{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T08:37:52Z","timestamp":1780475872450,"version":"3.54.1"},"reference-count":38,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2020,6,27]],"date-time":"2020-06-27T00:00:00Z","timestamp":1593216000000},"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>Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether they can indicate a reduction or loss of treatment efficiency, however, has not been systematically addressed for obvious reasons. We established and validated measurement of Lyso-Gb1 from dried blood spots (DBSs) by mass spectrometry. We then characterized the assay\u2019s longitudinal performance in 19 stably ERT-treated GD patients by dense monitoring over a 3-year period. The observed level of fluctuation was accounted for in the subsequent development of a unifying data normalization concept. The resulting approach was eventually applied to data from Lyso-Gb1 measurements after an involuntary treatment break for all 19 patients. It enabled separation of the \u201cunder treatment\u201d versus \u201cnot under treatment\u201d conditions with high sensitivity and specificity. We conclude that Lyso-Gb1 determination from DBSs indicates treatment issues already at an early stage before clinical consequences arise. In addition to its previously shown diagnostic utility, Lyso-Gb1 thereby qualifies as a monitoring biomarker in GD patients.<\/jats:p>","DOI":"10.3390\/ijms21134577","type":"journal-article","created":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T05:28:56Z","timestamp":1593408536000},"page":"4577","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Treatment Efficiency in Gaucher Patients Can Reliably Be Monitored by Quantification of Lyso-Gb1 Concentrations in Dried Blood Spots"],"prefix":"10.3390","volume":"21","author":[{"given":"Claudia","family":"Cozma","sequence":"first","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paskal","family":"Cullufi","sequence":"additional","affiliation":[{"name":"Pediatric Department, University Hospital \u2019Mother Teresa\u2019, 1000 Tirana, Albania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Kramp","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Hovakimyan","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virtut","family":"Velmishi","sequence":"additional","affiliation":[{"name":"Pediatric Department, University Hospital \u2019Mother Teresa\u2019, 1000 Tirana, Albania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agim","family":"Gjikopulli","sequence":"additional","affiliation":[{"name":"Pediatric Department, University Hospital \u2019Mother Teresa\u2019, 1000 Tirana, Albania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonila","family":"Tomori","sequence":"additional","affiliation":[{"name":"Pediatric Department, University Hospital \u2019Mother Teresa\u2019, 1000 Tirana, Albania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Fischer","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Oppermann","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-0224","authenticated-orcid":false,"given":"Ulrike","family":"Grittner","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"},{"name":"Institute of Biometry and Clinical Epidemiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Str. 2, 10178 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bauer","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7061-2895","authenticated-orcid":false,"given":"Christian","family":"Beetz","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt","family":"Rolfs","sequence":"additional","affiliation":[{"name":"CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/humu.20676","article-title":"Gaucher disease: Mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)","volume":"29","author":"Hruska","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_2","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., and Amemiya, A. (1993). Gaucher Disease. GeneReviews((R)), Springer."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0002-9343(02)01150-6","article-title":"Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: A report from the Gaucher Registry","volume":"113","author":"Weinreb","year":"2002","journal-title":"Am. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S0022-2275(20)36768-7","article-title":"Isolation and characterization of glucosylsphingosine from Gaucher\u2019s spleen","volume":"15","author":"Raghavan","year":"1974","journal-title":"J. Lipid Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/j.1471-4159.1982.tb07950.x","article-title":"Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease","volume":"39","author":"Nilsson","year":"1982","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1203\/00006450-200008000-00018","article-title":"Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation","volume":"48","author":"Orvisky","year":"2000","journal-title":"Pediatr. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lukas, J., Cozma, C., Yang, F., Kramp, G., Meyer, A., Nesslauer, A.M., Eichler, S., Bottcher, T., Witt, M., and Brauer, A.U. (2017). Glucosylsphingosine Causes Hematological and Visceral Changes in Mice-Evidence for a Pathophysiological Role in Gaucher Disease. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102192"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e118","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_9","doi-asserted-by":"crossref","unstructured":"Rolfs, A., Giese, A.K., Grittner, U., Mascher, D., Elstein, D., Zimran, A., Bottcher, T., Lukas, J., Hubner, R., and Golnitz, 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_10","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13023-016-0413-3","article-title":"Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients","volume":"11","author":"Smid","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1002\/ajh.24491","article-title":"Glucosylsphingosine is a key biomarker of Gaucher disease","volume":"91","author":"Murugesan","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ymgme.2017.08.005","article-title":"Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naive and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials","volume":"122","author":"Elstein","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E140","DOI":"10.1002\/ajh.25074","article-title":"Glucosylsphingosine is a reliable response biomarker in Gaucher disease","volume":"93","author":"Arkadir","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1136\/jmedgenet-2019-106132","article-title":"Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy","volume":"57","author":"Kim","year":"2020","journal-title":"J. Med. Genet"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Dinur, T., Zimran, A., Becker-Cohen, M., Arkadir, D., Cozma, C., Hovakimyan, M., Oppermann, S., Demuth, L., Rolfs, A., and Revel-Vilk, S. (2019). Long Term Follow-Up of 103 Untreated Adult Patients with Type 1 Gaucher Disease. J. Clin. Med., 8.","DOI":"10.3390\/jcm8101662"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1373\/clinchem.2017.275966","article-title":"State of the Science in Dried Blood Spots","volume":"64","author":"Freeman","year":"2018","journal-title":"Clin. