Lysomal Storage Disorder

The Chameleon

Niemann-Pick Type C disease

In Niemann-Pick disease type C, a defect in the NPC1 gene (approximately 95% of cases) or in the NPC2 gene (approx. 5% of cases) leads to impaired intracellular cholesterol trafficking and consecutive to accumulation of unesterified cholesterol in the cells of various organs. The age of manifestation extends from the perinatal period to late adulthood. Clinical symptoms are very heterogeneous. In addition to visceral signs – consisting of a splenomegaly or hepatosplenomegaly – neurological symptoms, such as progressive cerebellar ataxia, dysarthria, vertical supranuclear gaze palsy, epilepsy, cataplexy and progressive dementia are characteristic. For the treatment of progressive neurological symptoms, substrate reduction therapy with miglustat is currently available.

Niemann-Pick Type C disease | SphinCS - Clinical Science for LSD

Synonym: Disordered intracellular lipid transport
Gene: NPC1 Gene; NPC2 Gene
Mode of inheritance: Autosomal recessive
Phenotypes:

  • Pre-/perinatal 
  • Early-infantile
  • Late-infantile
  • Juvenile
  • Adult 

Leading symptoms:

Pre-/perinatal
(Age of onset: < 2 months)

  • Fetal ascites/ Hydrops fetalis
  • Hepatosplenomegaly
  • Cholestatic Hepatopathy (Icterus prolongatus)
  • Muscular hypotonia
  • Pulmonale manifestation (NPC2)

Early-infantile
(Age of onset: 2 months to 1 year)

  • Hepatosplenomegaly or isolated splenomegaly
  • Psychomotor development delay/arrest
  • Spasticity
  • Vertical supranuclear gaze palsy

Late-infantile
(Age of onset: 2-5 years)

  • Hepatosplenomegaly or isolated splenomegaly
  • Psychomotor development delay
  • Progressive Ataxie
  • Vertical supranuclear gaze palsy
  • Epilepsie
  • Cataplexy

Juvenil
(Age of onset: 6-15 years)

  • Hepatosplenomegaly or isolated splenomegaly
  • Cognitive decline
  • Progressive ataxia
  • Vertical supranuclear gaze palsy
  • Dystonia
  • Epilepsy
  • Cataplexy

Adult
(Age of onset: > 15 years)

  • Cognitive decline
  • Psychiatric symptoms
  • Vertical supranuclear gaze palsy
  • Progressive ataxia
  • Dystonia

Diagnostics:

  • Oxysterols in plasma (screeningparameter, also elevated in LAL-D and ASMD)
  • Lyso-sphingomyelin 509
  • Molecular genetic analysis of NPC1 / NPC2 Gene

Therapy:
Miglustat (Substrate reduction therapy)

Current Studies

M. Niemann-Pick Typ C
CTD-TCNPC-301
A Phase 3, Double-blind, Randomized, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety , Tolerability, and Efficacy of ( 2000 mg/kg) of Trappsol® Cyclo ™(Hydroxypropyl-β-cyclodextrin) and Standard of Care Compared to Placebo and Standard of Care in Patients with Niemann-Pick Disease Type C1
Age

without age restriction

Status active

Patient admission closed

Institution SphinCS GmbH

Drug trial
ASMD M. Niemann-Pick Typ C
INPDR-NP registry
International Niemann-Pick Disease Registry – An International Rare Disease Registry for
Niemann-Pick Disease Type A, B or C.
Age

No age limit

Status active

Patient admission recruiting

Institution SphinCS Lyso gemeinnützige UG (haftungsbeschränkt)

Register-Study
M. Niemann-Pick Typ C
CT-ORZY-NPC-002
Arimoclomol prospective double-blind, randomised, placebo-controlled study in patients diagnosed with Niemann-Pick disease type C
Age

6 - 23 Month

Status active

Patient admission closed

Institution SphinCS GmbH

Drug trial
M. Niemann-Pick Typ C
IB1001-301
Effects of N-Acetyl-L-Leucine on Niemann-Pick disease type C (NPC): A Phase III, randomized, placebo-controlled, double-blind, crossover study
Age

From 4 years ago

Status active

Patient admission closed

Institution SphinCS GmbH

Drug trial
The "U.S. National Library of Medicine" provides a complete list of all international studies at www.clinicaltrials.gov. The comparable EU website is less comprehensive: www.clinicaltrialsregister.eu.

