TY  - JOUR
IS  - 10
KW  - Biomarker
KW  -  Ceramide dihexoside
KW  -  Fabry disease
KW  -  Galabiosylceramide
KW  -  Glycosphingolipid
KW  -  Lyso-Gb(3)
AV  - public
JF  - Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
SN  - 1879-260X
SP  - 2726
ID  - discovery10078971
EP  - 2735
N2  - Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of ?-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.
VL  - 1865
UR  - https://doi.org/10.1016/j.bbadis.2019.07.005
A1  - Heywood, W
A1  - Doykov, I
A1  - Spiewak, J
A1  - Hallqvist, J
A1  - Mills, K
A1  - Nowak, A
Y1  - 2019/10/01/
TI  - Global glycosphingolipid analysis in urine and plasma of female Fabry disease patients
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
ER  -