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Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier.

ABSTRACT: Microtubule-associated protein tau mutations result in 10-20% of cases of genetic frontotemporal lobar degeneration. Tau mutation carriers typically develop behavioral variant frontotemporal dementia with or without parkinsonism. Unlike most frontotemporal dementia gene mutations, heterozygous R406W tau mutation carriers most often develop clinical Alzheimer's disease. We report a homozygous tau R406W mutation carrier with behavioral variant frontotemporal dementia who developed symptoms 20 years before mean family symptom onset. Voxel-based morphometry showed frontoinsular, frontal, and mesial temporal cortical atrophy. Homozygous tau R406W mutations appear to accelerate symptom onset and drive a behavioral variant frontotemporal dementia syndrome.

SUBMITTER: Ng AS

PROVIDER: S-EPMC4693591 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier.

Ng Adeline S L AS Sias Ana C AC Pressman Peter S PS Fong Jamie C JC Karydas Anna M AM Zanto Theodore P TP De May Mary M Coppola Giovanni G Geschwind Daniel H DH Miller Bruce L BL Lee Suzee E SE

Annals of clinical and translational neurology 20151112 12

Microtubule-associated protein tau mutations result in 10-20% of cases of genetic frontotemporal lobar degeneration. Tau mutation carriers typically develop behavioral variant frontotemporal dementia with or without parkinsonism. Unlike most frontotemporal dementia gene mutations, heterozygous R406W tau mutation carriers most often develop clinical Alzheimer's disease. We report a homozygous tau R406W mutation carrier with behavioral variant frontotemporal dementia who developed symptoms 20 year ...[more]

PMID: 26734663

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Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs.

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de novo MAPT mutation G335A causes severe brain atrophy, 3R and 4R PHF-tau pathology and early onset frontotemporal dementia.

Project description: Not available

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Frontotemporal dementia with the V337M <i>MAPT</i> mutation: Tau-PET and pathology correlations.

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Project description:The Arg406Trp (R406W) missense mutation in the microtubule-associated protein-tau gene (MAPT) is a known cause of early-onset dementia. Various dementia phenotypes have been described, including frontotemporal dementia (FTD), FTD with parkinsonism, and early-onset Alzheimer disease (EOAD)-like presentations.Using whole-exome capture with subsequent sequencing, we identified the R406W mutation in a family with multiple individuals with clinically diagnosed EOAD, in a pattern suggesting autosomal dominant inheritance. We reevaluated all available family members clinically.Each of the affected individuals had a course meeting clinical criteria for EOAD. Two distinct disease trajectories were apparent: one rapidly progressive, and the other long and gradual. Four of five affected individuals also manifested parkinsonian symptoms. FTD features were not prominent and, when present, appeared only late in the course of dementia.The MAPT R406W mutation is associated with EOAD-like symptoms and parkinsonism without FTD, as well as distinct cognitive courses.

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Project description:We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD).Presymptomatic MAPT (n?=?15) and GRN mutation carriers (n?=?31), and healthy controls (n?=?39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression.MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p?<?0.05). Cognitive decline in ScreeLing phonology (p?=?0.046) and letter fluency (p?=?0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p?=?0.025) for an underlying MAPT mutation.Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD.

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