C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients.

Autor: König T; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Wurm R; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Parvizi T; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Silvaieh S; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Hotzy C; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Cetin H; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Klotz S; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Gelpi E; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Bancher C; Department of Neurology, Landesklinikum Horn-Allentsteig, 3580, Horn, Austria., Benke T; Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria., Dal-Bianco P; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Defrancesco M; Department of Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, 6020 Innsbruck, Austria., Fischer P; Department of Psychiatry, Danube Hospital Vienna, 1220 Vienna, Austria., Marksteiner J; Department of Psychiatry and Psychotherapy A, Landesklinikum Hall, 6060 Hall in Tirol, Austria., Sutterlüty H; Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria., Ransmayr G; Department of Neurology 2, Medical Faculty, Johannes Kepler University, 4040 Linz, Austria., Schmidt R; Department of Neurology, Medical University of Graz, 8036 Graz, Austria., Zimprich A; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria., Stögmann E; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: elisabeth.stoegmann@meduniwien.ac.at.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2022 Dec; Vol. 175, pp. 105927. Date of Electronic Publication: 2022 Nov 13.
DOI: 10.1016/j.nbd.2022.105927
Abstrakt: Background: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype.
Methods: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting.
Results: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01).
Conclusions: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.
Competing Interests: Conflict of interest statement For the present study, SE received support from Roche and RG from the Jubilee Funds of the Austrian National Bank. In the past 36 months, SE received grants from Roche, FFG/AAL, Horizon2020 and the Austrian Alzheimer Association (all to the institution), CH from Roche and Novartis, SK from the Hochschuljubiläumsfonds, RG and SR from the Austrian Science Fund. SE received consulting fees from Biogen, WR from Alnylam Austria, BC from Roche Austria, RG from Abbvie, Alpine Market Research, Grünenthal, Novartis, Ratiopharm, Roche, Sanofi Aventis, Stada and UBC, SR from Axon Neuroscience, Roche and Biogen. For lectures, presentations, speakers bureaus, manuscript writing, or educational events payment was received by SE (Biogen, Roche, Eisai), WR (Pfizer), GE (Sanofi), BC (Schwabe), DM and RG (MedAhead). GE received payment for expert testimony from the Medical University of Vienna. BC received support for the Landesklinikum Horn for attending meetings from Genzyme. WR issued a patent for means and methods for the early prediction of poor neurological outcome in out-of-hospital cardiac arrest survivors. SE participated on an advisory board (Aboard Biogen, Roche), as well as CH (Roche), GE (IDIBAPS), BC (Roche), DBP (Roche), DM and SR (Rymind, no payment). GE held leadership or a fiduciary role in scientific societies (unpaid), SE in the Austrian Alzheimer Association, the EAN scientific panel dementia and in the steering committee DACh Tagung Biogen, BC in the Austrian Alzheimer Association (vize president). None of the authors received royalties or licences, held stock or stock options in entities related to the current manuscript, received equipment, materials, drugs, medical writing, gifts, or other services or had other financial or non-financial interests in the past 36 months. KT, PT, SS, HC, BT, FP, MJ, SH and ZA have nothing to disclose.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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