Abstract
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-3β,5α,6β-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-3β,5α,6β-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-3β,5α,6β-triol concentration markedly above the reference range was found.
Conclusions: Measurement of plasma cholestane-3β,5α,6β-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.
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alavi A, Nafissi S, Shamshiri H, Nejad MM, Elahi E (2013) Identification of mutation in NPC2 by exome sequencing results in diagnosis of Niemann-Pick disease type C. Mol Genet Metab 110:139–144
Blanchette-Mackie EJ, Dwyer NK, Amende LM et al (1988) Type-C Niemann-Pick disease: low density lipoprotein uptake is associated with premature cholesterol accumulation in the Golgi complex and excessive cholesterol storage in lysosomes. Proc Natl Acad Sci U S A 85:8022–8026
Boenzi S, Deodato F, Taurisano R et al (2014) 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. Clin Chim Acta 437:93–100. doi:10.1016/j.cca.2014.07.010
Bonney DK, O’Meara A, Shabani A et al (2010) Successful allogeneic bone marrow transplant for Niemann–Pick disease type C2 is likely to be associated with a severe “graft versus substrate” effect. J Inherit Metab Dis 33:171–173. doi:10.1007/s10545-010-9060-3
Breen C, Wynn RF, O’Meara A et al (2013) Developmental outcome post allogenic bone marrow transplant for Niemann Pick Type C2. Mol Genet Metab 108:82–84. doi:10.1016/j.ymgme.2012.11.006
Carstea ED, Morris JA, Coleman KG et al (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:228–231. doi:10.1126/science.277.5323.228
Griese M, Brasch F, Aldana V et al (2010) Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis. Clin Genet 77:119–130. doi:10.1111/j.1399-0004.2009.01325.x
Higgins ME, Davies JP, Chen FW, Ioannou YA (1999) Niemann–Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol Genet Metab 68:1–13. doi:10.1006/mgme.1999.2882
Hollak CE, van Weely S, van Oers MH, Aerts JM (1994) Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 93:1288–1292. doi:10.1172/JCI117084
Jiang X, Sidhu R, Porter FD et al (2011) A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma. J Lipid Res 52:1435–1445. doi:10.1194/jlr.D015735
Klansek JJ, Yancey P, Clair RWS et al (1995) Cholesterol quantitation by GLC: artifactual formation of short-chain steryl esters. J Lipid Res 36:2261–2266
Klünemann HH, Elleder M, Kaminski WE et al (2002) Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol 52:743–749
Lin N, Zhang H, Qiu W et al (2014) Determination of 7-ketocholesterol in plasma by LC-MS for rapid diagnosis of acid SMase-deficient Niemann-Pick disease. J Lipid Res 55:338–343. doi:10.1194/jlr.D044024
Mengel E, Klunemann H-H, Lourenco CM et al (2013) Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet J Rare Dis 8:166. doi:10.1186/1750-1172-8-166
Millat G, Chikh K, Naureckiene S et al (2001) Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet 69:1013–1021. doi:10.1086/324068
Millat G, Baïlo N, Molinero S et al (2005) Niemann–Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab 86:220–232. doi:10.1016/j.ymgme.2005.07.007
Okamura N, Kiuchi S, Tamba M et al (1999) A porcine homolog of the major secretory protein of human epididymis, HE1, specifically binds cholesterol. Biochim Biophys Acta BBA Mol Cell Biol Lipids 1438:377–387. doi:10.1016/S1388-1981(99)00070-0
Patterson MC, Hendriksz CJ, Walterfang M et al (2012) Recommendations for the diagnosis and management of Niemann–Pick disease type C: an update. Mol Genet Metab 106:330–344. doi:10.1016/j.ymgme.2012.03.012
Porter FD, Scherrer DE, Lanier MH et al (2010) Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann–Pick C1 disease. Sci Transl Med 2:56ra81. doi:10.1126/scitranslmed.3001417
Reddy JV, Ganley IG, Pfeffer SR (2006) Clues to neuro-degeneration in Niemann-Pick type C disease from global gene expression profiling. PloS One 1:e19. doi:10.1371/journal.pone.0000019