Self-help groups

Niemann-Pick Selbsthilfegruppe Deutschland e.V.
https://www.niemann-pick-selbsthilfegruppe.de

At the moment we are not aware of any self-help groups.

Literature

Belmatoug, N., A. Burlina, P. Giraldo, C. J. Hendriksz, D. J. Kuter, E. Mengel, and G. M. Pastores. 

Gastrointestinal Disturbances and Their Management in Miglustat-Treated Patients
J Inherit Metab Dis 34, no. 5 (Oct 2011): 991-1001.
Link to the publication

Bonnot, O., C. S. Gama, E. Mengel, M. Pineda, M. T. Vanier, L. Watson, M. Watissee, B. Schwierin, and M. C. Patterson. "Psychiatric and Neurological Symptoms in Patients with Niemann-Pick Disease Type C (Np-C).

Psychiatric and Neurological Symptoms in Patients with Niemann-Pick Disease Type C (Np-C): Findings from the International Npc Registry
World J Biol Psychiatry 20, no. 4 (Apr 2019): 310-19.
Link to the publication

Bremova, T., V. Malinova, Y. Amraoui, E. Mengel, J. Reinke, M. Kolnikova, and M. Strupp.

Acetyl-Dl-Leucine in Niemann-Pick Type C: A Case Series
Neurology 85, no. 16 (Oct 20 2015): 1368-75.
Link to the publication

Cortina-Borja, M., D. Te Vruchte, E. Mengel, Y. Amraoui, J. Imrie, S. A. Jones, I. Dali C, P. Fineran, T. Kirkegaard, H. Runz, R. Lachmann, T. Bremova-Ertl, M. Strupp, and F. M. Platt.

Annual Severity Increment Score as a Tool for Stratifying Patients with Niemann-Pick Disease Type C and for Recruitment to Clinical Trials.
Orphanet J Rare Dis 13, no. 1 (Aug 16 2018): 143.
Link to the publication

Geberhiwot, T., A. Moro, A. Dardis, U. Ramaswami, S. Sirrs, M. P. Marfa, M. T. Vanier, M. Walterfang, S. Bolton, C. Dawson, B. Heron, M. Stampfer, J. Imrie, C. Hendriksz, P. Gissen, E. Crushell, M. J. Coll, Y. Nadjar, H. Klunemann, E. Mengel, M. Hrebicek, S. A. Jones, D. Ory, B. Bembi, M. Patterson, and Registry International Niemann-Pick Disease.

Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C
Orphanet J Rare Dis 13, no. 1 (Apr 6 2018): 50.
Link to the publication

Group, Np- C. Guidelines Working, J. E. Wraith, M. R. Baumgartner, B. Bembi, A. Covanis, T. Levade, E. Mengel, M. Pineda, F. Sedel, M. Topcu, M. T. Vanier, H. Widner, F. A. Wijburg, and M. C. Patterson

Recommendations on the Diagnosis and Management of Niemann-Pick Disease Type C
Mol Genet Metab 98, no. 1-2 (Sep-Oct 2009): 152-65.
Link to the publication

Maekawa, M., A. Narita, I. Jinnoh, T. Iida, T. Marquardt, E. Mengel, Y. Eto, P. T. Clayton, H. Yamaguchi, and N. Mano

Diagnostic Performance Evaluation of Sulfate-Conjugated Cholesterol Metabolites as Urinary Biomarkers of Niemann-Pick Disease Type C
Clin Chim Acta 494 (Jul 2019): 58-63.
Link to the publication

Mengel, E., H. H. Klunemann, C. M. Lourenco, C. J. Hendriksz, F. Sedel, M. Walterfang, and S. A. Kolb

Niemann-Pick Disease Type C Symptomatology: An Expert-Based Clinical Description
Orphanet J Rare Dis 8 (Oct 17 2013): 166.
Link to the publication

