Inborn Errors of Metabolism Section, Genetics & Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London, London WC1 1EH, UK.
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, University College London, London WC1 1EH, UK.
Int J Mol Sci. 2023 Jun 15;24(12):10177. doi: 10.3390/ijms241210177.
Dried blood spots (DBSs) biomarkers are convenient for monitoring for specific lysosomal storage diseases (LSDs), but they could have relevance for other LSDs. To determine the specificity and utility of glycosphingolipidoses biomarkers against other LSDs, we applied a multiplexed lipid liquid chromatography tandem mass spectrometry assay to a DBS cohort of healthy controls ( = 10) and Gaucher ( = 4), Fabry ( = 10), Pompe ( = 2), mucopolysaccharidosis types I-VI ( = 52), and Niemann-Pick disease type C (NPC) ( = 5) patients. We observed no complete disease specificity for any of the markers tested. However, comparison among the different LSDs highlighted new applications and perspectives of the existing biomarkers. We observed elevations in glucosylceramide isoforms in the NPC and Gaucher patients relative to the controls. In NPC, there was a greater proportion of C24 isoforms, giving a specificity of 96-97% for NPC, higher than 92% for the NPC biomarker N-palmitoyl-O-phosphocholineserine ratio to lyso-sphingomyelin. We also observed significantly elevated levels of lyso-dihexosylceramide in Gaucher and Fabry disease as well as elevated lyso-globotriaosylceramide (Lyso-Gb3) in Gaucher disease and the neuronopathic forms of Mucopolysaccharidoses. In conclusion, DBS glucosylceramide isoform profiling has increased the specificity for the detection of NPC, thereby improving diagnostic accuracy. Low levels of lyso-lipids can be observed in other LSDs, which may have implications in their disease pathogenesis.
干血斑 (DBS) 生物标志物便于监测特定的溶酶体贮积病 (LSD)，但它们可能与其他 LSD 有关。为了确定糖脂代谢病生物标志物对其他 LSD 的特异性和实用性，我们应用多重脂质液相色谱串联质谱法对健康对照组 (n = 10) 和戈谢病 (n = 4)、法布里病 (n = 10)、庞贝病 (n = 2)、黏多糖贮积症 I-VI 型 (n = 52) 和尼曼-匹克病 C 型 (NPC) (n = 5) 患者的 DBS 队列进行了分析。我们观察到，没有任何一种测试标志物具有完全的疾病特异性。然而，不同 LSD 之间的比较突出了现有生物标志物的新应用和新视角。我们观察到 NPC 和戈谢病患者的葡萄糖神经酰胺异构体升高，与对照组相比。在 NPC 中，C24 异构体的比例更大，因此 NPC 的特异性为 96-97%，高于 NPC 生物标志物 N-棕榈酰-O-磷酸胆碱与溶磷脂酰丝氨酸的比值的 92%。我们还观察到戈谢病和法布里病中溶神经酰胺二己糖苷的水平显著升高，以及戈谢病和黏多糖贮积症神经病变形式中溶神经酰胺糖基甘油二酯的水平升高。总之，DBS 葡萄糖神经酰胺异构体谱分析提高了 NPC 的检测特异性，从而提高了诊断准确性。其他 LSD 中也可以观察到低水平的溶脂，这可能对其发病机制有影响。
