Multiplex Analysis of Novel Urinary Lyso-Gb3-Related Biomarkers for Fabry Disease by Tandem Mass Spectrometry
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- 作者：Pamela Lavoie ; Michel Boutin ; Christiane Auray-Blais
- 刊名：Analytical Chemistry
- 出版年：2013
- 出版时间：February 5, 2013
- 年：2013
- 卷：85
- 期：3
- 页码：1743-1752
- 全文大小：568K
- 年卷期：v.85,no.3(February 5, 2013)
- ISSN：1520-6882
文摘
Fabry disease is a lysosomal storage disorder caused by the absence or reduction of 伪-galactosidase A enzyme activity. The enzymatic deficiency results in the impaired catabolism of neutral sphingolipids with terminal 伪-galactosyl residues and subsequent accumulation in several tissues. Biomarkers reflecting disease severity and progression, the response to therapeutic intervention, and details of molecular pathogenesis are needed. Until now, two sphingolipids were targeted as biomarkers in urine and plasma of Fabry patients: globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Using metabolomic approaches, our group recently discovered seven novel urinary lyso-Gb3-related Fabry disease biomarkers with mass-to-charge ratios (m/z) of 758, 774, 784, 800, 802, 820, and 836. All these biomarkers exhibited modifications of the lyso-Gb3 sphingosine moiety. The aims of the present study were to devise and validate a specific tandem mass spectrometry multiplex methodology for the relative quantification of these seven analogues and to evaluate their urinary excretion levels in samples from 164 Fabry patients and 94 healthy controls. We found no detectable analogues in healthy controls, except for trace amounts of the analogue with m/z 836. Significant correlations were established between lyso-Gb3 analogue levels in urine and gender (p < 0.001). Fabry males had higher excretion levels compared to females with the disease. Lyso-Gb3 analogue levels correlated well with enzyme replacement therapy (ERT) status in males (p < 0.05). The urinary analogue distributions varied among Fabry patients. However, the analogues with m/z 802, 820, and 836 were generally more abundant in the majority of patients. Lyso-Gb3 analogues are promising urinary biomarkers for Fabry disease.