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BMC Neurology

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Open Access 01-12-2015 | Research article

Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database

Authors: Jackie Imrie, Lesley Heptinstall, Stephen Knight, Kate Strong

Published in: BMC Neurology | Issue 1/2015

Abstract

Background

Niemann-Pick disease type C (NP-C) is a rare neurovisceral lipid storage disorder characterised by progressive, disabling neurological symptoms and premature death in most patients. During the last decade, national cohort studies have accrued a great deal of data on the symptomatology and natural history of NP-C.

Methods

In an observational cohort study, we present a substantial update based on the clinical presentation and follow-up of all known UK-based patients with a confirmed diagnosis of NP-C who have been tracked on an electronic database at the Department of Genetic Medicine, University of Manchester, UK. Patients were stratified according to accepted age-at-neurological-onset categories. Data on patients’ clinical signs and symptoms, medical history and genetic studies are summarised using descriptive methods.

Results

A total of 146 patients with NP-C were included, representing the full known UK NP-C cohort, as observed from database information between 1999 and the end of 2011: 72 patients (49 %) were alive at the end of the observation period. Among a total of 116 patients (79 %) who possessed at least one identified, disease-causing NP-C gene mutation, 114 (98 %) had NPC1 and two (2 %) had NPC2 mutations. Overall, 53/194 (27 %) identified mutations were novel. Six patients (4 %) had an early, non-neurological neonatal onset form of NP-C. The numbers (%) of patients with accepted age-at-neurological onset forms were: 8 (5 %) early-infantile onset, 51 (35 %) late-infantile onset, 42 (29 %) juvenile onset, and 25 (17 %) adolescent/adult onset. Fourteen patients diagnosed based on visceral symptoms and/or sibling history, confirmed in most cases by genetic analysis, did not have any neurological manifestations at last follow up (11 patients with mean [SD] age at last follow up 2.5 [1.8] years: 3 with mean [SD] age at death 20.8 [15.9] years). A total of 51 patients (35 %) received miglustat therapy. The mean (SD) overall treatment duration up to the end of the observation period was 2.6 (2.3) years.

Conclusions

This UK cohort is the largest national NP-C cohort reported to date, and confirms the wide phenotypic variability of the disease, as reported in other countries. Further analyses are required to assess the impact of miglustat therapy on neurological disease progression.

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Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F, et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab. 2012;106:330–44.CrossRefPubMed

Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16.PubMedCentralCrossRefPubMed

Walterfang M, Chien YH, Imrie J, Rushton D, Schubiger D, Patterson MC. Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat. Orphanet J Rare Dis. 2012;7:76.PubMedCentralCrossRefPubMed

Jahnova H, Dvorakova L, Vlaskova H, Hulkova H, Poupetova H, Hrebicek M, et al. Observational, retrospective study of a large cohort of patients with Niemann-Pick disease type C in the Czech Republic: a surprisingly stable diagnostic rate spanning almost 40 years. Orphanet J Rare Dis. 2014;9:140.PubMedCentralCrossRefPubMed

McKay K, Gissen P. Genetic and laboratory diagnostic approach in Niemann Pick disease type C. J Neurol. 2014;261 Suppl 2:569–75.CrossRef

Vanier MT, Pentchev P, Rodriguez-Lafrasse C, Rousson R. Niemann-Pick disease type C: an update. J Inherit Metab Dis. 1991;14:580–95.CrossRefPubMed

Hendriksz CJ, Pineda M, Fahey M, Walterfang M, Stampfer M, Runz H, et al. The Niemann-Pick disease Type C suspicion index: development of a new tool to aid diagnosis. J Rare Disord Diag Ther. 2015;1:11.

Wraith JE, Sedel F, Pineda M, Wijburg FA, Hendriksz CJ, Fahey M, et al. Niemann-Pick type C Suspicion Index tool: analyses by age and association of manifestations. J Inherit Metab Dis. 2014;37:93–101.PubMedCentralCrossRefPubMed

Wijburg FA, Sedel F, Pineda M, Hendriksz CJ, Fahey M, Walterfang M, et al. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. Neurology. 2012;78:1560–7.CrossRefPubMed

10.

Boenzi S, Deodato F, Taurisano R, Martinelli D, Verrigni D, Carrozzo R, et al. 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. 2014;437:93–100.CrossRefPubMed

11.

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;52:1435–45.PubMedCentralCrossRefPubMed

12.

Porter FD, Scherrer DE, Lanier MH, Langmade SJ, Molugu V, Gale SE, et al. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. 2010;2:56ra81.PubMedCentralPubMed

13.

Welford RW, Garzotti M, Marques Lourenco C, Mengel E, Marquardt T, Reunert J, et al. Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study. PLoS ONE. 2014;9:e114669.PubMedCentralCrossRefPubMed

14.

Giese AK, Mascher H, Grittner U, Eichler S, Kramp G, Lukas J, et al. A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease. Orphanet J Rare Dis. 2015;10:78.PubMedCentralCrossRefPubMed

15.

Imrie J, Dasgupta S, Besley GT, Harris C, Heptinstall L, Knight S, et al. The natural history of Niemann-Pick disease type C in the UK. J Inherit Metab Dis. 2007;30:51–9.CrossRefPubMed

16.

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

17.

Heron B, Valayannopoulos V, Baruteau J, Chabrol B, Ogier H, Latour P, et al. Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C. Orphanet J Rare Dis. 2012;7:36.PubMedCentralCrossRefPubMed

18.

Lachmann RH, te Vruchte D, 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;16:654–8.CrossRefPubMed

19.

