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.
Highlights
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
In patients with Niemann Pick type C (NPC) disease, another lysosomal storage disorder (LSD) caused by deficiency of gene NPC1 or NPC2, cholesterol oxidation products are found to be significantly elevated in the plasma [19, 20]
To test whether the concentration of 7-KC might serve as a marker for acid sphingomyelinase (ASMase)-deficient NPD, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method without a derivatization step and analyzed plasma samples from patients with ASMasedeficient NPD, Niemann-Pick type C (NPC) disease, and patients that have similar clinical presentations or laboratory investigations to ASMase-deficient NPD, such as hepatomegaly, splenomegaly, hepatosplenomegaly, or abnormal lipid profile
Summary
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. It has been previously noted that tissue and plasma cholesterol and triglyceride levels are increased in patients with ASMase-deficient NPD [18]. In patients with Niemann Pick type C (NPC) disease, another LSD caused by deficiency of gene NPC1 or NPC2, cholesterol oxidation products are found to be significantly elevated in the plasma [19, 20].
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