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1046\/j.1365-2141.2000.02177.x","article-title":"Withdrawal of enzyme replacement therapy in Gaucher\u2019s disease","volume":"110","author":"Elstein","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1046\/j.1365-2141.2001.02821-9.x","article-title":"Clinical monitoring after cessation of enzyme replacement therapy in M. Gaucher","volume":"113","author":"Poll","year":"2001","journal-title":"Br. J. Haematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.bcmd.2009.09.006","article-title":"Force majeure: Therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease","volume":"44","author":"Hollak","year":"2010","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.bcmd.2010.05.001","article-title":"Nonprecipitous changes upon withdrawal from imiglucerase for Gaucher disease because of a shortage in supply","volume":"46","author":"Zimran","year":"2011","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.bcmd.2010.09.005","article-title":"Evaluation of Spanish Gaucher disease patients after a 6-month imiglucerase shortage","volume":"46","author":"Giraldo","year":"2011","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s13023-015-0275-0","article-title":"Impact of imiglucerase supply constraint on the therapeutic management and course of disease in French patients with Gaucher disease type 1","volume":"10","author":"Stirnemann","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.bcmd.2016.10.008","article-title":"Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease","volume":"68","author":"Biegstraaten","year":"2018","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0009-9120(99)00098-3","article-title":"Changes in serum chitotriosidase activity with cessation of replacement enzyme (cerebrosidase) administration in Gaucher disease","volume":"33","author":"Czartoryska","year":"2000","journal-title":"Clin. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1046\/j.1365-2141.2001.02821-13.x","article-title":"Effects of imilglucerase withdrawal on an adult with Gaucher disease","volume":"113","author":"Schwartz","year":"2001","journal-title":"Br. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00005-014-0308-8","article-title":"Impact of imiglucerase supply shortage on clinical and laboratory parameters in Norrbottnian patients with Gaucher disease type 3","volume":"63","author":"Machaczka","year":"2015","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_28","first-page":"127","article-title":"Extended interval between enzyme therapy infusions for adult patients with Gaucher\u2019s disease type 1","volume":"49","author":"Giraldo","year":"2003","journal-title":"J. Postgrad Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13643-017-0483-x","article-title":"Plasma chitotriosidase activity versus CCL18 level for assessing type I Gaucher disease severity: Protocol for a systematic review with meta-analysis of individual participant data","volume":"6","author":"Raskovalova","year":"2017","journal-title":"Syst. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/BF02436762","article-title":"Elevated plasma chitotriosidase activity in various lysosomal storage disorders","volume":"18","author":"Guo","year":"1995","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1189\/jlb.1204712","article-title":"Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes","volume":"78","author":"Schutyser","year":"2005","journal-title":"J. Leukoc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/1873-3468.12104","article-title":"Lysosomal glycosphingolipid catabolism by acid ceramidase: Formation of glycosphingoid bases during deficiency of glycosidases","volume":"590","author":"Ferraz","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"25680","DOI":"10.1074\/jbc.273.40.25680","article-title":"The human chitotriosidase gene. Nature of inherited enzyme deficiency","volume":"273","author":"Boot","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1089\/gte.1997.1.5","article-title":"Gaucher disease: Gene frequencies and genotype\/phenotype correlations","volume":"1","author":"Grabowski","year":"1997","journal-title":"Genet Test"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E58","DOI":"10.1002\/humu.20776","article-title":"Haplotype analysis suggests a single Balkan origin for the Gaucher disease [D409H;H255Q] double mutant allele","volume":"29","author":"Santamaria","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_36","unstructured":"(2020, June 27). ISO 15189:2012. Medical Laboratories \u2014 Requirements for Quality and Competence. Available online: https:\/\/www.iso.org\/standard\/56115.html."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.4155\/bio.15.110","article-title":"Self-sampling and quantitative analysis of DBS: Can it shift the balance in over-burdened healthcare systems?","volume":"7","author":"Tanna","year":"2015","journal-title":"Bioanalysis"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mielczarek, P., Silberring, J., and Smoluch, M. (2019). Miniaturization in Mass Spectrometry. Mass Spectrom. Rev.","DOI":"10.1002\/mas.21614"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/13\/4577\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:43:46Z","timestamp":1760175826000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/13\/4577"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,27]]},"references-count":38,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["ijms21134577"],"URL":"https:\/\/doi.org\/10.3390\/ijms21134577","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,27]]}}}