{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:36:30Z","timestamp":1760060190112,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The sphingolipidoses Fabry disease, Gaucher disease and Acid sphingomyelinase deficiency (ASMD) are the three most common lysosomal storage diseases for which treatment is currently available. Timely diagnosis with estimation of the disease severity and possibilities of follow-up of patients, whether or not under therapy, is crucial for providing good care and for the prevention of possible lethal complications. With this research we provide an efficient and sensitive detection method; its implementation in clinical practice could optimize the diagnosis and follow-up of patients with Gaucher, Fabry and ASMD. This detection method on dried blood spots (DBS) was validated according to the international Clinical and Laboratory Standards Institute (CLSI) guidelines, looking at reproducibility, linearity, carry-over and lower limit of quantification. Analogously, validation and subsequent comparison of the method validation results using another matrix, the Capitainer blood sampling cards (Capitainers), was fulfilled. The results showed that this detection method is fully applicable clinically when using DBS as well as Capitainers. In addition, even additional improvements of some validation parameters were found when using the Capitainers. Twenty-six patient samples and fifteen healthy samples were analyzed for case finding control. All patient cases were detected without ambiguity. We present a high-resolution mass spectrometry method that provides an accurate analysis for targeted screening, aiming for improved\/accelerated diagnosis when added in the diagnostic pathway and monitoring of Fabry, Gaucher and ASMD in DBS as well as in Capitainers, with the main advantages of a small volume of blood samples, guaranteeing stability and easy transportation from the collection site to the laboratory.<\/jats:p>","DOI":"10.3390\/ijms26157641","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"7641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-Resolution Mass Spectrometry Method for Targeted Screening and Monitoring of Fabry, Gaucher and ASMD Using Dried Blood Spots and Capitainers: Impact of Sample Matrix on Measurement Results"],"prefix":"10.3390","volume":"26","author":[{"given":"Amber","family":"Van Baelen","sequence":"first","affiliation":[{"name":"Center of Inherited Metabolic Diseases, University Hospital of Antwerp, 2650 Antwerp, Belgium"},{"name":"Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Pediatric Department, University Hospital of Antwerp, Drie Eikenstraat 655, 2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stijn","family":"Verhulst","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Pediatric Department, University Hospital of Antwerp, Drie Eikenstraat 655, 2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Eyskens","sequence":"additional","affiliation":[{"name":"Center of Inherited Metabolic Diseases, University Hospital of Antwerp, 2650 Antwerp, Belgium"},{"name":"Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Metabolic Lab Chromatography, University Hospital of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cozma, C., Cullufi, P., Kramp, G., Hovakimyan, M., Velmishi, V., Gjikopulli, A., Tomori, S., Fischer, S., Oppermann, S., and Grittner, U. (2020). Treatment Efficiency in Gaucher Patients Can Reliably Be Monitored by Quantification of Lyso-Gb1 Concentrations in Dried Blood Spots. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134577"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dinur, T., Bauer, P., Beetz, C., Kramp, G., Cozma, C., Iura\u0219cu, M.-I., Becker-Cohen, M., Istaiti, M., Rolfs, A., and Zimran, A. (2022). Gaucher Disease Diagnosis Using Lyso-Gb1 on Dry Blood Spot Samples: Time to Change the Paradigm?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031627"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Revel-Vilk, S., Fuller, M., and Zimran, A. (2020). Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197159"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ymgme.2017.08.004","article-title":"A simple method for quantification of plasma globotriaosylsphingosine: Utility for Fabry disease","volume":"122","author":"Talbot","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ymgme.2016.10.006","article-title":"Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes","volume":"120","author":"Nowak","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_6","first-page":"100780","article-title":"Plasma lyso-sphingomyelin levels are positively associated with clinical severity in acid sphingomyelinase deficiency","volume":"28","author":"Breilyn","year":"2021","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Breiden, B., and Sandhoff, K. (2021). Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22169001"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1097\/00125817-200211000-00003","article-title":"Lysosomal storage disorders: Diagnostic dilemmas and prospects for therapy","volume":"4","author":"Wenger","year":"2002","journal-title":"Genet. Med."