Introduction Recent studies showed the usefulness of globotriaosylsphingosine (lyso-Gb3) and related analogues, deacylated forms of globotriaosylceramide (Gb3), for high-risk screening, treatment monitoring and follow-up for patients with Fabry disease.
Methods We evaluated Gb3, lyso-Gb3 and analogues using tandem mass spectrometry in 57 women with Fabry disease followed during a period of 15.4 years. Twenty-one women were never treated and 36 received treatment (agalsidase-beta, n=30; agalsidase-alfa, n=5; or migalastat, n=1). Lyso-Gb3 and analogues at m/z (−28), (−2), (+16), (+34) and (+50) were analysed in plasma and urine. Total Gb3 and lyso-Gb3 analogues at m/z (−12) and (+14) were evaluated in urine while the analogue at m/z (+18) was evaluated in plasma.
Results A strong correlation between plasma and urine lyso-Gb3 and analogue levels was revealed. Plasma and urine lyso-Gb3 and analogue levels were not statistically different between patients carrying missense (n=49), nonsense (n=6) or deletion mutations (n=2). Never treated patients had lower plasma lyso-Gb3 and analogues at m/z (−28), (−2), (+16), (+34) and the seven urinary lyso-Gb3 analogues compared with pretreatment levels of the treated patients. A significant reduction of plasma lyso-Gb3 and five analogues, as well as urine Gb3 and six lyso-Gb3 analogues, but not lyso-Gb3 and lyso-Gb3 at m/z (+50), was observed post-treatment with agalsidase-beta. The same tendency was observed with agalsidase-alfa.
Conclusion Women with Fabry disease who started treatment based on clinical manifestations had higher lyso-Gb3 and analogue biomarker levels than never treated women. This indicates that a biomarker cut-off could potentially be a decision tool for treatment initiation in women with Fabry disease.
- genetic research
- human genetics
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Contributors GE: performed the writing of the manuscript and the analysis of data. UF-R: was key initiator and advisor of the project, responsible for compiling the patient samples for analysis and patient data, continuously evaluated the data and progress and revised the manuscript critically. ÅKR: was an advisor in the project, involved in the interpretation of data and revised the manuscript critically. PL: wrote the first draft of the introduction, evaluated and interpreted data and revised the manuscript critically. MA: performed mass spectrometry biomarker analyses. MB: performed mass spectrometry biomarker analyses and revised the manuscript. CA-B: participated in the design of the study, provided the mass spectrometry infrastructure for all biomarker analyses, performed the evaluation and interpretation of data, provided insight in the writing of the draft and revised the final version of the manuscript critically. All authors approved the final manuscript.
Funding This Investigator-Initiated Research was supported by a grant (IIR-DNK-001030) from Shire International GmbH, now part of Takeda Pharmaceutical. The research salary of UF-R was supported by the Novo Nordisk Foundation.
Disclaimer The funding organisation played no role in the design of the study, choice of enrolled patients, interpretation of data, nor in preparation of the manuscript.
Competing interests GE has received conference registration fees and travel grants from Sanofi Genzyme and Amicus Therapeutics and speaker’s fees from Sanofi Genzyme. UF-R has received speaker’s honoraria and unrestricted research and educational grants from Sanofi Genzyme, Shire/Takeda Pharmaceutical and Amicus Therapeutics. She is a member of Advisory Boards at Sanofi Genzyme and Amicus Therapeutics. PL has received conference registration fees and travel grants from Amicus Therapeutics and Sanofi Genzyme. MB has received salary support from Shire/Takeda Pharmaceutical. CA-B has received unrestricted investigator-initiated research grants and honoraria from Shire/Takeda Pharmaceutical and BioMarin Pharmaceutical Inc. She has service contract analyses from 4D Molecular Therapeutics, Protalix and Avrobio. She is a consultant and has received speaker’s honoraria from Amicus Therapeutics and Sanofi Genzyme. She is the Scientific director of the Waters Centre of Innovation in Sherbrooke, QC.
Patient consent for publication Not required.
Ethics approval This project was approved by the Research Ethics Board at the Capital Region, Rigshospitalet, Copenhagen University Hospital (Journal number: H-18024706), at the Danish Data Protection Agency (2014-641-0055) and at the Faculty of Medicine and Health Sciences at the Centre intégré universitaire de santé et de services sociaux de l’Estrie-Centre hospitalier universitaire de Sherbrooke (CIUSSSE-CHUS).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. This research project involves prospective data (15 years) from a retrospective cohort. Patients were part of the nationwide Danish long-term clinical Fabry Disease cohort.