Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

Abstract

Mutations in the MAPT gene cause frontotemporal dementia with tau deposits. We report the novel p.P397S MAPT variant in eight subjects from five apparently nonrelated families suffering from frontotemporal dementia with autosomal dominant pattern of inheritance. In silico analysis reported conflicting evidence of pathogenicity. The segregation analysis support that this variant is likely pathogenic. The mean age at onset (61.4 years) and mean disease duration (13.9 years) of these subjects and their affected relatives were significantly higher compared with our series of p.P301L MAPT mutation carriers. These findings suggest that p.P397S variant could be a new MAPT mutation associated with a less aggressive phenotype than other MAPT mutations.

Figure 1

Pedigree of the five reported families. Arrows indicate the probands described in the main text. Upper ages beneath each symbol are age at onset. Lower ages beneath each symbol are age at death.

Figure 2

MRI of subject III.II.VI showing important medial and polar bitemporal atrophy (A). Longitudinal MRI examinations of subject II.II.IX (B).

Figure 3

Distribution of onset ages, disease durations, and ages at death associated with p.P397S and P301L MAPT carriers (A). Survival curves of p.P397S and P301L MAPT carriers (B).