, J.C.; Giugliani, R. Twelve different enzyme assays on dried-blood filter paper samples for detection of patients with selected inherited lysosomal storage diseases. Clin. Chim. Acta 2006, 372, 98–102. [Google Scholar] [CrossRef] [PubMed]
- Campos, D.; Monaga, M.; González, E.C.; Herrera, D. Identification of mucopolysaccharidosis I heterozygotes based on biochemical characteristics of L-iduronidase from DBS. Clin. Chim. Acta 2014, 430, 24–27. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Eadala, B.; Sadilek, M.; Chamoles, N.A.; Turecek, F.; Scott, C.R.; Gelb, M.H. Tandem mass spectrometric analysis of DBS for screening of mucopolysaccharidosis I in newborns. Clin. Chem. 2005, 51, 898–900. [Google Scholar] [CrossRef] [PubMed]
- Gelb, M.H.; Turecek, F.; Scott, C.R.; Chamoles, N.A. Direct multiplex assay of enzymes in DBS by tandem mass spectrometry for the newborn screening of lysosomal storage disorders. J. Inherit. Metab. Dis. 2006, 29, 397–404. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.K.; Elbin, C.S.; Chuang, W.L.; Cooper, S.K.; Marashio, C.A.; Beauregard, C.; Keutzer, J.M. Multiplex enzyme assay screening of DBS for lysosomal storage disorders by using tandem mass spectrometry. Clin. Chem. 2008, 54, 1725–1728. [Google Scholar] [CrossRef] [PubMed]
- Chennamaneni, N.K.; Kumar, A.B.; Barcenas, M.; Spáčil, Z.; Scott, C.R.; Tureček, F.; Gelb, M.H. Improved reagents for newborn screening of mucopolysaccharidosis types I, II, and VI by tandem mass spectrometry. Anal. Chem. 2014, 86, 4508–4514. [Google Scholar] [CrossRef] [PubMed]
- Kumar, A.B.; Masi, S.; Ghomashchi, F.; Chennamaneni, N.K.; Ito, M.; Scott, C.R.; Turecek, F.; Gelb, M.H.; Spacil, Z. Tandem mass spectrometry has a larger analytical range than fluorescence assays of lysosomal enzymes: Application to newborn screening and diagnosis of mucopolysaccharidoses types II, IVa, and VI. Clin. Chem. 2015, 61, 1363–1371. [Google Scholar] [CrossRef] [PubMed]
- Elliott, S.; Buroker, N.; Cournoyer, J.J.; Potier, A.M.; Trometer, J.D.; Elbin, C.; Schermer, M.J.; Kantola, J.; Boyce, A.; Turecek, F.; et al. Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry. Mol. Genet. Metab. 2016, 118, 304–309. [Google Scholar] [CrossRef] [PubMed]
- Brand, G.D.; Matos, H.C.; Cruz, G.C.; Fontes Ndo, C.; Buzzi, M.; Brum, J.M. Diagnosing lysosomal storage diseases in a Brazilian non-newborn population by tandem mass spectrometry. Clinics 2013, 68, 1469–1473. [Google Scholar] [CrossRef] [PubMed]
- Spada, M.; Pagliardini, S.; Yasuda, M.; Tukel, T.; Thiagarajan, G.; Sakuraba, H.; Ponzone, A.; Desnick, R.J. High incidence of later-onset fabry disease revealed by newborn screening. Am. J. Hum. Genet. 2006, 79, 31–40. [Google Scholar] [CrossRef] [PubMed]
- Lin, S.P.; Lin, H.Y.; Wang, T.J.; Chang, C.Y.; Lin, C.H.; Huang, S.F.; Tsai, C.C.; Liu, H.L.; Keutzer, J.; Chuang, C.K. A pilot newborn screening program for Mucopolysaccharidosis type I in Taiwan. Orphanet J. Rare Dis. 2013, 8, 147. [Google Scholar] [CrossRef] [PubMed]
- Mechtler, T.P.; Stary, S.; Metz, T.F.; De Jesús, V.R.; Greber-Platzer, S.; Pollak, A.; Herkner, K.R.; Streubel, B.; Kasper, D.C. Neonatal screening for lysosomal storage disorders: Feasibility and incidence from a nationwide study in Austria. Lancet 2012, 379, 335–341. [Google Scholar] [CrossRef]
