Objective: We compiled clinical data of a new kindred with the MAPT c.1216C>T (p.Arg406Trp; R406W) mutation and systematically reviewed previously described cases with this mutation.

Background: MAPT R406W is a known cause of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with Alzheimer’s disease (AD)-like clinical features.

Methods: Patients were enrolled when symptomatic and followed for up to 22 years. Neuropathological examination was performed in three family members. Exome sequencing revealed MAPT R406W heterozygosity in the family. Clinical, radiological and neuropathological data in previously described R406W cases were systematically reviewed, yielding an assessment of 70 R406W heterozygotes and three confirmed homozygotes in total.

Results: Ventromedial temporal lobe atrophy was present early in the new kindred and was at first observed around the collateral sulcus, with ensuing atrophy of the parahippocampal gyrus. Neuropathological examination of three family members showed tauopathy with neurofibrillary tangles (NFTs), more distinct in the ventromedial temporal lobe. Mild concomitant alfa-synuclein pathology was present in one of these patients and there was widespread TDP-43 pathology in another. In previously described cases and also in the new kindred combined, impaired memory was the most frequent symptom, behavioral disturbance and language impairment were less common and Parkinsonism was rare. Overall median age of onset was 55 years and median disease duration 13 years. The most frequent clinical diagnosis was AD. Previously reported R406W homozygotes had lower age at onset and higher frequency of behavioral symptoms and Parkinsonism, compared to R406W heterozygotes.

Conclusions: The disease course of R406W patients is most often slow, and reminiscent of AD but with a risk of developing behavioral symptoms or language impairment at any disease duration. We postulate the ventromedial temporal lobe to be atrophic at all stages of R406W associated disease and an early focus not only for AD pathogenesis but also for R406W associated neurodegeneration. The same tau isoforms and ultrastructure are aggregated into NFTs in R406W associated disease and AD. We hence hold R406W-associated disease as an interesting crossing of tauopathies, AD and the debated primary age-related tauopathy, spanning the whole spectrum from neuropathology to clinical disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/atypical-and-slowly-progressive-ftdp-17-caused-by-mapt-p-r406w-mutations-similarities-to-ad-and-psp/