Phenotypic variation in hereditary frontotemporal dementia with tau mutations

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17) is associated with mutations in the tau gene.
• Understanding genotype-phenotype correlations is crucial for diagnosing and managing FTDP-17.

Purpose of the Study:

• To correlate specific tau gene mutations (deltaK280, G272V, P301L, R406W) with clinical and pathological features in six FTDP-17 families.
• To investigate tau pathology in patients with P301L and R406W mutations.

Main Methods:

• Genotype analysis of six families with FTDP-17.
• Clinical assessment of disease onset, duration, and symptoms.
• Neuroimaging to evaluate frontotemporal atrophy.
• Post-mortem neuropathological examination of tau pathology in P301L and R406W brains.
• Biochemical analysis of tau protein bands.

Main Results:

• The R406W family exhibited a later age of onset (59.2 years) and longer disease duration (12.7 years) compared to other mutations.
• No early parkinsonism was observed in any of the six families.
• Frontotemporal atrophy was less severe in the R406W family than in P301L and deltaK280 families.
• P301L brains showed pretangles, neurofibrillary tangles, and plaques, with three to four tau bands.
• R406W brains displayed abundant neurofibrillary tangles and four tau bands.

Conclusions:

• The R406W mutation is associated with a distinct clinical and pathological profile in FTDP-17, characterized by later onset and slower progression.
• The coexistence of P301L tau pathology and Alzheimer's disease pathology warrants further investigation.
• The microtubule-binding properties of the mutant tau protein may influence disease progression in R406W families.