},{"key":"ref_9","first-page":"3635","article-title":"Gaucher Disease","volume":"Volume 3","author":"Scriver","year":"2001","journal-title":"The Metabolic and Molecular Bases of Inherited Disease"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Stirnemann, J., Belmatoug, N., Camou, F., Serratrice, C., Froissart, R., Caillaud, C., Levade, T., Astudillo, L., Serratrice, J., and Brassier, A. (2017). A review of gaucher disease pathophysiology, clinical presentation and treatments. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020441"},{"key":"ref_11","first-page":"3733","article-title":"\u03b1-Falactosidase Deficiency: Fabry Disease","volume":"Volume 3","author":"Scriver","year":"2001","journal-title":"The Metabolic and Molecular Bases of Inherited Disease"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1590\/1806-9282.66.s1.10","article-title":"Fabry disease: Genetics, pathology, and treatment","volume":"66","author":"Bernardes","year":"2020","journal-title":"Rev. Assoc. Med. Bras."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gragnaniello, V., Burlina, A.P., Polo, G., Giuliani, A., Salviati, L., Duro, G., Cazzorla, C., Rubert, L., Maines, E., and Germain, D.P. (2021). Newborn screening for fabry disease in northeastern Italy: Results of five years of experience. Biomolecules, 11.","DOI":"10.3390\/biom11070951"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/qjmed\/hcq117","article-title":"Fabry disease: A review of current management strategies","volume":"103","author":"Gragnaniello","year":"2010","journal-title":"QJM"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/cge.13936","article-title":"Accuracy diagnosis improvement of fabry disease from dried blood spots: Enzyme activity, lyso-Gb3 accumulation and GLA gene sequencing","volume":"99","author":"Santotoribio","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.clineuro.2012.11.003","article-title":"Phenotypical characterization of \u03b1-galactosidase A gene mutations identified in a large fabry disease screening program in stroke in the young","volume":"115","author":"Yperzeele","year":"2013","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ymgme.2016.12.008","article-title":"Types A and B Niemann-Pick disease","volume":"120","author":"Schuchman","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.beem.2014.08.004","article-title":"Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening","volume":"29","author":"Sandra","year":"2015","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13023-017-0572-x","article-title":"Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)","volume":"12","author":"McGovern","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Giacomarra, M., Colomba, P., Francofonte, D., Zora, M., Caocci, G., Diomede, D., Giuffrida, G., Fiori, L., Montanari, C., and Sapuppo, A. (2024). Gaucher disease or acid sphingomyelinase deficiency? The importance of differential diagnosis. J. Clin. Med., 13.","DOI":"10.3390\/jcm13051487"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ejim.2022.11.028","article-title":"Similarities and differences between Gaucher disease and acid sphingomyelinase deficiency: An algorithm to support the diagnosis","volume":"108","author":"Cappellini","year":"2023","journal-title":"Eur. J. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.ymgme.2012.06.015","article-title":"Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: Disease spectrum and natural course in attenuated patients","volume":"107","author":"Hollak","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ymgme.2013.11.012","article-title":"Lyso-sphingomyelin is elevated in dried blood spots of Niemann-Pick B patients","volume":"111","author":"Chuang","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.cca.2018.08.039","article-title":"The impact of biomarkers analysis in the diagnosis of Niemann-Pick C disease and acid sphingomyelinase deficiency","volume":"486","author":"Deodato","year":"2018","journal-title":"Clin. Chim. Acta."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.bcmd.2012.11.004","article-title":"Diagnosing Gaucher disease: An on-going need for increased awareness amongst haematologists","volume":"50","author":"Thomas","year":"2013","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hurvitz, N., Dinur, T., Becker-Cohen, M., Cozma, C., Hovakimyan, M., Oppermann, S., Demuth, L., Rolfs, A., Abramov, A., and Zimran, A. (2019). Glucosylsphingosine (lyso-gb1) as a biomarker for monitoring treated and untreated children with gaucher disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123033"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1182\/blood-2011-05-352971","article-title":"Elevated plasma glucosylsphingosine in gaucher disease: Relation to phenotype, storage cell markers, and therapeutic response","volume":"118","author":"Dekker","year":"2011","journal-title":"Blood"},{"key":"ref_28","first-page":"100798","article-title":"Incremental biomarker and clinical outcomes after switch from enzyme therapy to eliglustat substrate reduction therapy in gaucher disease","volume":"29","author":"Kleytman","year":"2021","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Rolfs, A., Giese, A.K., Grittner, U., Mascher, D., Elstein, D., Zimran, A., B\u00f6ttcher, T., Lukas, J., H\u00fcbner, R., and G\u00f6lnitz, U. (2013). 