Detecting lysosomal storage disorders by glycomic profiling using liquid chromatography mass spectrometry.
Detecting lysosomal storage disorders by glycomic profiling using liquid chromatography mass spectrometry.
复制标题
利用液相色谱质谱法通过糖组学分析检测溶酶体胆积症。
DOI：
10.1016/j.ymgme.2021.08.006
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发表时间：
2021-09
影响因子：
3.8
通讯作者：
Cowan, Tina M.
中科院分区：
文献类型：
--
作者：
Mak, Justin;Cowan, Tina M.
关键词：
通过液相色谱质谱 (LC-MS) 检测尿液和血浆溶酶体贮积症生物标志物目前需要多种分析方法来检测寡糖、粘多糖和糖脂的异常积累。为了提高临床检测效率，我们开发了一种单一的 LC-MS 方法，以最少的样品制备同时鉴定寡糖、粘多糖和糖脂代谢紊乱。我们创建了一种使用酰胺柱和高 pH 条件分离天然形式的游离聚糖和糖脂的单一色谱方法。我们使用这种糖组分析方法，使用 LC 离子淌度高分辨率 MS 对患者和对照尿液进行非靶向分析（生物标志物发现），并通过 LC-MS/MS 对尿液、血清和干血斑样本进行靶向分析（临床验证）。非靶向糖组分析揭示了二十种可以识别粘多糖症并对其进行亚型分类的生物标志物。我们将这些与已知的寡糖和糖脂生物标志物结合到快速测试中，识别至少 27 种溶酶体贮积症，包括寡糖贮积症、粘多糖贮积症、鞘脂贮积症、糖原贮积症以及先天性糖基化和去糖基化疾病。在包含来自溶酶体贮积症患者的 115 个尿液样本的验证集中，所有样本都与正常对照明确区分，88% (101/115) 的病例的疾病亚型正确。戈谢病患者的干血斑中葡萄糖基鞘氨醇确实升高，半乳糖基鞘氨醇的基线分辨率得到提高。通过液相色谱质谱法进行糖组分析可识别一系列溶酶体贮积症。该测试可用于临床评估，以快速集中诊断，以及澄清或支持其他基因测序和酶研究。
Urine and plasma biomarker testing for lysosomal storage disorders by liquid chromatography mass spectrometry (LC-MS) currently requires multiple analytical methods to detect the abnormal accumulation of oligosaccharides, mucopolysaccharides, and glycolipids. To improve clinical testing efficiency, we developed a single LC-MS method to simultaneously identify disorders of oligosaccharide, mucopolysaccharide, and glycolipid metabolism with minimal sample preparation. We created a single chromatographic method for separating free glycans and glycolipids in their native form, using an amide column and high pH conditions. We used this glycomic profiling method both in untargeted analyses of patient and control urines using LC ion-mobility high-resolution MS (biomarker discovery), and targeted analyses of urine, serum, and dried blood spot samples by LC-MS/MS (clinical validation). Untargeted glycomic profiling revealed twenty biomarkers that could identify and subtype mucopolysaccharidoses. We incorporated these with known oligosaccharide and glycolipid biomarkers into a rapid test that identifies at least 27 lysosomal storage disorders, including oligosaccharidoses, mucopolysaccharidoses, sphingolipidoses, glycogen storage disorders, and congenital disorders of glycosylation and de-glycosylation. In a validation set containing 115 urine samples from patients with lysosomal storage disorders, all were unambiguously distinguished from normal controls, with correct disease subtyping for 88% (101/115) of cases. Glucosylsphingosine was reliably elevated in dried blood spots from Gaucher disease patients with baseline resolution from galactosylsphingosine. Glycomic profiling by liquid chromatography mass spectrometry identifies a range of lysosomal storage disorders. This test can be used in clinical evaluations to rapidly focus a diagnosis, as well as to clarify or support additional gene sequencing and enzyme studies.
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