title: Determination of 7-ketocholesterol in plasma by LC-MS for rapid diagnosis of acid SMase-deficient Niemann-Pick disease.
abstract: Acid sphingomyelinase (ASMase)-deficient Niemann-Pick disease (NPD) is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, resulting in accumulation of sphingomyelin in the lysosomes and secondary changes in cholesterol metabolism. We hypothesized that the oxidation product of cholesterol, 7-ketocholesterol (7-KC), might increase in the plasma of patients with ASMase-deficient NPD. In this study, a rapid and nonderivatized method of measurement of plasma 7-KC by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Plasma samples from healthy subjects, patients with ASMase-deficient NPD, nonaffected ASMase-deficient NPD heterozygotes, Niemann-Pick type C (NPC) disease, glycogen storage disorder type II (GSDII), Gaucher disease (GD), mucopolysaccharidosis type II (MPSII), Krabbe disease (KD), and metachromatic leukodystrophy (MLD) were tested retrospectively. Markedly elevated 7-KC was found in patients with ASMase-deficient NPD and NPC disease that showed significant differences from ASMase-deficient NPD heterozygotes; patients with GSDII, GD, MPSII, KD, and MLD; and normal controls. The analysis of plasma 7-KC by LC-MS/MS offers the first simple, quantitative, and highly sensitive method for detection of ASMase-deficient NPD and could be useful in the diagnosis of both ASMase-deficient NPD and NPC disease.
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Na
authors.initials: N
authors.lastname: Lin
authors.forename: Huiwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Qiu
authors.forename: Jun
authors.initials: J
authors.lastname: Ye
authors.forename: Lianshu
authors.initials: L
authors.lastname: Han
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Xuefan
authors.initials: X
authors.lastname: Gu
mesh_terms: D015415:Biomarkers / Q000097:blood; D001774:Blood Chemical Analysis / Q000379:methods* / Q000592:standards; D002853:Chromatography, Liquid; D006579:Heterozygote; D006801:Humans; D007653:Ketocholesterols / Q000097:blood*; D013058:Mass Spectrometry; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D009542:Niemann-Pick Diseases / Q000097:blood* / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D012016:Reference Values; D015203:Reproducibility of Results; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D007653:Ketocholesterols; D013108:Sphingomyelin Phosphodiesterase; C003001:7-ketocholesterol
keywords: genetics; mass spectrometry; oxysterols; storage diseases