Mengel, E., M. Pineda, C. J. Hendriksz, M. Walterfang, J. V. Torres, and S. A. Kolb

Differences in Niemann-Pick Disease Type C Symptomatology Observed in Patients of Different Ages
Mol Genet Metab 120, no. 3 (Mar 2017): 180-89.
Link to the publication

Patterson, M. C., E. Mengel, M. T. Vanier, B. Schwierin, A. Muller, P. Cornelisse, M. Pineda, and N. P. C. Registry investigators

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 10 (May 28 2015): 65.
Link to the publication

Patterson, M. C., E. Mengel, F. A. Wijburg, A. Muller, B. Schwierin, H. Drevon, M. T. Vanier, and M. Pineda.

Disease and Patient Characteristics in Np-C Patients: Findings from an International Disease Registry
Orphanet J Rare Dis 8 (Jan 16 2013): 12.
Link to the publication

Pineda, M., E. Mengel, H. Jahnova, B. Heron, J. Imrie, C. M. Lourenco, V. van der Linden, P. Karimzadeh, V. Valayannopoulos, P. Jesina, J. V. Torres, and S. A. Kolb

A Suspicion Index to Aid Screening of Early-Onset Niemann-Pick Disease Type C (Np-C)
BMC Pediatr 16 (Jul 22 2016): 107.
Link to the publication

Pineda, M., J. E. Wraith, E. Mengel, F. Sedel, W. L. Hwu, M. Rohrbach, B. Bembi, M. Walterfang, G. C. Korenke, T. Marquardt, C. Luzy, R. Giorgino, and M. C. Patterson

Miglustat in Patients with Niemann-Pick Disease Type C (Np-C): A Multicenter Observational Retrospective Cohort Study
Mol Genet Metab 98, no. 3 (Nov 2009): 243-9.
Link to the publication

Reunert, J., A. S. Lotz-Havla, G. Polo, F. Kannenberg, M. Fobker, M. Griese, E. Mengel, A. C. Muntau, P. Schnabel, O. Sommerburg, I. Borggraefe, A. Dardis, A. P. Burlina, M. A. Mall, G. Ciana, B. Bembi, A. B. Burlina, and T. Marquardt

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3beta,5alpha,6beta-Triol and Further Insight into the Clinical Phenotype
JIMD Rep 23 (2015): 17-26.
Link to the publication

Ries, M., E. Schaefer, T. Luhrs, L. Mani, J. Kuhn, M. T. Vanier, F. Krummenauer, A. Gal, M. Beck, and E. Mengel

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, no. 5 (Oct 2006): 647-52.
Link to the publication

Speak, A. O., N. Platt, M. Salio, D. te Vruchte, D. A. Smith, D. Shepherd, N. Veerapen, G. S. Besra, N. M. Yanjanin, L. Simmons, J. Imrie, J. E. Wraith, R. H. Lachmann, R. Hartung, H. Runz, E. Mengel, M. Beck, C. J. Hendriksz, F. D. Porter, V. Cerundolo, and F. M. Platt

Invariant Natural Killer T Cells Are Not Affected by Lysosomal Storage in Patients with Niemann-Pick Disease Type C
Eur J Immunol 42, no. 7 (Jul 2012): 1886-92.
Link to the publication

Speak, A. O., D. Te Vruchte, L. C. Davis, A. J. Morgan, D. A. Smith, N. M. Yanjanin, L. Simmons, R. Hartung, H. Runz, E. Mengel, M. Beck, J. Imrie, E. Jacklin, J. E. Wraith, C. Hendriksz, R. Lachmann, C. Cognet, R. Sidhu, H. Fujiwara, D. S. Ory, A. Galione, F. D. Porter, E. Vivier, and F. M. Platt

Altered Distribution and Function of Natural Killer Cells in Murine and Human Niemann-Pick Disease Type C1
Blood 123, no. 1 (Jan 2 2014): 51-60.
Link to the publication

Stampfer, M., S. Theiss, Y. Amraoui, X. Jiang, S. Keller, D. S. Ory, E. Mengel, C. Fischer, and H. Runz

