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

Background: The mis sense 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 10p.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.Method: Longitudinal follow-up over 19 years provided clinical and neuropathologic.data. We investigated potential modifying effects on phenotype of MAPT H1/H2 andAPOE genotypes.Result: Of 55 p.R406W carriers, 39 were symptomatic. Allele-based haplotype sharinganalysis confirmed a genetic kinship among all carriers suggesting a common ancestor.The frequent diagnoses were dementia (unspecified) (43.6%), AD (28.2%) and behavioralvariant FTD (bvFTD) (25.6%). Average onset age and disease duration were 59.8and 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.Conclusion: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, lowerin bvFTD than AD phenotypes. CSF biomarkers showed some AD-like abnormalities.