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Distinct genetic forms of frontotemporal dementia.
H Seelaar1, W Kamphorst, S M Rosso
1Erasmus University Medical Center Rotterdam, Department of Neurology, Rotterdam, The Netherlands.
Neurology
|August 16, 2008
Summary
Genetic analysis revealed that 27% of frontotemporal dementia (FTD) patients have a family history, with MAPT and GRN mutations identified. Further research is needed to find genetic causes for other familial FTD forms.
Area of Science:
- Neuroscience
- Genetics
- Neuropathology
Background:
- Frontotemporal dementia (FTD) is a common presenile dementia with various clinical subtypes.
- Genetic factors, including MAPT and GRN mutations and TDP-43 protein, define FTD subtypes.
- Familial FTD cases with unknown genetic defects remain a significant area of study.
Purpose of the Study:
- Investigate the frequency and characteristics of FTD patients with a positive family history.
- Identify genetic mutations associated with familial FTD.
- Characterize neuropathological findings in familial FTD subtypes.
Main Methods:
- Prospective cohort study of 364 FTD patients.
- Genetic analysis of FTD-associated genes in patients with a family history.
- Immunohistochemical studies using tau, ubiquitin, and TDP-43 antibodies on autopsy brains.
Main Results:
- 27% of FTD patients exhibited a positive family history, suggesting autosomal inheritance.
- MAPT (11%) and GRN (6%) mutations were identified in familial FTD cases.
- A novel Gln300X GRN mutation was found in a sporadic FTD case; GRN patients had a later age of onset than MAPT patients.
- 10% of patients with suspected autosomal dominant inheritance had unidentified genetic defects.
- Neuropathological distinction into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis was observed.
Conclusions:
- Genetic defects in at least two distinct familial FTD forms require identification.
- Future research should focus on elucidating the genetic underpinnings of familial frontotemporal lobe degeneration with motor neuron disease and frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis.
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