FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
Urwin
Hazel
H
UCL Institute of Neurology, London, UK.
Josephs
Keith A
KA
Rohrer
Jonathan D
JD
Mackenzie
Ian R
IR
Neumann
Manuela
M
Authier
Astrid
A
Seelaar
Harro
H
Van Swieten
John C
JC
Brown
Jeremy M
JM
Johannsen
Peter
P
Nielsen
Jorgen E
JE
Holm
Ida E
IE
Dickson
Dennis W
DW
Rademakers
Rosa
R
Graff-Radford
Neill R
NR
Parisi
Joseph E
JE
Petersen
Ronald C
RC
Hatanpaa
Kimmo J
KJ
White
Charles L
CL
Weiner
Myron F
MF
Geser
Felix
F
Van Deerlin
Vivianna M
VM
Trojanowski
John Q
JQ
Miller
Bruce L
BL
Seeley
William W
WW
van der Zee
Julie
J
Kumar-Singh
Samir
S
Engelborghs
Sebastiaan
S
De Deyn
Peter P
PP
Van Broeckhoven
Christine
C
Bigio
Eileen H
EH
Deng
Han-Xiang
HX
Halliday
Glenda M
GM
Kril
Jillian J
JJ
Munoz
David G
DG
Mann
David M
DM
Pickering-Brown
Stuart M
SM
Doodeman
Valerie
V
Adamson
Gary
G
Ghazi-Noori
Shabnam
S
Fisher
Elizabeth M C
EM
Holton
Janice L
JL
Revesz
Tamas
T
Rossor
Martin N
MN
Collinge
John
J
Mead
Simon
S
Isaacs
Adrian M
AM
D000328:Adult; D017668:Age of Onset; D004268:DNA-Binding Proteins / Q000378:metabolism; D020820:Dyskinesias / Q000453:epidemiology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000453:epidemiology; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D016875:tau Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D034702:RNA-Binding Protein FUS; D016875:tau Proteins