- Paciotti, S.; Persichetti, E.; Pagliardini, S.; Deganuto, M.; Rosano, C.; Balducci, C.; Codini, M.; Filocamo, M.; Menghini, A.R.; Pagliardini, V.; et al. First pilot newborn screening for four lysosomal storage diseases in an Italian region: Identification and analysis of a putative causative mutation in the GBA gene. Clin. Chim. Acta 2012, 413, 1827–1831. [Google Scholar] [CrossRef] [PubMed]
- Scott, C.R.; Elliott, S.; Buroker, N.; Thomas, L.I.; Keutzer, J.; Glass, M.; Gelb, M.H.; Turecek, F. Identification of infants at risk for developing Fabry, Pompe, or mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry. J. Pediatr. 2013, 163, 498–503. [Google Scholar] [CrossRef] [PubMed]
- Whittmann, J.; Karg, E.; Turi, S.; Legnini, E.; Wittmann, G.; Giese, A.K.; Lukas, J.; Gölnitz, U.; Klingenhäger, M.; Bodamer, O.; et al. Newborn screening for lysosomal storage disorders in Hungary. JIMD Rep. 2012, 6, 117–125. [Google Scholar]
- Chiang, S.C.; Hwu, W.L.; Lee, N.C.; Hsu, L.W.; Chien, Y.H. Algorithm for Pompe disease newborn screening: Results from the Taiwan screening program. Mol. Genet. Metab. 2012, 106, 281–286. [Google Scholar] [CrossRef] [PubMed]
- Chien, Y.H.; Chiang, S.C.; Zhang, X.K.; Keutzer, J.; Lee, N.C.; Huang, A.C.; Chen, C.A.; Wu, M.H.; Huang, P.H.; Tsai, F.J.; et al. Early detection of Pompe disease by newborn screening is feasible: Results from the Taiwan screening program. Pediatrics 2008, 122, e39–e45. [Google Scholar] [CrossRef] [PubMed]
- Gelb, M.H.; Scott, C.R.; Turecek, F. Newborn screening for lysosomal storage diseases. Clin. Chem. 2015, 61, 335–346. [Google Scholar] [CrossRef] [PubMed]
- Tan, M.A.; Dean, C.J.; Hopwood, J.J.; Meikle, P.J. Diagnosis of metachromatic leukodystrophy by immune quantification of arylsulphatase A protein and activity in dried blood spots. Clin. Chem. 2008, 54, 1925–1927. [Google Scholar]
- Spacil, Z.; Babu Kumar, A.; Liao, H.C.; Auray-Blais, C.; Stark, S.; Suhr, T.R.; Scott, C.R.; Turecek, F.; Gelb, M.H. Sulfatide Analysis by Mass Spectrometry for Screening of Metachromatic Leukodystrophy in Dried Blood and Urine Samples. Clin. Chem. 2015, 62, 279–286. [Google Scholar] [CrossRef] [PubMed]
- Leinekugel, P.; Michel, S.; Conzelmann, E.; Sandhoff, K. Quantitative correlation between the residual activity of beta-hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease. Hum. Genet. 1992, 8, 513–523. [Google Scholar] [CrossRef]
- Li, Y.; Scott, C.R.; Chamoles, N.A.; Ghavami, A.; Pinto, B.M.; Turecek, F.; Gelb, M.H. Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem. 2004, 50, 1785–1796. [Google Scholar] [CrossRef] [PubMed]
- Hopkins, P.V.; Campbell, C.; Klug, T.; Rogers, S.; Raburn-Miller, J.; Kiesling, J. Lysosomal storage disorder screening implementation: Findings from the first six months of full population pilot testing in Missouri. J. Pediatr. 2015, 166, 172–177. [Google Scholar] [CrossRef] [PubMed]
- Hopkins, P. Updates from Missouri NBS Program, 2015 Lysosomal Storage Disorders (LSDs) Workshop. Available online: http://www.aphl.org/aphlprograms/newborn-screening-and-genetics/Pages/2015-LSDs-Workshop.aspx (accessed on 21 December 2015).
- CLIR Database. Available online: https://clir.mayo.edu (accessed on 21 January 2017).
- Sevier, D.; Matern, D. Kentucky. Presentation at the 2016 Hunter’s Hope Symposium. 2016. Available online: http://www.huntershope.org/site/DocServer/2016_Medical_Symposium_Agenda_FINAL.pdf?docID=18404 (accessed on 21 January 2017).
