A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L)

Abstract

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.

Atrophy patterns in IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M MAPT mutations

“…However, the P301L subjects also showed widespread loss including the frontal lobes but had a relatively short time from onset to scan of only 4 years, which suggests either that frontal lobe loss is an early feature of P301L mutations or P301L mutations may have a more rapidly progressive disease, and therefore atrophy has spread further through the brain in the same time. Previous studies have typically reported both temporal and frontal atrophy in P301L patients, 8,[26][27][28] and others have suggested that P301L subjects are rapidly progressive. 8 We also identified severe involvement of the basal ganglia in both the P301L and V337M subjects.…”

Promotion of Hyperphosphorylation by Frontotemporal Dementia Tau Mutations

“…Clinically, FTDP-17 phenotypes appear to be quite variable, not only between mutations, but also within a single mutation and even within individual families either with intronic (60) or missense mutations (61). Despite the variability, some similarities are observed, as for example parkinsonism is present more frequently in families with intronic mutations (for review, see Ref.…”

Prominent phenotypic variability associated with mutations in Progranulin

“…To underscore this point, Kindred 2 had several members with primarily amnestic difficulties, one individual with PPA, another with FTDP, and one individual presented with amnestic complaints which quickly evolved into FTD. Phenotypic heterogeneity has been seen both within families and among families having identical mutations in MAPT as well (Bird et al 1999). …”