Role of Niemann-Pick Type C Disease Mutations in Dementia

J Alzheimers Dis. 2017;55(3):1249-1259. doi: 10.3233/JAD-160214.


Background: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance.

Objective: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus.

Methods: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients.

Results: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2.

Conclusions: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

Keywords: Dementia; NPC1 gene; NPC2 gene; Niemann Pick type C; heterozygous state; neurodegeneration.

MeSH terms

  • Aged
  • Animals
  • Brain / diagnostic imaging
  • Carrier Proteins / genetics*
  • DNA Mutational Analysis
  • Dementia / diagnostic imaging
  • Dementia / genetics*
  • Dementia / pathology
  • Female
  • Glycoproteins / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Magnetic Resonance Imaging
  • Male
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Niemann-Pick C1 Protein
  • Tomography, Emission-Computed, Single-Photon
  • Vesicular Transport Proteins


  • Carrier Proteins
  • Glycoproteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • NPC2 protein, human
  • Niemann-Pick C1 Protein
  • Vesicular Transport Proteins