title: Role of Niemann-Pick Type C Disease Mutations in Dementia.
abstract: 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.
  
  
  
  To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus.
  
  
  
  We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients.
  
  
  
  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.
  
  
  
  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.
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Chiara
authors: C
authors: Cupidi
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Francesca
authors: F
authors: Frangipane
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Maura
authors: M
authors: Gallo
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Alessandra
authors: A
authors: Clodomiro
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Rosanna
authors: R
authors: Colao
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Livia
authors: L
authors: Bernardi
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Maria
authors: M
authors: Anfossi
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Maria Elena
authors: ME
authors: Conidi
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Franca
authors: F
authors: Vasso
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Sabrina Anna Maria
authors: SA
authors: Curcio
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Maria
authors: M
authors: Mirabelli
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Nicoletta
authors: N
authors: Smirne
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Giusi
authors: G
authors: Torchia
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Maria Gabriella
authors: MG
authors: Muraca
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Gianfranco
authors: G
authors: Puccio
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Raffaele
authors: R
authors: Di Lorenzo
authors: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors: Stefania
authors: S
authors: Zampieri
authors: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors: Milena
authors: M
authors: Romanello
authors: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors: Andrea
authors: A
authors: Dardis
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Raffaele Giovanni
authors: RG
authors: Maletta
authors: Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors: Amalia Cecilia
authors: AC
authors: Bruni
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D003704:Dementia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D015899:Tomography, Emission-Computed, Single-Photon; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins
keywords: Dementia; NPC1 gene; NPC2 gene; Niemann Pick type C; heterozygous state; neurodegeneration