Phenotypic variation in hereditary frontotemporal dementia with tau mutations

several mutations in the tau gene have been found in families with heredita ry frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 ( FTDP-17). This study is the first attempt to correlate genotype and phenoty pe in six families with FTDP-17 with mutations in the tau gene (Delta K280, G272V, P301L, and R486W). We have investigated tau pathology in 1 P301L an d 1 R406W patient. The R406W family showed a significantly higher age at on set (59.2 +/- 5.5 years) and longer duration of illness (12.7 +/- 1.5 years ) than the families with the other mutations. The six families showed consi derable variation in clinical presentation, but none of them had early park insonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W fam ily was less severe than in the P301L and Delta K280 families. The P301L br ain contained many pretangles in the frontal and temporal cortex, and the d entate gyrus of hippocampus, showing three tau bands. (64, 68, and 72 kd) o f extracted tau from the frontal cortex. The presence of many neurofibrilla ry tangles, many diffuse and classic neuritic plaques in the temporal and p arietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl-insoluble (60, 64, 68, and 72 kd) tau bands, The coexistence of characteristic P301L and Alzheimer pathology in the sam e brain needs further explanation. The R406W brain showed abundant neurofib rillary tangles in several brain regions, and four tau bands (60, 64, 68, a nd 72 kd) of extracted tau from these regions. The slower progression of th e disease in the R406W family might be explained by the microtubule-binding properties of the mutant protein.