Familial Alzheimer's disease associated with heterozygous NPC1 mutation.

التفاصيل البيبلوغرافية
العنوان:	Familial Alzheimer's disease associated with heterozygous NPC1 mutation.
المؤلفون:	Lopergolo D; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Bianchi S; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Gallus GN; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Locci S; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Pucci B; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.; UOC Neurologia e Neurofisiologia Clinica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Leoni V; Laboratory of Clinical Chemistry, Hospital of Desio, ASST Brianza, School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy., Gasparini D; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Tardelli E; Unit of Nuclear Medicine, Department of Diagnostic Imaging, PO - S. Stefano, Azienda U.S.L. Toscana Centro, Prato, italy., Chincarini A; National Institute of Nuclear Physics ((INFN), Genoa, Italy., Sestini S; Unit of Nuclear Medicine, Department of Diagnostic Imaging, PO - S. Stefano, Azienda U.S.L. Toscana Centro, Prato, italy., Santorelli FM; Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Calambrone, Italy., Zetterberg H; Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; UK Dementia Research Institute at UCL, London, UK.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.; Hong Kong Center for Neurodegenerative Diseases, Hong Kong Special Administrative Region, People's Republic of China., De Stefano N; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Mignarri A; Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy andrea.mignarri@ao-siena.toscana.it.; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
المصدر:	Journal of medical genetics [J Med Genet] 2024 Mar 21; Vol. 61 (4), pp. 332-339. Date of Electronic Publication: 2024 Mar 21.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: British Medical Association Country of Publication: England NLM ID: 2985087R Publication Model: Electronic Cited Medium: Internet ISSN: 1468-6244 (Electronic) Linking ISSN: 00222593 NLM ISO Abbreviation: J Med Genet Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: London : British Medical Association
مواضيع طبية MeSH:	Alzheimer Disease/genetics , Neurodegenerative Diseases , Niemann-Pick Disease, Type C/diagnosis , Niemann-Pick Disease, Type C/genetics , Oxysterols*, Humans ; Mutation ; Niemann-Pick C1 Protein/genetics
مستخلص:	Introduction: NPC1 mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous NPC1 mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous NPC1 mutation. Methods: All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed. Results: We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in NPC1 , shared by all the siblings. No other point mutations or deletions in NPC1 or NPC2 were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3β,5α,6β-triol. Discussion: We describe a novel NPC1 heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our NPC1 mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with NPC1 heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association. Competing Interests: Competing interests: HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, ALZ Path, Annexon, Apellis, Artery Therapeutics, AZ Therapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme (outside submitted work). None of the other authors have a conflict of interest to disclose. (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
فهرسة مساهمة:	Keywords: brain diseases, metabolic; central nervous system diseases; dementia; neurodegenerative diseases
المشرفين على المادة:	0 (Oxysterols) 0 (NPC1 protein, human) 0 (Niemann-Pick C1 Protein)
تواريخ الأحداث:	Date Created: 20231121 Date Completed: 20240325 Latest Revision: 20240325
رمز التحديث:	20240325
DOI:	10.1136/jmg-2023-109219
PMID:	37989569
قاعدة البيانات:	MEDLINE

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تدمد:	1468-6244
DOI:	10.1136/jmg-2023-109219