Determination of 7-ketocholesterol in plasma by LC-MS for rapid diagnosis of acid SMase-deficient Niemann-Pick disease

• Published in: Journal of lipid research Vol. 55; no. 2; pp. 338 - 343
• Main Authors: Lin, Na, Zhang, Huiwen, Qiu, Wenjuan, Ye, Jun, Han, Lianshu, Wang, Yu, Gu, Xuefan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2014; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Biomarkers - blood; Blood Chemical Analysis - methods; Blood Chemical Analysis - standards; Chromatography, Liquid; genetics; Heterozygote; Humans; Ketocholesterols - blood; Mass Spectrometry; Methods; Niemann-Pick Disease, Type C - blood; Niemann-Pick Disease, Type C - diagnosis; Niemann-Pick Disease, Type C - enzymology; Niemann-Pick Disease, Type C - genetics; Niemann-Pick Diseases - blood; Niemann-Pick Diseases - diagnosis; Niemann-Pick Diseases - enzymology; Niemann-Pick Diseases - genetics; oxysterols; Reference Values; Reproducibility of Results; Sphingomyelin Phosphodiesterase - deficiency; storage diseases; Time Factors; mass spectrometry; genetics; storage diseases; oxysterols
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.D044024

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.