TY - JOUR
T1 - Familial early-onset dementia with complex neuropathologic phenotype and genomic background
AU - Alexander, John
AU - Kalev, Ognian
AU - Mehrabian, Shima
AU - Traykov, Latchezar
AU - Raycheva, Margariata
AU - Kanakis, Dimitrios
AU - Drineas, Petros
AU - Lutz, Mirjam I.
AU - Ströbel, Thomas
AU - Penz, Thomas
AU - Schuster, Michael
AU - Bock, Christoph
AU - Ferrer, Isidro
AU - Paschou, Peristera
AU - Kovacs, Gabor G.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - Early-onset dementia
KW - Exome sequencing
KW - LRRK2
KW - Tau
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=84962886819&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2016.03.012
DO - 10.1016/j.neurobiolaging.2016.03.012
M3 - Article
C2 - 27143436
AN - SCOPUS:84962886819
SN - 0197-4580
VL - 42
SP - 199
EP - 204
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -