Service of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12th Avenue North, Sherbrooke, Québec J1H 5N4, Canada.
Anal Chem. 2014 Apr 1;86(7):3476-83. doi: 10.1021/ac404000d. Epub 2014 Mar 17.
Fabry disease is a multisystemic, X-linked lysosomal storage disorder caused by a deficit in α-galactosidase A enzyme activity leading to glycosphingolipid accumulation, mainly globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Recent metabolomic studies have led to the discovery of novel biomarkers related to lyso-Gb3 in plasma and urine. These biomarkers show modifications of the sphingosine moiety of the lyso-Gb3 molecule. The objectives of this study were to develop and validate a liquid chromatography-tandem mass spectrometry method for the relative quantification of novel plasma lyso-Gb3-related analogues, to evaluate their levels in plasma of 74 Fabry patients and 41 healthy controls and to correlate these results with patient gender, enzyme replacement therapy treatment, and lyso-Gb3 analogue levels previously measured in urine for the same patients. As expected, the concentrations of lyso-Gb3 and its related analogues in plasma are higher in Fabry males compared to Fabry females and higher for untreated males compared to treated males. The concentration of lyso-Gb3 and its related analogues in plasma decrease significantly after the beginning of enzyme replacement therapy (ERT) treatment and remain stable for 30 months of monitored therapy in a Fabry male. In plasma, lyso-Gb3 is significantly more abundant than its related analogues, which differs from urine where the majority of the lyso-Gb3 analogues are more increased than lyso-Gb3 itself. In contrast to urine, the relative distribution of lyso-Gb3 and its analogues in plasma is similar from one individual to another in the same group of Fabry patients, irrespective of ERT. This study revealed a large discrepancy between the relative abundance of lyso-Gb3 and its analogues in urine and plasma. Further studies will thus be needed to better understand the metabolic relationship between plasma and urine lyso-Gb3-related biomarkers.
法布里病是一种多系统、X 连锁溶酶体贮积症，由α-半乳糖苷酶 A 酶活性缺陷引起，导致糖鞘脂积累，主要为神经酰胺三己糖苷（Gb3）和神经酰胺三己糖苷（lyso-Gb3）。最近的代谢组学研究发现了与血浆和尿液中 lyso-Gb3 相关的新型生物标志物。这些生物标志物显示 lyso-Gb3 分子的神经鞘氨醇部分发生了修饰。本研究的目的是开发和验证一种液相色谱-串联质谱法，用于相对定量新型血浆 lyso-Gb3 相关类似物，并评估其在 74 例法布里病患者和 41 例健康对照者血浆中的水平，同时将这些结果与患者性别、酶替代治疗以及同一患者尿液中先前测量的 lyso-Gb3 类似物水平相关联。正如预期的那样，与法布里女性相比，法布里男性血浆中 lyso-Gb3 及其相关类似物的浓度更高，与未治疗的男性相比，接受治疗的男性的浓度更高。酶替代治疗（ERT）治疗开始后，血浆中 lyso-Gb3 及其相关类似物的浓度显著降低，在接受 Fabry 男性 30 个月的监测治疗后保持稳定。在血浆中，lyso-Gb3 的浓度明显高于其相关类似物，这与尿液不同，尿液中大部分 lyso-Gb3 类似物的增加程度大于 lyso-Gb3 本身。与尿液不同，在同一组法布里患者中，无论 ERT 如何，血浆中 lyso-Gb3 及其类似物的相对分布在个体之间相似。本研究揭示了尿液和血浆中 lyso-Gb3 及其类似物相对丰度之间存在较大差异。因此，需要进一步研究以更好地了解血浆和尿液 lyso-Gb3 相关生物标志物之间的代谢关系。
