Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition

Article type: Research Article

Authors: Sorrentino, Federica^{a; b; 1} | Arighi, Andrea^{a; 1} | Serpente, Maria^{a; b} | Arosio, Beatrice^{a; b} | Arcaro, Marina^a | Visconte, Caterina^a | Rotondo, Emanuela^a | Vimercati, Roberto^a | Ferri, Evelyn^a | Fumagalli, Giorgio G.^a | Pietroboni, Anna M.^a | Carandini, Tiziana^a | Scarpini, Elio^{a; b} | Fenoglio, Chiara^{b; 1} | Galimberti, Daniela^{a; b; *; 1}

Affiliations: [a] Fondazione IRCCS Ca’ Granda, Ospedale Policlinico, Milan, Italy | [b] University of Milan, Milan, Italy

Correspondence: [*] Correspondence to: Daniela Galimberti, Fondazione IRCCS Ca’ Granda, Ospedale Policlinico, via Francesco Sforza, 35, 20122, Milan, Italy. Tel.: +39 02 55033847; Fax: +39 02 55036580; E-mails: [email protected], [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer’s disease (AD). Objective:The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1–42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. Methods:A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Results:Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p > 0.05). Conclusion:The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

Keywords: Amyloid, cerebrospinal fluid, NPC1, NPC2, Niemann-Pick Type C, psychiatric onset, variability

DOI: 10.3233/JAD-210453

Journal: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1313-1323, 2021