November 2011
27
storage, little effect on the onset of neurological symptoms was found.
15
And while bone marrow
transplantation ameliorated the systemic features of NPC, it did not halt the neurological
deterioration.
16
In a patient with NPC2 a bone marrow transplantation has been successful,
although this was probably due to a severe post transplantation ‘graft versus substrate’ reaction
that required intense immune suppression.
17
Liver transplantation in humans corrects hepatic
dysfunction but does not ameliorate the neurologic disease.
10
Future perspectives
A number of experimental disease specific therapies have been tested in cell culture and animal
models, including small-molecule therapies (aiming to interdict apoptosis), neurosteroïd
replacement therapy, over-expression of GTPase Rab 9 (attempting to activate alternative
pathways for mobilizing endosomale cargoes), curcumin (stabilizing calcium homeostasis and lipid
metabolism) and cyclodextrin
18,19
(
reversing the lysosomal transport defect by inducing movement
of unesterified cholesterol from the lysosomes to the cytosolic pool). These studies have shown
promising results in delaying disease progression in animal models of NPC, however further
research is mandatory.
8,10
A clinical trial utilizing cyclodextrin for Niemann-Pick Type C patients is in the planning phase.
6.1
Reference List
1.
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;98:250-254.
2.
Champion H, Ramaswami U, Imrie J, Lachmann RH, Gallagher J, Cox TM, et al. Dietary
modifications in patients receiving Miglustat.
J Inherit Metab Dis.
2010.
3.
Vanier MT, Millat G. Niemann-Pick disease type C.
Clin Genet.
2003;64:269-281.
4.
Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, et al. Niemann-Pick
Disease Type C: A Lipid Trafficking Disorder. In: Valle D, Beaudet A, Vogelstein B, Kinzler K,
Antonarakis S, Ballabio A, editors. Scriver's Metabolic and Molecular Bases of Inherited
Diseases Online. The Online Metabolic and Molecular Bases of Inherited Diseases ed. New
York : McGraw-Hill; 2011.
5.
Millat G, Chikh K, Naureckiene S, Sleat DE, Fensom AH, Higaki K, et al. Niemann-Pick disease
type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group.
Am J Hum Genet.
2001;69:1013-1021.
6.
Millat G, Bailo N, Molinero S, Rodriguez C, Chikh K, Vanier MT. 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.
2005;86:220-232.
7.
Vance JE. Lipid imbalance in the neurological disorder, Niemann-Pick C disease.
FEBS Lett.
2006;580:5518-5524.
8.
Wraith JE, Baumgartner MR, Bembi B, Covanis A, Levade T, Mengel E, et al.
Recommendations on the diagnosis and management of Niemann-Pick disease type C.
Mol
Genet Metab.
2009;98:152-165.