Service of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke (Québec), Canada J1H 5N4.
Curr Med Chem. 2013;20(2):280-8. doi: 10.2174/092986713804806685.
Fabry disease is an X-linked, multisystemic lysosomal storage disorder due to alpha-galactosidase A deficiency. It is characterized by the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb(3)), in biological fluids, vascular endothelium, heart, and kidneys. Treatment by enzyme replacement therapy has been shown to be beneficial in both males and females affected with the disease. In addition to Gb(3), increased concentrations of globotriaosylsphingosine (lyso-Gb(3)) have recently been reported in urine and plasma of Fabry patients. The overall objective of this metabolomic study was to identify and characterize new potential plasma biomarkers in treated and untreated males and females affected with Fabry disease which might better reflect disease severity and progression. We employed a time-of-flight mass spectrometry metabolomic approach using plasma samples of Fabry patients compared to age-matched controls. We found three new lyso-Gb(3) analogs in Fabry patients presenting m/z ratios at 802, 804, and 820. As previously detected by our group, we also found a m/z ratio of 784 corresponding to the lyso-Gb(3) molecule minus two hydrogen atoms. Using exact mass measurements and tandem mass spectrometry, we confirmed that these analogs result from modifications of the lyso-Gb(3) sphingosine moiety. We evaluated the relative plasma concentration by measuring area counts for each lyso-Gb(3) analog. None of these analogs was detected in the majority of healthy controls. The relative concentration of each analog was higher in males compared to female Fabry patients. We demonstrated that mass spectrometry combined to a metabolomic approach is a powerful tool to detect and identify new potential biomarkers.
法布里病是一种 X 连锁的多系统溶酶体贮积病，由于α-半乳糖苷酶 A 缺乏所致。其特征在于生物体液、血管内皮、心脏和肾脏中糖鞘脂，主要是神经节苷脂 Gb3 的积累。酶替代疗法的治疗已被证明对受该病影响的男性和女性均有益。除 Gb3 外，最近在法布里病患者的尿液和血浆中也报道了神经节苷脂鞘氨醇（lyso-Gb3）浓度增加。这项代谢组学研究的总体目标是鉴定和表征新的潜在血浆生物标志物，用于治疗和未治疗的男性和女性法布里病患者，这些标志物可能更好地反映疾病的严重程度和进展。我们采用了飞行时间质谱代谢组学方法，使用法布里病患者的血浆样本与年龄匹配的对照进行比较。我们在法布里病患者中发现了三种新的 lyso-Gb3 类似物，其质荷比分别为 802、804 和 820。与我们之前的研究结果一致，我们还发现了质荷比为 784 的 lyso-Gb3 分子减去两个氢原子的类似物。通过精确质量测量和串联质谱，我们证实这些类似物是 lyso-Gb3 神经鞘氨醇部分修饰的结果。我们通过测量每个 lyso-Gb3 类似物的面积计数来评估相对血浆浓度。在大多数健康对照者中未检测到这些类似物。与女性法布里病患者相比，男性患者中这些类似物的相对浓度更高。我们证明，质谱结合代谢组学方法是一种强大的工具，可用于检测和识别新的潜在生物标志物。
