{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:11:07Z","timestamp":1780337467791,"version":"3.54.1"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundo de Incentivo \u00e0 Pesquisa e Eventos (FIPE) of the HCPA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gaucher disease (GD, OMIM 230800) is one of the most common lysosomal disorders, being caused by the deficient activity of the enzyme acid \u03b2-glucocerebrosidase (Gcase). Three clinical forms of Gaucher\u2019s disease (GD) are classified based on neurological involvement. Type 1 (GD1) is non-neuronopathic, while types 2 (GD2) and 3 (GD3) are neuronopathic forms. Gcase catalyzes the conversion of glucosylceramide (GlcCer) into ceramide and glucose. As GlcCer accumulates in lysosomal macrophages, it undergoes deacylation to become glycosylsphingosine (lyso-Gb1), which has shown to be a useful and reliable biomarker for the diagnosis and monitoring of treated and untreated patients with GD. Multiple myeloma (MM) is one of the leading causes of cancer-related death among patients with GD and monoclonal gammopathy of undetermined significance (MGUS) is a non-neoplastic condition that can be a telltale sign of a B clonal proliferation caused by the chronic activation of B cells. This study aimed to quantify Lyso-Gb1 levels in dried blood spots (DBS) and cerebrospinal fluid (CSF) as biomarkers for Gaucher disease (GD) and discuss the association of this biomarker with other clinical parameters. This is a mixed-methods study incorporating both cross-sectional and longitudinal elements within a cohort design with a convenience-sampling strategy. Data collection took place from January 2012 to March 2023. Lyso-Gb1 extraction from DBS involved the use of a methanol\u2013acetonitrile\u2013water mixture, followed by incubation and centrifugation. Analysis was performed using UPLC-MS\/MS with MassLynx software version 4.2 and the control group for the DBS measurements included general newborns. CSF Lyso-Gb1 was extracted using ethyl acetate, analyzed by UPLC-MS\/MS with a calibration curve, and expressed in pmol\/L. Lysosomal activity in CSF was assessed by measuring chitotriosidase (Cht), and other lysosomal enzyme activities were assessed as previously described in the literature. Patients with metachromatic leukodystrophy (MLD) were used as controls. Thirty-two treated patients (twenty-nine GD1 and three GD3, all on ERT except for one GD type on SRT with eliglustat) and three untreated patients (one GD1, one GD2, and one GD3) were included. When analyzing only the treated GD1 group, a significant correlation was found between lyso-Gb1 and age (rho = \u22120.447, p = 0.001), ChT, and IgG levels (rho = 0.73, p &lt; 0.001; and rho = 0.36, p = 0.03, respectively). Five GD1 patients (three females, mean age 40 years) also had their CSF collected and analyzed. The average measurement of lyso-Gb1 in CSF was 94 pmol\/L (range: 57.1\u2013157.9 pmol\/L) versus &lt;6.2 pmol\/L in the control group (MLD). This is the first time, to the best of our knowledge, that lyso-Gb1 has been associated with IgG levels. While this finding reflects a risk for MGUS or MM and not only chronic plasma B-cell activation, it still requires further studies. Moreover, the analysis of CSF lyso-Gb1 levels in GD1 patients was demonstrated to be significantly higher than the control group. This raises the hypothesis that CSF lyso-Gb1 may serve as a valuable indicator for neurological involvement in GD, providing insights into the potential implications for neurological manifestations in GD, including GD1. The correlation between lyso-Gb1 and ChT levels in treated GD1 patients further underscores the interconnectedness of lysosomal markers and their relevance in monitoring.<\/jats:p>","DOI":"10.3390\/ijms25052870","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T06:07:53Z","timestamp":1709273273000},"page":"2870","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Brazilian Rare-Disease Center\u2019s Experience with Glucosylsphingosine (lyso-Gb1) in Patients with Gaucher Disease: Exploring a Novel Correlation with IgG Levels in Plasma and a Biomarker Measurement in CSF"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8302-7705","authenticated-orcid":false,"given":"Matheus","family":"Vernet Machado Bressan Wilke","sequence":"first","affiliation":[{"name":"Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre 90035003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle Dineck","family":"Iop","sequence":"additional","affiliation":[{"name":"Biodiscovery Laboratory, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Faqueti","sequence":"additional","affiliation":[{"name":"Biodiscovery Laboratory, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layzon Antonio","family":"Lemos da Silva","sequence":"additional","affiliation":[{"name":"Biodiscovery