Diagnosis and Treatment Options for Niemann-Pick Disease Type C

Authors: H. Jahnová 1,2;  L. Dvořáková 1;  H. Hůlková 1;  M. Hřebíček 1;  P. Ješina 1
Authors‘ workplace: Ústav dědičných metabolických poruch 1. LF UK a VFN v Praze 1;  Klinika dětí a dorostu 3. LF UK a FN Královské Vinohrady v Praze 2
Published in: Cesk Slov Neurol N 2012; 75/108(3): 303-308
Category: Review Article


Niemann-Pick disease type C is an autosomal recessive lysosomal disorder clinically characterized by age-specific symptomatology with possible manifestation any time from neonatal age to late adulthood. Except for its neonatal form with cholestasis, respiratory failure and hepatosplenomegaly, the disease presents as a neurodegenerative disorder, frequently with splenomegaly. Pathophysiology involves dysfunction of the late endosome/lysosome membraneous system with accumulation of unesterified cholesterol and glycosphingolipids due to mutations in the NPC1 and NPC2 genes coding the corresponding lysosomal proteins. Results of clinical examination must be confirmed by specific loading tests in cultivated fibroblasts and/or molecular genetic analysis of the concerned genes. In the last years the disease is treated with a reversible glucosylceramide synthase inhibitor miglustat, potentially stabilizing its course. Recently, clinical testing of cyclodextrin has been initiated. In the Czech Republic, comprehensive diagnostics is available at The Institute of Inherited Metabolic Disorders (67 confirmed patients including 42 Czechs).

Key words:
Niemann-Pick disease type C – unesterified cholesterol – NPC1 gene – NPC2 gene – miglustat – cyclodextrin


1. Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea A, Neufeld EB et al. Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL et al (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York: McGraw Hill 2001: 3611–3634.

2. Wraith JE, Guffon N, Rohrbach M, Hwu WL, Korenke GC, Bembi B et al. Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study. Mol Genet Metab 2009; 98(3): 250–254.

3. Vanier MT. Niemann-Pick disease type C. Orphanet Journal of Rare Diseases [online]. 3 June 2010. Available from: http://www.ojrd.com/content/5/1/16.

4. Sévin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT et al. The adult form of Niemann-Pick disease type C. Brain 2007; 130(Pt 1): 120–133.

5. Wraith JE, Baumgartner MR, Bembi B, Covanis A, Levade T, Mengel E et al. NP-C Guidelines Working Group. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab 2009; 98(1–2): 152–165.

6. Poupetová H, Ledvinová J, Berná L, Dvoráková L, Kozich V, Elleder M. The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations. J Inherit Metab Dis 2010; 33(4): 387–396.

7. Pentchev PG, Comly ME, Kruth HS, Vanier MT, Wenger DA, Patel S et al. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci USA 1985; 82(23): 8247–8251.

8. Sturley LS, Patterson MC, Balch W, Liscum L. The pathophysiology and mechanism of NP-C disease. Bio­chim Biophys Acta 2004; 1685(1–3): 83–87.

9. Patterson MC. A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C. Neurologist 2003; 9(6): 301–310.

10. Paul CA, Boegle AK, Maue RA. Before the loss: neuronal dysfunction in Niemann-Pick type C disease. Biochim Biophys Acta 2004; 1685(1–3): 63–76.

11. Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol 2008; 9(2): 125–138.

12. Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T et al. Identification of cholesterol-regulating genes by targeted RNAi screening. Cell Met 2009; 10(1): 63–75.

13. Ximing D, Hongyuan Y. Sterol-binding proteins and endosomal cholesterol transport. Front Biol 2011; 6(3): 190–196.

14. Helquist P, Wiest O. Current status of drug therapy development for Niemann-Pick type C disease. Drugs Fut 2009; 34: 315–331.

15. Pipalia NH, Cosner CC, Huang A, Chatterjee A, Bourbon P, Farley N et al. Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts. Proc Natl Acad Sci USA 2011; 108(14): 5620–5625.

16. Dvořáková L, Sikora J, Hřebíček M, Hůlková H, Boučková M, Stolnaja L et al. Subclinical course of adult visceral Niemann-Pick type C1 disease. A rare or underdiagnosed disorder? J Inherit Met Dis 2006; 29(4): 591.

17. Walterfang M, Fahey MC, Desmond P, Wood A, Seal ML, Steward C et al. White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study. Neurology 2010; 75(1): 49–56.

18. Wajner A, Michelin K, Burin MG, Pires RF, Pereira ML, Giugliani R et al. Biochemical characterization of chitotriosidase enzyme: comparison between normal individual and patients with Gaucher and with Niemann-Pick diseases. Clin Biochem 2004; 37(10): 893–897.

19. Park WD, O’Brien JF, Lundquist PA, Kraft DL, Vockley CW, Karnes PS et al. Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutat 2003; 22(4): 313–325.

20. Ory D, Porter F, Scherrer D, Lanier M, Langmade S, Mologu V et al. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Mol Genet Metab 2010; 99: S28.

21. Jiang X, Sidhu R, Porter FD, Yanjanin NM, Speak AO, te Vruchte DT et al. A sensitive and specific LC-MS//MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma. J Lipid Res 2011; 52(7): 1435–1445.

22. Patterson MC, Platt F. Therapy of Niemann-Pick disease, type C. Biochim Biophys Acta 2004; 1685(1–3): 77–82.

23. Lachmann RH, te Vruchte DT, Lloyd-Evans E, Reinkensmeier G, Sillence DJ, Fernandez-Guillen L et al. Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C. Neurobiol Dis 2004; 16(3): 654–658.

24. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007; 6(9): 765–772.

25. Pineda M, Wraith JE, Mengel E, Sedel F, Hwu WL, Rohrbach M et al. Miglustat in patients with Niemann-Pick disease type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab 2009; 98(3): 243–249.

28. Rosenbaum AI, Zhang G, Warren JD, Max­field FR. Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells. Proc Natl Acad Sci USA 2010; 107(12): 5477–5482.

29. Iturriaga A, Pineda M, Fernández-Valero EM, Vanier MT, Coll MJ. Niemann-Pick C disease in Spain: clinical spectrum and development of a disability scale. J Neurol Sci 2006; 249(1): 1–6.

30. Yanjanin NM, Vélez JI, Gropman A, King K, Bianconi SE, Conley SK et al. Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet 2009; 153B(1): 132–140.

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