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

We investigated three separate families (designated D, F and G) with fronto temporal dementia that have the same molecular mutation in exon 10 of the t au gene (P301L), The families share many clinical characteristics, includin g 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 versu s 61-64 and 7.3-8.0 years, respectively), Two members of Families D and F h ad neuropathological studies demonstrating lobar atrophy, but the brain fro m Family D had prominent and diffuse circular, intraneuronal, neurofibrilla ry tangles not seen in Family F. The brain from Family F had ballooned neur ons typical of Pick's disease type B not found in Family D, A second autops y from Family D showed neurofibrillary tangles in the brainstem with a dist ribution similar to that found in progressive supranuclear palsy. These thr ee families demonstrate that a missense mutation in the exon 10 microtubule -binding domain of the tau protein gene can produce severe behavioural abno rmalities with frontotemporal lobar atrophy and microscopic tau pathology, However, the findings in these families also emphasize that additional unid entified environmental and/or genetic factors must be producing important p henotypic variability on the background of an identical mutation, Apolipopr otein E genotype does not appear to be such a factor influencing age of ons et in this disease.