A new simple and rapid LC–ESI-MS/MS method for quantification of plasma oxysterols as dimethylaminobutyrate esters. Its successful use for the diagnosis of Niemann–Pick type C disease

Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Martinelli, Diego; Verrigni, Daniela; Carrozzo, Rosalba; Bertini, Enrico; Pastore, Anna; Dionisi‐Vici, Carlo; Johnson, David W.

doi:10.1016/j.cca.2014.07.010

Cited by 62 publications

(46 citation statements)

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“…All patients had biochemical, enzymatic and/or molecular diagnosis. Twelve out of 16 NP-C patients were those reported in the previous study ( 6 ), but, in the present study, for those patients, supplemental sample results were added. All patients were followed at the Division of Metabolism, "Bambino Gesù" Children's Hospital.…”

Section: Patients and Controlsmentioning

confidence: 99%

“…Chromatography was performed on an Agilent series 1290 pump equipped with autosampler. The column for chromatographic separation was a Phenomenex Synergy Fusion C18, 50 mm × 2.0 mm internal diameter, 4 m. Chromatographic separation of metabolites was obtained with gradient elution of two solutions as previously described ( 6 ). Total run was 5.1 min.…”

Section: Plasma Oxysterol Analysismentioning

confidence: 99%

“…Derivatization was performed adding 20 l of derivatizing solution (100 mM dimethyl-aminobutyric acid imidazolide) at 65°C for 15 min. Finally, the sample was dried again and reconstituted with 200 l solvent, and 5 l was injected for the detection and quantifi cation of free or unesterifi ed oxysterols, C-triol, and 7-KC, as DMAB monoderivatives ( 6 ).…”

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confidence: 99%

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Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

Boenzi

Deodato

Taurisano

et al. 2016

Journal of Lipid Research

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Section: Patients and Controlsmentioning

confidence: 99%

Section: Plasma Oxysterol Analysismentioning

confidence: 99%

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Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

Boenzi

Deodato

Taurisano

et al. 2016

Journal of Lipid Research

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“…In the NPC murine model, an increase of two oxysterols, cholestane-3 b ,5 a ,6 b -triol (CT) and 7-ketocholesterol (7-KC), has been observed ( 8 ). This evidence was later confi rmed in NPC patients (8)(9)(10)(11)(12)(13), showing a correlation between the oxysterol profi le and the age of onset and severity of the disease ( 8,14 ). Moreover, CT specifi cally has been found to be increased in NPC disease compared with other lysosomal and neurodegenerative diseases ( 8 ).…”

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confidence: 96%

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Pajares

Arias

García‐Villoria

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org Niemann-Pick type C (NPC; MIM#257220) is a progressive neurodegenerative disease caused by a disorder in the intracellular traffi cking of cholesterol that leads to a lysosomal/endosomal accumulation of unesterifi ed cholesterol and glycolipids in many tissues ( 1-3 ). The detection of free cholesterol accumulation by fi lipin staining in fibroblasts has been for many years the gold standard methodology for the biochemical diagnosis of the disease. This method has good sensitivity and specifi city. However, juvenile or adult onset forms sometimes present interpretation diffi culties ( 4 ). In addition, the method involves an invasive skin biopsy and the culture of fi broblasts that requires several weeks for the cellular growth, which delays the diagnosis. Some studies in cellular and animal models showed a correlation between lipid accumulation and cellular oxidative stress that produces an increase of reactive oxygen species and lipid peroxidation ( 5-8 ). In the NPC murine model, an increase of two oxysterols, cholestane-3 b ,5 a ,6 b -triol (CT) and 7-ketocholesterol (7-KC), has been observed ( 8 ). This evidence was later confi rmed in NPC patients (8)(9)(10)(11)(12)(13), showing a correlation between the oxysterol profi le and the age of onset and severity of the disease ( 8,14 ). Moreover, CT specifi cally has been found to be increased in NPC disease compared with other lysosomal and neurodegenerative diseases ( 8 ). These results Abstract Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterifi ed cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3 ␤ ,5 ␣ ,6 ␤ -triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specifi city of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 pa- 26,26,26,27,27, ; AUC, area under receiver-operating characteristic curve; BHT, butylhydroxytoluene; CI, confi dence interval; CT, cholestane-3 b ,5 a ,6 b -triol; 5 a ,26,26,26,27,27, ; CTX, cerebrotendinous xanthomatosis; % CV, percentage coeffi cient of variation; LAL, lysosomal acid lipase; LOD, limit of detection; LOQ, limit of quantifi cation; LSD, lysosomal storage disease; MRM, multiple reaction monitoring; NPC, Niemann-Pick type C; ROC, receiver-operating characteristic; SLO, Smith-Lemli-Opitz.

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“…In fact, the plasmatic levels of these oxysterols allow distinguishing between NPC1 patients and controls. Only one NPC2 patient has been detected after oxysterol analysis so far (Boenzi et al 2014). …”

Section: Introductionmentioning

confidence: 99%

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

et al. 2015

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Introduction: Niemann-Pick type C disease is a rare disorder caused by impaired intracellular lipid transport due to mutations in either the NPC1 or the NPC2 gene. Ninety-five % of NPC patients show mutations in the NPC1 gene. A much smaller number of patients suffer from NPC2 disease and present respiratory failure as one of the most frequent symptoms. Several plasma oxysterols are highly elevated in NPC1 and can be used as a biomarker in the diagnosis of NPC1.Methods: Plasma cholestane-3b,5a,6b-triol was evaluated as biomarker for NPC2 by GC/MS and LC-MS/MS analysis. The diagnosis was confirmed by Sanger sequencing and filipin staining.Results: We report three NPC2 patients with typical respiratory problems and a detailed description of the nature of the lung disease in one of them. All patients had elevated levels of plasma cholestane-3b,5a,6b-triol. In two of these patients, the positive oxysterol result led to a rapid diagnosis of NPC2 by genetic analysis. The phenotype of the third patient has been described previously. In this patient a cholestane-3b,5a,6b-triol concentration markedly above the reference range was found.Conclusions: Measurement of plasma cholestane3b,5a,6b-triol enables to discriminate between controls and NPC1 and NPC2 patients, making it a valuable biomarker for the rapid diagnosis not only for NPC1 but also for NPC2 disease.The measurement of oxysterols should be well kept in mind in the differential diagnosis of lysosomal diseases, as the elevation of oxysterols in plasma may speed up the diagnosis of NPC1 and NPC2.

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A new simple and rapid LC–ESI-MS/MS method for quantification of plasma oxysterols as dimethylaminobutyrate esters. Its successful use for the diagnosis of Niemann–Pick type C disease

Cited by 62 publications

References 21 publications

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

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