- Ghomashchi, F.; Barcenas, M.; Turecek, F.; Scott, C.R.; Gelb, M.H. Reliable Assay of Acid Sphingomyelinase Deficiency with the Mutation Q292K by Tandem Mass Spectrometry. Clin. Chem. 2015, 61, 771–772. [Google Scholar] [CrossRef] [PubMed]
- Harzer, K.; Rolfs, A.; Bauer, P.; Zschiesche, M.; Mengel, E.; Backes, J.; Kustermann-Kuhn, B.; Bruchelt, G.; van Diggelen, O.P.; Mayrhofer, H.; et al. Niemann–Pick disease type A and B are clinically but also enzymatically heterogeneous: Pitfall in the laboratory diagnosis of sphingomyelinase deficiency associated with the mutation Q292 K. Neuropediatrics 2003, 34, 301–306. [Google Scholar] [PubMed]
- An, Y.; Young, S.P.; Hillman, S.L.; van Hove, J.L.; Chen, Y.T.; Millington, D.S. Liquid chromatographic assay for a glucose tetrasaccharide, a putative biomarker for the diagnosis of pompe disease. Anal. Biochem. 2000, 287, 136–143. [Google Scholar] [CrossRef] [PubMed]
- Groener, J.E.M.; Poorthuis, B.J.H.M.; Kuiper, S.; Hollak, C.E.M.; Aerts, J.M.F.G. Plasma glucosylceramide and ceramide in type 1 Gaucher disease patients: Correlations with disease severity and response to therapeutic intervention. Biochim. Biophys. Acta 2008, 1781, 72–78. [Google Scholar] [CrossRef] [PubMed]
- Rolfs, A.; Giese, A.K.; Grittner, U.; Mascher, D.; Elstein, D.; Zimran, A.; Böttcher, T.; Lukas, J.; Hübner, R.; Gölnitz, U.; et al. Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in gaucher disease in a non-jewish, caucasian cohort of gaucher disease patients. PLoS ONE 2013, 8, e79732. [Google Scholar] [CrossRef] [PubMed]
- Chuang, W.L.; Pacheco, J.; Zhang, X.K.; Martin, M.M.; Biski, C.K.; Keutzer, J.M.; Wenger, D.A.; Caggana, M.; Orsini, J.J., Jr. Determination of psychosine concentration in dried blood spots from newborns that were identified via newborn screening to be at risk for krabbe disease. Clin. Chim. Acta 2013, 18, 73–76. [Google Scholar] [CrossRef] [PubMed]
- Turgeon, C.T.; Orsini, J.J.; Sanders, K.A.; Magera, M.J.; Langan, T.J.; Escolar, M.L.; Duffner, P.; Oglesbee, D.; Gavrilov, D.; Tortorelli, S.; et al. Measurement of psychosine in dried blood spots--a possible improvement to newborn screening programs for Krabbe disease. J. Inherit. Metab. Dis. 2015, 38, 923–929. [Google Scholar] [CrossRef] [PubMed]
- Chuang, W.L.; Pacheco, J.; Cooper, S.; McGovern, M.M.; Cox, G.F.; Keutzer, J.; Zhang, X.K. Lyso-sphingomyelin is elevated in dried blood spots of Niemann–Pick B patients. Mol. Genet. Metabol. 2014, 11, 209–211. [Google Scholar] [CrossRef] [PubMed]
- Jiang, X.; Sidhu, R.; Mydock-McGrane, L.; Hsu, F.F.; Covey, D.F.; Scherrer, D.E.; Earley, B.; Gale, S.E.; Farhat, N.Y.; Porter, F.D.; et al. Development of a bile acid-based newborn screen for Niemann–Pick disease type C. Sci. Transl. Med. 2016, 8, 337ra63. [Google Scholar] [CrossRef] [PubMed]
- De Ruijter, J.; de Ru, M.H.; Wagemans, T.; Ijlst, L.; Lund, A.M.; Orchard, P.J.; Schaefer, G.B.; Wijburg, F.A.; van Vlies, N. Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III. Mol. Genet. Metab. 2012, 107, 705–710. [Google Scholar] [CrossRef] [PubMed]
- Tomatsu, S.; Fujii, T.; Fukushi, M.; Oguma, T.; Shiada, T.; Maeda, M.; Kida, K.; Shibata, Y.; Futatsumori, H.; Montaño, A.M.; et al. Newborn screening and diagnosis of mucopolysaccharidoses. Mol. Genet. Metabol. 2013, 110, 42–53. [Google Scholar] [CrossRef] [PubMed]
- Lawrence, R.; Brown, E.; Lowry, F.; Dickson, P.I.; Crawford, B.E.; Esko, J.D. Glycan-based biomarkers for mucopolysaccharidoses. Mol. Genet. Metabol. 2014, 111, 73–83. [Google Scholar] [CrossRef] [PubMed]
- Kubaski, F.; Mason, R.W.; Nakatomi, A.; Shintaku, H.; Xie, L.; van Vlies, N.N.; Church, H.; Giugliani, R.; Kobayashi, H.; Yamaguchi, S.; et al. Newborn screening for mucopolysaccharidoses: A pilot study of measurement of glycosaminoglycans by tandem mass spectrometry. J. Inherit. Metab. Dis. 2017, 40, 151–158. [Google Scholar] [CrossRef] [PubMed]
- Orsini, J.J.; Kay, D.M.; Saavedra-Matiz, C.A.; Wenger, D.A.; Duffner, P.K.; Erbe, R.W.; Biski, C.; Martin, M.; Krein, L.M.; Nichols, M.; et al. Newborn screening for Krabbe disease in New York State: The first eight years’ experience. Genet. Med. 2016, 18, 239–248. [Google Scholar] [CrossRef] [PubMed]
- Liao, H.-C.; Chan, M.-J.; Yang, C.-F.; Chiang, C.-C.; Ming, D.-N.; Huang, C.-K.; Gelb, M.H. Mass spectrometry but not fluorimetry distinguishes affected and pseudodeficienies in newborn screening for pompe disease. Clin. Chem. 2017, in press. [Google Scholar]
- Health Council of the Netherlands. Neonatal Screening: New Recommendations; Health Council of the Netherlands: The Hague, The Netherlands, 2015. [Google Scholar]
- The UK NSC Recommendation on Mucopolysaccharidosis Type I. Available online: http://legacy.screening.nhs.uk/mps1 (accessed on 21 June 2016).
