The genetic and pathological classification of familial frontotemporal dementia.
BACKGROUND
Frontotemporal dementia (FTD) is an important cause of neurodegenerative dementia, particularly in younger patients. TAU has been identified as the gene responsible for FTD linked to chromosome 17, but it is likely that there is pathological and genetic heterogeneity among families with FTD.


OBJECTIVE
To explore the genetic and pathological basis of familial FTD.


METHODS
Clinical case series with genetic analysis of each family, and pathological confirmation of diagnosis where possible.


METHODS
Specialist dementia research group, particularly recruiting patients with young-onset dementia.


METHODS
Twenty-two families with an index member with FTD, meeting Lund-Manchester criteria, and a family history of other affected members with dementia were ascertained.


RESULTS
Half of the families had mutations in the TAU gene (TAU exon 10 +14, +16, and P301S), and pathological diagnoses were available in 17 of 22 families. Three main pathological diagnoses were made: FTD with neuronal and glial tau deposition, FTD with ubiquitin inclusions, and FTD with neuronal loss and spongiosis but without intracellular inclusions. No cases of familial Pick disease were identified. With the use of the pathological diagnoses, each family with FTD with neuronal and glial tau deposition had a TAU mutation, whereas TAU mutations were not identified in families in the other 2 diagnostic groups.


CONCLUSIONS
This study illustrates the value of TAU sequencing in FTD and suggests that around one half of individuals with familial FTD have TAU mutations and dementia with tau pathological findings. Furthermore, these data suggest that there are at least 2 additional genes to be identified among families with autosomal dominant FTD.
Morris
H R
HR
Neurogenetics Section, Institute of Neurology, University College London, England.
Khan
M N
MN
Janssen
J C
JC
Brown
J M
JM
Perez-Tur
J
J
Baker
M
M
Ozansoy
M
M
Hardy
J
J
Hutton
M
M
Wood
N W
NW
Lees
A J
AJ
Revesz
T
T
Lantos
P
P
Rossor
M N
MN
D000328:Adult; D000368:Aged; D003704:Dementia / Q000145:classification / Q000235:genetics* / Q000473:pathology; D018891:Dentate Gyrus / Q000737:chemistry / Q000473:pathology; D005625:Frontal Lobe / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020774:Pick Disease of the Brain / Q000235:genetics / Q000473:pathology; D013702:Temporal Lobe / Q000737:chemistry / Q000473:pathology*; D025801:Ubiquitin / Q000032:analysis; D016875:tau Proteins / Q000032:analysis / Q000235:genetics*
D025801:Ubiquitin; D016875:tau Proteins