在怀疑有脂贮积症(鞘脂类疾病,lipidoses),诊断的确认主要依赖于特定酶活性的测量和遗传研究。已经开发了新的UPLC-MS/MS方法来测量溶血鞘脂和氧固醇,which,与壳三糖苷酶活性结合可能代表脂质贮积症的快速一线筛查.
由溶菌粒三甲神经酰胺(LysoGb3)组成的溶菌鞘脂组,溶己糖神经酰胺(LysoHexCer:溶糖神经酰胺和溶糖半乳糖神经酰胺),在对照受试者和患有脂质贮积障碍的主要未治疗患者的血浆样品中测量了溶鞘磷脂(LysoSM)及其羧化类似物溶鞘磷脂-509(LysoSM-509)(n=74)。此外,氧固醇胆甾烷-3β,5α,在这些患者的一部分(n=36)中测量了6β-三醇和7-酮胆固醇以及壳三糖苷酶活性(n=43)。对文献进行了系统回顾,以评估这些生化标志物的有用性。
代谢物的特定升高,即对照和其他脂质贮积症之间没有重叠,发现了几种溶酶体贮积病:酸性鞘磷脂酶缺乏症(Niemann-PickA型)中的溶酶体SM水平升高,在Gaucher和Krabe病中具有经典表型Fabry病和LysoHexCer(即溶糖神经酰胺/溶糖半乳糖神经酰胺)的男性中的LysoGb3水平。虽然LysoSM-509和胆甾烷-3β的水平升高,5α,6β-三醇不区分尼曼匹克病C型和酸性鞘磷脂酶缺乏,LysoSM-509/LysoSM比率在尼曼-皮克病C型中特别升高。在戈谢病I型中,发现几种溶鞘鞘脂的轻度增加,包括LysoGb3,其水平在非经典Fabry男性和女性的范围内。壳三糖苷酶在有症状的戈谢病中显示出特定的升高,在所有其他脂质贮积障碍中轻度升高。文献综述确定了44种出版物。大多数发现与我们的队列一致。在广泛的其他地方发现了几种中等程度的生化标志物升高,主要是遗传代谢,疾病。
通过UPLC-MS/MS与壳三糖苷酶活性的组合在血浆中测量溶菌酶和氧固醇提供了对疑似脂质贮积病的患者的有用的第一层筛选。LysoSM-509/LysoSM比率是Niemann-Pick疾病C型的有希望的参数。需要在更大的未治疗患者和对照组中进行进一步的研究以提高发现的特异性。
In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and
oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders.
A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74). In addition, the
oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol were measured in a subset of these patients (n=36) as well as chitotriosidase activity (n=43). A systematic
review of the literature was performed to assess the usefulness of these biochemical markers.
Specific elevations of metabolites, i.e. without overlap between controls and other lipid storage disorders, were found for several lysosomal storage diseases: increased LysoSM levels in acid sphingomyelinase deficiency (Niemann-Pick disease type A/B), LysoGb3 levels in males with classical phenotype Fabry disease and LysoHexCer (i.e. lysoglucosylceramide/lysogalactosylceramide) in Gaucher and Krabbe diseases. While elevated levels of LysoSM-509 and cholestane-3β,5α,6β-triol did not discriminate between Niemann Pick disease type C and acid sphingomyelinase deficiency, LysoSM-509/LysoSM ratio was specifically elevated in Niemann-Pick disease type C. In Gaucher disease type I, mild increases in several lysosphingolipids were found including LysoGb3 with levels in the range of non-classical Fabry males and females. Chitotriosidase showed specific elevations in symptomatic Gaucher disease, and was mildly elevated in all other lipid storage disorders.
Review of the literature identified 44 publications. Most findings were in line with our cohort. Several moderate elevations of biochemical markers were found across a wide range of other, mainly inherited metabolic, diseases.
Measurement in plasma of LysoSLs and
oxysterols by UPLC-MS/MS in combination with activity of chitotriosidase provides a useful first tier screening of patients suspected of lipid storage disease. The LysoSM-509/LysoSM ratio is a promising parameter in Niemann-Pick disease type C. Further studies in larger groups of untreated patients and controls are needed to improve the specificity of the findings.