Extensive genetic and phenotypic description of MAPT p.R406W in the Flanders‐Belgian population

Abstract

The missense mutation p.R406W in the MAPT gene is associated with frontotemporal lobar degeneration (FTLD) pathology and an atypical, Alzheimer's disease (AD)-like phenotype. In our Flanders-Belgian patient cohort, we identified 10 p.R406W carriers. Of 3 index carriers, we sampled family members, generating a total cohort of 55 p.R406W carriers. We analyzed phenotypical and genetic characteristics. Longitudinal follow-up over 19 years provided clinical and neuropathologic data. We investigated potential modifying effects on phenotype of MAPT H1/H2 and APOE genotypes. Of 55 p.R406W carriers, 39 were symptomatic. Allele-based haplotype sharing analysis confirmed a genetic kinship among all carriers suggesting a common ancestor. The frequent diagnoses were dementia (unspecified) (43.6%), AD (28.2%) and behavioral variant FTD (bvFTD) (25.6%). Average onset age and disease duration were 59.8 and 12.7 years (ranges 40-75, 5-25). at death differed significantly between clinical subgroups (69.3 in bvFTD, 78.3 in AD). Common symptoms among carriers were disinhibition and behavioral problems in all groups (72.7%). CSF biomarker profiles showed decreased Aβ1-42 and Aβ1-42 / Aβ1-40 ratio, and elevated P-tau and T-tau. Neuropathology was FTLD-tau. We observed a in carriers of an APOE ε4 allele compared to non-carriers. We observed a nonconforming clinical phenotype of p.R406W carriers in the Flemish-Belgian cohort with 25.6 % bvFTD. Contrary to previous reports, prominent behavioral symptoms were highly frequent in the entire cohort (72.7%). Ages at onset and death varied widely but, intriguingly, correlated with clinical diagnosis, lower in bvFTD than AD phenotypes. CSF biomarkers showed some AD-like abnormalities.