Global glycosphingolipid analysis in urine and plasma of female Fabry disease patients

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Global glycosphingolipid analysis in urine and plasma of female Fabry disease patients

Heywood, W; Doykov, I; Spiewak, J; Hallqvist, J; Mills, K; Nowak, A; (2019) Global glycosphingolipid analysis in urine and plasma of female Fabry disease patients. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease , 1865 (10) pp. 2726-2735. 10.1016/j.bbadis.2019.07.005. Green open access

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Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase-A, which results in accumulation of the glycosphingolipid (GSL) globotriaosylceramide (Gb3). Gb3 and globotriaosylsphingosine (lyso-Gb3) levels in plasma and urine are used routinely for diagnosis and treatment monitoring. FD female patients are problematic to diagnose and to predict when to begin treatment. Further biomarkers are needed to detect pre-symptomatic females that will develop the chronic symptoms associated with FD. A LC-MS/MS glycosphingolipidomic assay was developed to measure lyso-Gb3 and GSLs from the lysosomal GSL degradation pathway, including globoside (Gb4), Gb3, ceramide dihexosides (CDH) and ceramide monohexosides (CMH). We analysed plasma and urine from a cohort of Fabry patients, grouped according to clinical symptoms and independent of treatment status (asymptomatic females n = 18, symptomatic females n = 18, males n = 27 and control urines n = 16 and control plasmas n = 58). Multivariate and subsequent univariate analysis showed urine GSLs which had highest significance in identifying asymptomatic females were total levels of CDH, in particular the long chain isoforms C22:1,C22:0,C22:1-OH,C22:0-OH,C24:2,C24:0,C24:2-OH,C24:1-OH,C24:0-OH,C26:0 which likely represent Galabiosylceramide (Ga2) and not lactosylceramide. These long chain Ga2 isoforms were found to be 5-fold elevated and more statistically significant (p < 0.0001) than plasma lyso-Gb3 (p < 0.01) in identifying asymptomatic Fabry female patients. Receiver operating characteristic curve analysis gave an area under the curve of 0.82 (p = 0.001) for lyso-Gb3 and 0.88 (p = 0.0006) for long-chain CDH isoforms indicating the long chain CDH isoforms were as, if not more, a better biomarker for the identification of female FD patients.

Type:	Article
Title:	Global glycosphingolipid analysis in urine and plasma of female Fabry disease patients
Location:	Netherlands
Open access status:	An open access version is available from UCL Discovery
DOI:	10.1016/j.bbadis.2019.07.005
Publisher version:	https://doi.org/10.1016/j.bbadis.2019.07.005
Language:	English
Additional information:	This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords:	Biomarker, Ceramide dihexoside, Fabry disease, Galabiosylceramide, Glycosphingolipid, Lyso-Gb(3)
UCL classification:	UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI:	https://discovery.ucl.ac.uk/id/eprint/10078971