Niemann-Pick Disease Type C Clinical Database: Cognitive and Coordination Deficits Are Early Disease Indicators
Orphanet J Rare Dis 8 (Feb 22 2013): 35.
Link to the publication

Tangemo, C., D. Weber, S. Theiss, E. Mengel, and H. Runz

Niemann-Pick Type C Disease: Characterizing Lipid Levels in Patients with Variant Lysosomal Cholesterol Storage
J Lipid Res 52, no. 4 (Apr 2011): 813-25.
Link to the publication

Valayannopoulos, V., E. Mengel, A. Brassier, and G. Grabowski. "Lysosomal Acid Lipase Deficiency: Expanding Differential Diagnosis

Lysosomal Acid Lipase Deficiency: Expanding Differential Diagnosis
Mol Genet Metab 120, no. 1-2 (Jan - Feb 2017): 62-66.
Link to the publication

Vom Dahl, S., and E. Mengel

Lysosomal Storage Diseases as Differential Diagnosis of Hepatosplenomegaly
Best Pract Res Clin Gastroenterol 24, no. 5 (Oct 2010): 619-28.
Link to the publication

Welford, R. W., M. Garzotti, C. Marques Lourenco, E. Mengel, T. Marquardt, J. Reunert, Y. Amraoui, S. A. Kolb, O. Morand, and P. Groenen

Plasma Lysosphingomyelin Demonstrates Great Potential as a Diagnostic Biomarker for Niemann-Pick Disease Type C in a Retrospective Study
PLoS One 9, no. 12 (2014): e114669.
Link to the publication

Vruchte D, Speak AO, Wallom KL, Al Eisa N, Smith DA, Hendriksz CJ, Simmons L, Lachmann RH, Cousins A, Hartung R, Mengel E, Runz H, Beck M, Amraoui Y, Imrie J, Jacklin E, Riddick K, Yanjanin NM, Wassif CA, Rolfs A, Rimmele F, Wright N, Taylor C, Ramaswami U, Cox TM, Hastings C, Jiang X, Sidhu R, Ory DS, Arias B, Jeyakumar M, Sillence DJ, Wraith JE, Porter FD, Cortina-Borja M, Platt FM.

Relative acidic compartment volume as a lysosomal storage disorder-associated Biomarker
J Clin Invest. 2014 Mar;124(3):1320-8.

McGovern, M. M., C. Dionisi-Vici, R. Giugliani, P. Hwu, O. Lidove, Z. Lukacs, K. Eugen Mengel, P. K. Mistry, E. H. Schuchman, and M. P. Wasserstein. 


Consensus Recommendation for a Diagnostic Guideline for Acid Sphingomyelinase DeficiencyGenet Med 19, no. 9 (Sep 2017)
Genet Med 19, no. 9 (Sep 2017): 967-74.
Link to the publication

Mengel, E., B. Bembi, M. Del Toro, F. Deodato, M. Gautschi, S. Grunewald, S. Gronborg, B. Heron, E. M. Maier, A. Roubertie, S. Santra, A. Tylki-Szymanska, S. Day, T. Symonds, S. Hudgens, M. C. Patterson, C. Guldberg, L. Ingemann, N. H. T. Petersen, T. Kirkegaard, and I. Dali C.

Clinical Disease Progression and Biomarkers in Niemann-Pick Disease Type C: A Prospective Cohort Study
Orphanet J Rare Dis 15, no. 1 (Nov 23 2020): 328.
Link to the publication

Patterson, M. C., E. Mengel, M. T. Vanier, P. Moneuse, D. Rosenberg, and M. Pineda

Treatment Outcomes Following Continuous Miglustat Therapy in Patients with Niemann-Pick Disease Type C: A Final Report of the Npc Registry
Orphanet J Rare Dis 15, no. 1 (Apr 25 2020): 104.
Link to the publication

Mengel, E., M. Beck, A. M. Das, F. Ebinger, S. Koch, H. H. Klünemann, M. Rohrbach, H. Runz, F. Rutsch, and G. C. Korenke

Morbus Niemann-Pick Typ C
Monatsschrift Kinderheilkunde 160, no. 1 (2011): 47-54.
Link to the publication

At present we have no literature available.

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