Patterson MC, Mengel E, Wijburg FA, Muller A, Schwierin B, Drevon H, et al. Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis. 2013;8:12.PubMedCentralCrossRefPubMed

20.

Patterson MC, Mengel E, Vanier MT, Schwierin B, Muller A, Cornelisse P, et al. Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J Rare Dis. 2015;10:65.PubMedCentralCrossRefPubMed

21.

Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, et al. Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001. p. 3611–33.

22.

Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003;64:269–81.CrossRefPubMed

23.

Mieli-Vergani G, Howard ER, Mowat AP. Liver disease in infancy: a 20 year perspective. Gut. 1991;Suppl:S123–8.CrossRefPubMed

24.

Kelly DA, Portmann B, Mowat AP, Sherlock S, Lake BD. Niemann-Pick disease type C: diagnosis and outcome in children, with particular reference to liver disease. J Pediatr. 1993;123:242–7.CrossRefPubMed

25.

Imrie J, Galani C, Gairy K, Lock K, Hunsche E. Cost of illness associated with Niemann-Pick disease type C in the UK. J Med Econ. 2009;12:219–29.CrossRefPubMed

26.

Wraith JE, Baumgartner MR, Bembi B, Covanis A, Levade T, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab. 2009;98:152–65.

27.

Salsano E, Umeh C, Rufa A, Pareyson D, Zee DS. Vertical supranuclear gaze palsy in Niemann-Pick type C disease. Neurol Sci. 2012;33:1225–32.CrossRefPubMed

28.

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;6:765–72.CrossRefPubMed

29.

Bauer P, Balding DJ, Klunemann HH, Linden DE, Ory DS, Pineda M, et al. Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study. Hum Mol Genet. 2013;22:4349–56.PubMedCentralCrossRefPubMed

30.

Shulman LM, David NJ, Weiner WJ. Psychosis as the initial manifestation of adult-onset Niemann-Pick disease type C. Neurology. 1995;45:1739–43.CrossRefPubMed

31.

Campo JV, Stowe R, Slomka G, Byler D, Gracious B. Psychosis as a presentation of physical disease in adolescence: a case of Niemann-Pick disease, type C. Dev Med Child Neurol. 1998;40:126–9.CrossRefPubMed

32.

Sandu S, Jackowski-Dohrmann S, Ladner A, Haberhausen M, Bachmann C. Niemann-Pick disease type C1 presenting with psychosis in an adolescent male. Eur Child Adolesc Psychiatry. 2009;18:583–5.CrossRefPubMed

33.

Nia S, Geiblinger S, Gruber C, Gallmetzer P, Gerschlager W, Baumgartner C. Psychiatric symptoms as an early sign of the adult form of lysosomal storage disease Niemann-Pick type C. J Neurol Neurochir Psychiatr. 2011;12:94–5.

34.

Walterfang M, Fietz M, Fahey M, Sullivan D, Leane P, Lubman DI, et al. The neuropsychiatry of Niemann-Pick type C disease in adulthood. J Neuropsychiatry Clin Neurosci. 2006;18:158–70.CrossRefPubMed

35.

Greenberg C, Barnes JG, Kogan S, Seargent LE: A rare case of Niemann–Pick disease type C without neurological involvement in a 66-year-old patient. Molec Genet Metab Rep [article in press] DOI: 10.1016/jymgmr201502004 2015.

36.

Benussi A, Alberici A, Premi E, Bertasi V, Cotelli MS, Turla M, et al. Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins. J Neurol. 2015;262:642–7.CrossRefPubMed

37.

Gelsthorpe ME, Baumann N, Millard E, Gale SE, Langmade SJ, Schaffer JE, et al. Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding. J Biol Chem. 2008;283:8229–36.PubMedCentralCrossRefPubMed

38.

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 U S A. 1985;82:8247–51.PubMedCentralCrossRefPubMed

39.

Millat G, Marcais C, Rafi MA, Yamamoto T, Morris JA, Pentchev PG, et al. Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am J Hum Genet. 1999;65:1321–9.PubMedCentralCrossRefPubMed

40.

Cox TM, Amato D, Hollak CE, Luzy C, Silkey M, Giorgino R, et al. Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study. Orphanet J Rare Dis. 2012;7:102.PubMedCentralCrossRefPubMed

41.

Cox T, Lachmann R, Hollak C, Aerts J, van Weely S, Hrebicek M, et al. Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet. 2000;355:1481–5.CrossRefPubMed

42.

Elstein D, Dweck A, Attias D, Hadas-Halpern I, Zevin S, Altarescu G, et al. Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood. 2007;110:2296–301.CrossRefPubMed

43.

Elstein D, Hollak C, Aerts JM, van Weely S, Maas M, Cox TM, et al. Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease. J Inherit Metab Dis. 2004;27:757–66.CrossRefPubMed

44.

Kuter DJ, Mehta A, Hollak CE, Giraldo P, Hughes D, Belmatoug N, et al. Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study. Blood Cells Mol Dis. 2013;51:116–24.CrossRefPubMed

45.

Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab. 2010;99:351–7.CrossRefPubMed

46.

Wraith JE, Imrie J. New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat. Ther Clin Risk Manag. 2009;5:877–87.PubMedCentralCrossRefPubMed

47.

Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010;25:300–5.CrossRefPubMed

48.

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;98:243–9.CrossRefPubMed

Title: Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database
Authors: Jackie Imrie
Lesley Heptinstall
Stephen Knight
Kate Strong
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Neurology / Issue 1/2015
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-015-0511-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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