title: Familial early-onset dementia with complex neuropathologic phenotype and genomic background.
abstract: Despite significant progress in our understanding of hereditary neurodegenerative diseases, the list of genes associated with early-onset dementia is not yet complete. In the present study, we describe a familial neurodegenerative disorder characterized clinically as the behavioral and/or dysexecutive variant of Alzheimer's disease with neuroradiologic features of Alzheimer's disease, however, lacking amyloid-β deposits in the brain. Instead, we observed a complex, 4 repeat predominant, tauopathy, together with a TAR DNA-binding protein of 43 kDa proteinopathy. Whole-exome sequencing on 2 affected siblings and 1 unaffected aunt uncovered a large number of candidate genes, including LRRK2 and SYNE2. In addition, DDI1, KRBA1, and TOR1A genes possessed novel stop-gain mutations only in the patients. Pathway, gene ontology, and network interaction analysis indicated the involvement of pathways related to neurodegeneration but revealed novel aspects also. This condition does not fit into any well-characterized category of neurodegenerative disorders. Exome sequencing did not disclose a single disease-specific gene mutation suggesting that a set of genes working together in different pathways may contribute to the etiology of the complex phenotype.
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Institute of Pathology and Neuropathology, Landes-Nervenklinik Wagner-Jauregg, Linz, Austria.
authors.forename: Ognian
authors.initials: O
authors.lastname: Kalev
authors.affiliation: Department of Neurology, UH "Alexandrovska", Sofia, Bulgaria.
authors.forename: Shima
authors.initials: S
authors.lastname: Mehrabian
authors.affiliation: Department of Neurology, UH "Alexandrovska", Sofia, Bulgaria.
authors.forename: Latchezar
authors.initials: L
authors.lastname: Traykov
authors.affiliation: Department of Neurology, UH "Alexandrovska", Sofia, Bulgaria.
authors.forename: Margariata
authors.initials: M
authors.lastname: Raycheva
authors.affiliation: Department of Pathology, School of Medicine, Democritus University of Thrace, Alexandroupoli, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kanakis
authors.affiliation: Department of Computer Science, Rensselaer Polytechnic Institute, Troy, NY, USA.
authors.forename: Petros
authors.initials: P
authors.lastname: Drineas
authors.affiliation: Institute of Neurology, Medical University Vienna, Vienna, Austria.
authors.forename: Mirjam I
authors.initials: MI
authors.lastname: Lutz
authors.affiliation: Institute of Neurology, Medical University Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ströbel
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Penz
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schuster
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.affiliation: Institute of Neuropathology, IDIBELL-Bellvitge University Hospital, University of Barcelona, Hospitalet de Llobregat; CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Barcelona, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece. Electronic address: ppaschou@mbg.duth.gr.
authors.forename: Peristera
authors.initials: P
authors.lastname: Paschou
authors.affiliation: Institute of Neurology, Medical University Vienna, Vienna, Austria. Electronic address: gabor.kovacs@meduniwien.ac.at.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D017423:Sequence Analysis, RNA; D057177:TDP-43 Proteinopathies; D024801:Tauopathies
chemical_list: D008840:Microfilament Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C485904:SYNE2 protein, human; C108175:TOR1A protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: Alzheimer disease; Early-onset dementia; Exome sequencing; LRRK2; TDP-43; Tau