Distinct genetic forms of frontotemporal dementia.
BACKGROUND
Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects.


METHODS
We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy.


RESULTS
In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis.


CONCLUSIONS
Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease.
Seelaar
H
H
Erasmus University Medical Center Rotterdam, Department of Neurology, Rotterdam, The Netherlands.
Kamphorst
W
W
Rosso
S M
SM
Azmani
A
A
Masdjedi
R
R
de Koning
I
I
Maat-Kievit
J A
JA
Anar
B
B
Donker Kaat
L
L
Breedveld
G J
GJ
Dooijes
D
D
Rozemuller
J M
JM
Bronner
I F
IF
Rizzu
P
P
van Swieten
J C
JC
D000328:Adult; D017668:Age of Onset; D000368:Aged; D003704:Dementia / Q000145:classification* / Q000235:genetics* / Q000503:physiopathology; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D006801:Humans; D040582:Inheritance Patterns; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D010375:Pedigree; D000077153:Progranulins; D011446:Prospective Studies; D013702:Temporal Lobe / Q000473:pathology; D016875:tau Proteins / Q000235:genetics
C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D016875:tau Proteins