Laboratory, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9330-0154","authenticated-orcid":false,"given":"Francyne","family":"Kubaski","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Laboratory, Greenwood Genetics Center, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0804-2876","authenticated-orcid":false,"given":"Fabiano O.","family":"Poswar","sequence":"additional","affiliation":[{"name":"Medical Genetics Service, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"},{"name":"Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristiane","family":"Michelin-Tirelli","sequence":"additional","affiliation":[{"name":"LEIM-Biochemical Genetics Laboratory, Medical Genetics Service, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9vora","family":"Randon","sequence":"additional","affiliation":[{"name":"BRAIN Laboratory, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wyllians Vendramini","family":"Borelli","sequence":"additional","affiliation":[{"name":"Neurology Service, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9655-3686","authenticated-orcid":false,"given":"Roberto","family":"Giugliani","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre 90035003, Brazil"},{"name":"Biodiscovery Laboratory, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035903, Brazil"},{"name":"Medical Genetics Service, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"},{"name":"Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035003, Brazil"},{"name":"Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035003, Brazil"},{"name":"Dasa Gen\u00f4mica, S\u00e3o Paulo 04078013, Brazil"},{"name":"Casa dos Raros, Porto Alegre 90035003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Vanessa D.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre 90035003, Brazil"},{"name":"Medical Genetics Service, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"},{"name":"BRAIN Laboratory, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"},{"name":"Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035003, Brazil"},{"name":"Instituto Nacional de Doen\u00e7as Raras\u2014InRaras, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"key":"ref_1","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_2","unstructured":"Adam, M.P., Everman, D.B., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J., Gripp, K.W., and Amemiya, A. (2022, September 17). Gaucher Disease, GeneReviews\u00ae, Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1269\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1186\/s13023-023-02875-3","article-title":"Follow-up of pre-motor symptoms of Parkinson\u2019s disease in adult patients with Gaucher disease type 1 and analysis of their lysosomal enzyme profiles in the CSF","volume":"18","author":"Wilke","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13023-019-1079-4","article-title":"Evaluation of the frequency of non-motor symptoms of Parkinson\u2019s disease in adult patients with Gaucher disease type 1","volume":"14","author":"Wilke","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e862","DOI":"10.1002\/ctm2.862","article-title":"Identification of a novel therapeutic target underlying atypical manifestation of Gaucher disease","volume":"12","author":"Kim","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100729","DOI":"10.1016\/j.ymgmr.2021.100729","article-title":"The role of glucosylsphingosine as an early indicator of disease progression in early symptomatic type 1 Gaucher disease","volume":"27","author":"Stiles","year":"2021","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lukas, J., Cozma, C., Yang, F., Kramp, G., Meyer, A., Ne\u00dflauer, A.-M., Eichler, S., B\u00f6ttcher, T., Witt, M., and Br\u00e4uer, 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":"S81","DOI":"10.21037\/atm.2018.10.69","article-title":"Biomarker combination is necessary for the assessment of Gaucher disease?","volume":"6","author":"Giraldo","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1182\/hematology.2020000123","article-title":"A patient with Gaucher disease and plasma cell dyscrasia: Bidirectional impact","volume":"2020","author":"Zimran","year":"2020","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1002\/ajmg.c.31870","article-title":"Outcomes of screening for gammopathies in children and adults with Gaucher disease type 1 in a cohort from Brazil and the United States","volume":"184","author":"Abell","year":"2020","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ymgme.2017.08.005","article-title":"Reductions in glucosylsphingosine (lyso-Gb1) in treatment-na\u00efve 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_12","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_13","doi-asserted-by":"crossref","first-page":"107736","DOI":"10.1016\/j.ymgme.2023.107736","article-title":"Treatment-naive and post-treatment glucosylsphingosine (lyso-GL1) levels in a cohort of pediatric patients with Gaucher