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Brain, Vol. 122, No. 4, 741-756, April 1999
© 1999 Oxford University Press

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

Thomas D. Bird1,2,3,5, David Nochlin4, Parvoneh Poorkaj5, Monique Cherrier6, Jeffrey Kaye7, Haydeh Payami7,8, Elaine Peskind3,6, Thomas H. Lampe3,5, Ellen Nemens5, Philip J. Boyer9 and Gerard D. Schellenberg1,2,5

1 Departments of Neurology, 2 Medicine, 3 Psychiatry and Behavioral Sciences and 4 Pathology, University of Washington, 5 Geriatric Research, Education and Clinical Center, 6 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington, 7 Departments of Neurology and 8 Molecular and Medical Genetics, Oregon Health Sciences University, Portland, Oregan and 9 Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence to: Thomas D. Bird, MD, GRECC (182B), 1660 South Columbian Way, Seattle, WA 98108, USA

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.

frontotemporal dementia; tau; mutations

ADRC = Alzheimer's Disease Research Center; CDR = Clinical Dementia Rating Scale; CERAD = Consortium to Establish a Registry for Alzheimer's Disease; FTDP-17 = frontotemporal dementia with parkinsonism linked to chromosome 17; MMSE = Mini-Mental State Examination; MSTD = multiple system tauopathy with presenile dementia


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