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Cited by 1,222Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusMetabolism and Genetic Disorders

Niemann-Pick disease type C

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Vanier, Marie T·2010·Orphanet Journal of Rare Diseases
DOI 10.1186/1750-1172-5-16PMC PMC2902432
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Abstract

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120,000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

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  • mTOR signaling and proliferation in HUVEC are inhibited by genetically knocking down NPC1 or NPC2 or by pharmacologically inhibiting cholesterol trafficking with imipramine and U18666A, albeit at far higher concentrations than itraconazole.

    “Since mTOR signaling and proliferation in HUVEC were also inhibited by either genetically knocking down NPC1 or NPC2 or by pharmacologically inhibiting cholesterol trafficking with two other known NPC-inducing small molecules, imipramine and U18666A albeit at far higher concentrations than ITZ, it was also deciphered to cease cholesterol trafficking resulting in mTOR inhibition.26,27”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [26]

    The Etiology sections (page unavailable) state that NPC1 and NPC2 are required for cholesterol to leave lysosomes and that cholesterol transport is disrupted in cells affected by either form of Niemann–Pick C disease. They do not report NPC1/NPC2 knockdown in HUVEC, inhibition of mTOR signaling or proliferation, effects of imipramine or U18666A, or a concentration comparison with itraconazole. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Itraconazole's cessation of cholesterol trafficking results in mTOR inhibition.

    “Since mTOR signaling and proliferation in HUVEC were also inhibited by either genetically knocking down NPC1 or NPC2 or by pharmacologically inhibiting cholesterol trafficking with two other known NPC-inducing small molecules, imipramine and U18666A albeit at far higher concentrations than ITZ, it was also deciphered to cease cholesterol trafficking resulting in mTOR inhibition.26,27”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [26]

    The Etiology sections describe impaired cholesterol export in NPC1- or NPC2-deficient cells, but do not address itraconazole or mTOR inhibition. Searches for itraconazole, mTOR, and the proposed trafficking-to-mTOR link found no passage supporting that claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Vanier, M. T.
Affiliations
Inserm (FR)
Corresponding author
Vanier, Marie T
ORCID
Vanier, Marie T
Venue
Orphanet Journal of Rare Diseases
Publisher
Springer Science and Business Media LLC
Published
2010-06-03
Volume
5
Issue
1
Pages
16-16
ISSN
1750-1172 (ISSN-L)
DOI
10.1186/1750-1172-5-16
PMC
PMC2902432
OpenAlex
W2068262899
Cited by
1,222
References
0
Citations by year
2026: 62 · 2025: 61 · 2024: 66 · 2023: 72 · 2022: 95 · 2021: 91 · 2020: 91 · 2019: 83 · 2018: 65 · 2017: 88 · 2016: 81 · 2015: 63 · 2014: 81 · 2013: 63 · 2012: 50
FWCI
5.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Institut National de la Santé et de la Recherche Médicale
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
Niemann-Pick disease type C, lysosomal lipid storage disorder, NPC1 gene, NPC2 gene, autosomal recessive inheritance, gangliosides, vertical supranuclear gaze palsy, cerebellar ataxia, cataplexy, filipin staining, genotype-phenotype correlation, miglustat, differential diagnosis
MeSH terms
Age Factors, Biological Transport, Cholesterol, Genetic Testing, Humans, 1-Deoxynojirimycin, Age of Onset, Niemann-Pick Disease, Type C, Genetic Association Studies

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