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, 8.","DOI":"10.1371\/journal.pone.0079732"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/jmedgenet-2014-102872","article-title":"Plasma globotriaosylsphingosine in relation to phenotypes of fabry disease","volume":"52","author":"Smid","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_31","first-page":"3733","article-title":"Clinical significance of plasma globotriaosylsphingosine levels in chinese patients with fabry disease","volume":"15","author":"Ouyang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1515\/cclm-2021-0316","article-title":"Multicenter evaluation of use of dried blood spot compared to conventional plasma in measurements of globotriaosylsphingosine (lysoGb3) concentration in 104 fabry patients","volume":"59","author":"Malvagia","year":"2021","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Burlina, A.B., Polo, G., Rubert, L., Gueraldi, D., Cazzorla, C., Duro, G., Salviati, L., and Burlina, A.P. (2019). Implementation of second-tier tests in newborn screening for lysosomal disorders in north eastern Italy. Int. J. Neonatal Screen, 5.","DOI":"10.3390\/ijns5020024"},{"key":"ref_34","unstructured":"Hannon, W.H., Ronald, W., Fernhoff, P., Halonen, T., and Lavochkin, M. (2023, November 14). Blood Collection on Filter Paper for Newborn Screening Programs; Approved Standard-Sixth Edition. CLSI Document NBS01-A6 from the Clinical & Laboratory Standards Institute 33, 2013, pp. 1\u201352. NBS01-A6: Blood Collection on Filter Paper for Newborn Screening Programs; Approved Standard\u2014Sixth Edition (clsi.org). Available online: https:\/\/www.researchgate.net\/publication\/288949889_Blood_Collection_on_Filter_Paper_for_Newborn_Screening_Programs_Approved_Standard-Fifth_Edition."},{"key":"ref_35","unstructured":"(2025, May 27). Capitainer\u00aeB\u2013Quantitative Dried Blood Spot Sampling. Available online: https:\/\/capitainer.com\/capitainerb-in-multi-panel-drug-testing\/."},{"key":"ref_36","first-page":"100993","article-title":"A new multiplex analysis of glucosylsphingosine and globotriaosylsphingosine in dried blood spots by tandem mass spectrometry","volume":"37","author":"Roosens","year":"2023","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_37","first-page":"101144","article-title":"Unexplained splenomegaly as a diagnostic marker for a rare but severe disease with an innovative and highly effective new treatment option: A case report","volume":"41","author":"Verhulst","year":"2024","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Blau, N., and Vaz, F.M. (2024). Sphingolipids. Laboratory Guide to the Methods in Biochemical Genetics, Springer.","DOI":"10.1007\/978-3-031-58819-8"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ymgme.2020.04.006","article-title":"A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females","volume":"130","author":"Stiles","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Baydakova, G., Ilyushkina, A., Gaffke, L., Pierzynowska, K., Bychkov, I., \u0141ugowska, A., Wegrzyn, G., Tylki-Szymanska, A., and Zakharova, E. (2020). Elevated LysoGb3 in the neuronopathic forms of mucopolysaccharidoses. Diagnostics, 10.","DOI":"10.3390\/diagnostics10030155"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s13023-023-02686-6","article-title":"Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A\/B)","volume":"18","author":"Geberhiwot","year":"2023","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1186\/s13023-023-02983-0","article-title":"Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: Open-label extension of the ASCEND trial","volume":"18","author":"Wasserstein","year":"2023","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/ansa.202300011","article-title":"Blood microsampling technologies: Innovations and applications in 2022","volume":"4","author":"Thangavelu","year":"2023","journal-title":"Anal. Sci. Adv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1038\/s41591-024-03465-x","article-title":"Population-based, first-tier genomic newborn screening in the maternity ward","volume":"31","author":"Boemer","year":"2025","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gragnaniello, V., Cazzorla, C., Gueraldi, D., Puma, A., Loro, C., Porc\u00f9, E., Stornaiuolo, M., Miglioranza, P., Salviati, L., and Burlina, A.P. (2023). Light and Shadows in Newborn Screening for Lysosomal Storage Disorders: Eight Years of Experience in Northeast Italy. Int. J. Neonatal. Screen., 10.","DOI":"10.20944\/preprints202311.0727.v1"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:25:28Z","timestamp":1760034328000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,7]]},"references-count":45,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157641"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157641","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,8,7]]}}}