disease","volume":"141","author":"Rasmussen","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_14","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_15","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_16","first-page":"307","article-title":"Hemophagocytic Lymphohistiocytosis Syndrome Associated with Gaucher Disease Type 2","volume":"31","author":"Gholamreza","year":"2014","journal-title":"Turk. J. Hematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1002\/ajmg.a.61880","article-title":"Consequences of treatment for hemophagocytic lymphohistiocytosis in a patient with undiagnosed Gaucher disease Type 1","volume":"182","author":"Anderson","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Smith, L., and Schapira, A.H.V. (2022). GBA Variants and Parkinson Disease: Mechanisms and Treatments. Cells, 11.","DOI":"10.3390\/cells11081261"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/acn3.292","article-title":"Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study","volume":"3","author":"Narita","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/j.1399-0004.1985.tb00229.x","article-title":"Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants","volume":"27","author":"Nilsson","year":"1985","journal-title":"Clin. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9617","DOI":"10.1523\/JNEUROSCI.1525-17.2017","article-title":"Glucosylsphingosine Promotes \u03b1-Synuclein Pathology in Mutant GBA-Associated Parkinson\u2019s Disease","volume":"37","author":"Taguchi","year":"2017","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1089\/ars.2015.6307","article-title":"Sustained Systemic Glucocerebrosidase Inhibition Induces Brain \u03b1-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice","volume":"23","author":"Rocha","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1615\/CritRevOncog.2013006145","article-title":"Gaucher disease and malignancy: A model for cancer pathogenesis in an inborn error of metabolism","volume":"18","author":"Mistry","year":"2013","journal-title":"Crit. Rev. Oncog."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1182\/blood-2014-10-567370","article-title":"Genetics of multiple myeloma: Another heterogeneity level?","volume":"125","author":"Corre","year":"2015","journal-title":"Blood"},{"key":"ref_25","unstructured":"(2023, July 24). Available online: http:\/\/antigo-conitec.saude.gov.br\/images\/Relatorios\/2017\/PCDT_Doen%C3%A7a_de_Gaucher_n278_2017.pdf."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s00277-008-0441-8","article-title":"Immunoglobulin and free light chain abnormalities in Gaucher disease type I: Data from an adult cohort of 63 patients and review of the literature","volume":"87","author":"Out","year":"2008","journal-title":"Ann. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nguyen, Y., Stirnemann, J., Lautredoux, F., Cador, B., Bengherbia, M., Yousfi, K., Hamroun, D., Astudillo, L., de Villemeur, T.B., and Brassier, A. (2020). Immunoglobulin Abnormalities in Gaucher Disease: An Analysis of 278 Patients Included in the French Gaucher Disease Registry. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041247"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1186\/s13023-020-01520-7","article-title":"Identification of risk features for complication in Gaucher\u2019s disease patients: A machine learning analysis of the Spanish registry of Gaucher disease","volume":"15","author":"Cebolla","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1056\/NEJMoa1508808","article-title":"Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma","volume":"374","author":"Nair","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1515\/cclm-2018-1301","article-title":"Plasma and dried blood spot lysosphingolipids for the diagnosis of different sphingolipidoses: A comparative study","volume":"57","author":"Polo","year":"2019","journal-title":"Clin. Chem. Lab. Med. CCLM"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1172\/JCI117084","article-title":"Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease","volume":"93","author":"Hollak","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_32","unstructured":"Sleiffer, D. (2024, February 22). Introducing JASP 0.16.3: Quality Control, GLMs, Bayesian State Space Models, Improvements to Bayesian ANOVA, and More. Available online: https:\/\/jasp-stats.org\/2022\/06\/16\/introducing-jasp-0-16-3-quality-control-glms-bayesian-state-space-models-improvements-to-bayesian-anova-and-more\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2870\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:07:49Z","timestamp":1760105269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2870"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,1]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25052870"],"URL":"https:\/\/doi.org\/10.3390\/ijms25052870","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,1]]}}}