Mutation Analysis of the Genes Associated with Parkinson’s Disease in a Finnish Cohort of Early-Onset Dementia

Article type: Research Article

Authors: Luukkainen, Laura^{a; b; c} | Huttula, Samuli^{a; c} | Väyrynen, Henri^{a; c} | Helisalmi, Seppo^d | Kytövuori, Laura^{a; c} | Haapasalo, Annakaisa^e | Hiltunen, Mikko^f | Remes, Anne M.^{a; c} | Krüger, Johanna^{a; c; *}

Affiliations: [a] Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland | [b] Unit of Cancer and Translational Research, Pathology, University of Oulu, Oulu, Finland | [c] MRC, Oulu University Hospital, Oulu, Finland | [d] Institute of Clinical Medicine – Neurology, University of Eastern Finland, Kuopio, Finland | [e] A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland | [f] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

Correspondence: [*] Correspondence to: Johanna Krüger, MD, PhD, Research Unit of Clinical Neuroscience, University of Oulu, B.O.X. 5000, 90014 Oulu, Finland. Tel.: +358 40 637 8906; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson’s disease (PD) overlap in clinical characteristics, neuropathology, and genetics. Objective:The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. Methods:Rare non-synonymous variants (MAF < 0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1, ATP13A2, UCHL1, HTRA2, GBA, and SNCAIP) and low-frequency (MAF < 0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) <65 years) dementia patients presenting with atypical features (e.g., myoclonia or spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n = 279, mean AAO 57, range 36–65) patients. Results:No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). Discussion:Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD.

Keywords: Alzheimer’s disease, dementia, dementia with Lewy bodies, frontotemporal dementia, frontotemporal lobar degeneration, gene, mutation, neurodegenerative disease, Parkinson’s disease, single nucleotide polymorphism

DOI: 10.3233/JAD-200069

Journal: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 955-965, 2020