TY - JOUR
T1 - A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L)
AU - Bird, Thomas D.
AU - Nochlin, David
AU - Poorkaj, Parvoneh
AU - Cherrier, Monique
AU - Kaye, Jeffrey
AU - Payami, Haydeh
AU - Peskind, Elaine
AU - Lampe, Thomas H.
AU - Nemens, Ellen
AU - Boyer, Philip J.
AU - Schellenberg, Gerard D.
N1 - Funding Information:
This work was supported by VA Medical Research funds and NIA Alzheimer Disease Research Center Grants AG 05136 and AG 08017. The Department of Pathology of University of Iowa provided autopsy material from II-3 in Family D. R. Fowler evaluated III-8 in Family F.
PY - 1999/4
Y1 - 1999/4
N2 - We investigated three separate families (designated D, F and G) with frontotemporal dementia that have the same molecular mutation in exon 10 of the tau gene (P301L). The families share many clinical characteristics, including behavioural aberrations, defective executive functions, language deficits, relatively preserved constructional abilities and frontotemporal atrophy on imaging studies. However, Family D has an earlier mean age of onset and shorter duration of disease than Families F and G (49.0 and 5.1 years versus 61-64 and 7.3-8.0 years, respectively). Two members of Families D and F had neuropathological studies demonstrating lobar atrophy, but the brain from Family D had prominent and diffuse circular, intraneuronal, neurofibrillary tangles not seen in Family F. The brain from Family F had ballooned neurons typical of Pick's disease type B not found in Family D. A second autopsy from Family D showed neurofibrillary tangles in the brainstem with a distribution similar to that found in progressive supranuclear palsy. These three families demonstrate that a missense mutation in the exon 10 microtubule-binding domain of the tau protein gene can produce severe behavioural abnormalities with frontotemporal lobar atrophy and microscopic tau pathology. However, the findings in these families also emphasize that additional unidentified environmental and/or genetic factors must be producing important phenotypic variability on the background of an identical mutation. Apolipoprotein E genotype does not appear to be such a factor influencing age of onset in this disease.
AB - We investigated three separate families (designated D, F and G) with frontotemporal dementia that have the same molecular mutation in exon 10 of the tau gene (P301L). The families share many clinical characteristics, including behavioural aberrations, defective executive functions, language deficits, relatively preserved constructional abilities and frontotemporal atrophy on imaging studies. However, Family D has an earlier mean age of onset and shorter duration of disease than Families F and G (49.0 and 5.1 years versus 61-64 and 7.3-8.0 years, respectively). Two members of Families D and F had neuropathological studies demonstrating lobar atrophy, but the brain from Family D had prominent and diffuse circular, intraneuronal, neurofibrillary tangles not seen in Family F. The brain from Family F had ballooned neurons typical of Pick's disease type B not found in Family D. A second autopsy from Family D showed neurofibrillary tangles in the brainstem with a distribution similar to that found in progressive supranuclear palsy. These three families demonstrate that a missense mutation in the exon 10 microtubule-binding domain of the tau protein gene can produce severe behavioural abnormalities with frontotemporal lobar atrophy and microscopic tau pathology. However, the findings in these families also emphasize that additional unidentified environmental and/or genetic factors must be producing important phenotypic variability on the background of an identical mutation. Apolipoprotein E genotype does not appear to be such a factor influencing age of onset in this disease.
KW - Frontotemporal dementia
KW - Mutations
KW - Tau
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U2 - 10.1093/brain/122.4.741
DO - 10.1093/brain/122.4.741
M3 - Article
C2 - 10219785
AN - SCOPUS:0032897924
SN - 0006-8950
VL - 122
SP - 741
EP - 756
JO - Brain
JF - Brain
IS - 4
ER -