LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases

被引:38
作者
Klinke, Glynis [1 ,2 ]
Rohrbach, Marianne [3 ]
Giugliani, Roberto [4 ,5 ]
Burda, Patricie [3 ]
Baumgartner, Matthias R. [2 ,3 ]
Tran, Christel [6 ]
Gautschi, Matthias [7 ,8 ]
Mathis, Deborah [1 ]
Hersberger, Martin [1 ,2 ]
机构
[1] Univ Childrens Hosp Zurich, Childrens Res Ctr, Div Clin Chem & Biochem, Zurich, Switzerland
[2] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland
[3] Univ Childrens Hosp Zurich, Childrens Res Ctr, Div Metab, Zurich, Switzerland
[4] HCPA, Med Genet Serv, Porto Alegre, RS, Brazil
[5] Univ Fed Rio Grande do Sul, Dept Genet, Porto Alegre, RS, Brazil
[6] Univ Lausanne Hosp, Ctr Mol Dis, Lausanne, Switzerland
[7] Univ Childrens Hosp Bern, Paediat Endocrinol Diabetol & Metab, Bern, Switzerland
[8] Inselspital Bern, Univ Inst Clin Chem, Bern, Switzerland
关键词
Oxysterols; Niemann-Pick; Liquid Chromatography-Tandem; Mass Spectrometry (LC-MS/ MS); Steglich esterification; Reference intervals; RAPID DIAGNOSIS; NPC1; PROTEIN; CHOLESTEROL; PLASMA; DISRUPTION; MUTATIONS; STEP;
D O I
10.1016/j.clinbiochem.2015.03.007
中图分类号
R446 [实验室诊断]; R-33 [实验医学、医学实验];
学科分类号
1001 ;
摘要
Background: Niemann-Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking. Methods: We established a LC-MS/MS assay to measure Cholestane-3 beta, alpha a, 6 beta-triol (C-triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them. Results: The reported method is linear (r > 0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4-61.7 ng/mL, 96.0 nM, 95% CI: 62.8-146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5-102.5 ng/mL, 187.2 nM, 95% CI: 138.53-255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46% +/- 23% for C-triol and 52% +/- 29% for 7-KC. Nevertheless, all Niemann-Pick patients showed increased C-triol levels including Niemann-Pick type A and B patients. Conclusions: The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann-Pick diseases. (C) 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
引用
收藏
页码:596 / 602
页数:7
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