Ries M, Schaefer E, Lührs T et al (2006) Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann–Pick disease type A/B and C. J Inherit Metab Dis 29:647–652. doi:10.1007/s10545-006-0363-3
Schofer O, Mischo B, Püschel W et al (1998) Early-lethal pulmonary form of Niemann-Pick type C disease belonging to a second, rare genetic complementation group. Eur J Pediatr 157:45–49. doi:10.1007/s004310050764
SSIEM (2014) Annual symposium: abstracts. J Inherit Metab Dis 37:27–185. doi:10.1007/s10545-014-9740-5
Storch J, Xu Z (2009) Niemann–Pick C2 (NPC2) and intracellular cholesterol trafficking. Biochim Biophys Acta BBA Mol Cell Biol Lipids 1791:671–678. doi:10.1016/j.bbalip.2009.02.001
Vanier MT, Rodriguez-Lafrasse C, Rousson R et al (1991) Type C Niemann–Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing. Biochim Biophys Acta 1096:328–337
Verot L, Chikh K, Freydière E et al (2007) Niemann–Pick C disease: functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2. Clin Genet 71:320–330. doi:10.1111/j.1399-0004.2007.00782.x
Wraith JE, Baumgartner MR, Bembi B et al (2009) Recommendations on the diagnosis and management of Niemann–Pick disease type C. Mol Genet Metab 98:152–165. doi:10.1016/j.ymgme.2009.06.008
Zampieri S, Mellon SH, Butters TD et al (2009) Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone. J Cell Mol Med 13:3786–3796. doi:10.1111/j.1582-4934.2008.00493.x
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Maurizio Scarpa, MD, PhD
Appendices
Compliance with Ethics Guidelines
Conflict of Interest
The work of Thorsten Marquardt and Janine Reunert is part of an investigator-initiated study, funded by a grant from Actelion Pharmaceuticals Ltd.
The work of Matthias Griese was supported by eRARE-2009 (EUPAPNet), DFG-970/8-1, and FP7-chILD-EU. The funding sources had no involvement in the collection, analysis, and interpretation of data or in the writing of the report.
Janine Reunert has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Giulia Polo has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Frank Kannenberg has received speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Eugen Mengel has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Andrea Dardis has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Alessandro Burlina has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Bruno Bembi has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Alberto Burlina has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Thorsten Marquardt has received travel reimbursements and speaker honorarium from Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Amelie Lotz-Havla, Manfred Fobker, Ania Muntau, Philipp Schnabel, Olaf Sommerburg, Ingo Borggraefe, Matthias Mall, and Giovanni Ciana declare that they have no conflict of interest. None of the authors has nonfinancial interests that may be relevant to the submitted work.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
Details of the Contributions of Individual Authors
Janine Reunert: acquisition and analysis of data, drafting, and revising the manuscript.
Amelie Lotz-Havla and Andrea Dardis: acquisition and interpretation of data, involved in drafting and revising the manuscript.
Giulia Polo, Matthias Griese, Frank Kannenberg, Eugen Mengel, Manfred Fobker, Ania Muntau, Ingo Borggraefe, Philipp Schnabel, Olaf Sommerburg, Alessandro Burlina, Matthias Mall, Giovanni Ciana, and Bruno Bembi: acquisition and interpretation of data, revising the manuscript.
Alberto Burlina and Thorsten Marquardt: supervising and design of the study, acquisition and interpretation of data, revising the manuscript.
Rights and permissions
Copyright information
© 2015 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Reunert, J. et al. (2015). Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 23. JIMD Reports, vol 23. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_423
Download citation
DOI: https://doi.org/10.1007/8904_2015_423
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-47466-2
Online ISBN: 978-3-662-47467-9
eBook Packages: MedicineMedicine (R0)