- Boucher, A.A.; Miller, W.; Shanley, R.; Ziegler, R.; Lund, T.; Raymond, G.; Orchard, P.J. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: The largest single-institution cohort report. Orphanet. J. Rare Dis. 2015, 7, 94. [Google Scholar] [CrossRef] [PubMed]
LSD | Number of Screen Positives per 100,000 Newborns | |||
---|---|---|---|---|
WA MS/MS 3-Plex [28] | WA MS/MS 6-Plex [22] | NY MS/MS 2-Plex * | MO DMF-Fluor. 4-Plex [38] | |
Pompe | 16 | 20 | 21 | 48 |
MPS-I | 8 | 13.6 | no data | 29 |
Fabry | 15 | 18 | no data | 63 |
Gaucher | no data | 6.8 | no data | 11.4 |
Krabbe | no data | 25 | 19 | no data |
Niemann–Pick-A/B | no data | 11.4 | no data | no data |
LSD | Incidence (According to Orphanet) | Enzyme | Method of Detection | Biomarkers in Second-Tier Testing or Follow Up Testing | Therapeutic Possibilities | Pilot (P)- or Routine (R) Screening 1 |
---|---|---|---|---|---|---|
Pompe | 1 in 40,000 2 | acid alpha-1,4-glucosidase | MS/MS, fluorimetry | glucose tetramer, creatine kinase | ERT | R: Taiwan, MO, NY, OH, KY, IL P: Austria 3, NJ, WA |
Hurler/Scheie (MPS-1) | 1–9 in 1,000,000 | alpha-l-iduronidase | MS/MS, fluorimetry | heparan sulphate, dermatan sulphate 4 | ERT, HSCT | R; Taiwan, MO, NY, KY, IL P: NJ, WA, PA |
Fabry | 1–5 in 10,000 | alpha-galactosidase A | MS/MS, fluorimetry | lyso-Gb3, tissue Gb3 | ERT | R: MO, IL, Taiwan P: NJ, WA |
Gaucher | 1–9 in 100,000 | beta-glucosidase | MS/MS, fluorimetry | Glucosylsphingosine | ERT, SRT | R: MO, IL, Taiwan P: NJ, WA, Austria |
Krabbe | 1–9 in 100,000 | galactosylceramidase | MS/MS, fluorimetry | Psychosine (galactosyl-sphingosine) | HSCT | R: MO, NY, KY, OH P: WA, NJ |
Niemann–Pick A/B | <1 in 1,000,000 (A), 1–9 in 1,000,000 (B) | sphingomyelin phosphodiesterase-1 | MS/MS, fluorimetry | lysosphingomyelin | SRT | R: IL P: WA, Austria, |
Metachromatic leukodystrophy | 1–9 in 1,000,000 | arylsulfatase A | MS/MS | - | HSCT | P: WA |
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Schielen, P.C.J.I.; Kemper, E.A.; Gelb, M.H. Newborn Screening for Lysosomal Storage Diseases: A Concise Review of the Literature on Screening Methods, Therapeutic Possibilities and Regional Programs. Int. J. Neonatal Screen. 2017, 3, 6. https://doi.org/10.3390/ijns3020006
Schielen PCJI, Kemper EA, Gelb MH. Newborn Screening for Lysosomal Storage Diseases: A Concise Review of the Literature on Screening Methods, Therapeutic Possibilities and Regional Programs. International Journal of Neonatal Screening. 2017; 3(2):6. https://doi.org/10.3390/ijns3020006
Chicago/Turabian StyleSchielen, Peter C. J. I., Evelien A. Kemper, and Michael H. Gelb. 2017. "Newborn Screening for Lysosomal Storage Diseases: A Concise Review of the Literature on Screening Methods, Therapeutic Possibilities and Regional Programs" International Journal of Neonatal Screening 3, no. 2: 6. https://doi.org/10.3390/ijns3020006