We aimed at analyzing the phenotypical and genetic characteristics of patients carrying the p.R406W in the tau gene MAPT. Carriers present clinically with a nonconforming phenotype, with an underlying frontotemporal lobe degeneration (FTLD) pathology.

The p.R406W mutation is known to segregate in an autosomal dominant manner. In several pedigrees patients were reported with an amnestic (AD)-like phenotype. In our Flemish-Belgian population we identified 10 index patients with the p.R406W mutation. Additional family members of 3 of them were included, resulting in a total cohort of 56 mutation carriers. Haplotype sharing analysis confirmed genetic kinship between patients and families suggesting the presence of a common ancestor. 

We gathered data with longitudinal follow-up over 19 years and assembled results of clinical diagnoses, neuropsychological testing, cerebral imaging and cerebrospinal fluid (CSF) biomarkers. We investigated the potential modifying effect of the MAPT H1/H2 haplotype and the APOE genotype on onset age, disease duration, age at death and diagnosis. We compared the results with carriers of other FTLD genes (C9orf72, GRN, TBK1).

We compiled the data of 56 mutation carriers (3 pedigrees and 7 unrelated patients). Mean onset age and disease duration were 59.5 and 13 years. The most frequent clinical diagnoses were dementia (unspecified) (45.9%), AD (27.0%) and behavioral variant frontotemporal dementia (bvFTD) (24.3%). Frontal disinhibition and pronounced behavioral changes occurred in 71.4% patients. No modifying effect was shown of the MAPT H1/H2 haplotype and the APOE genotype.

The observations of the MAPT p.R406W carriers in the Flemish-Belgian cohort and families differ from earlier reports which showed amnestic presentation closely resembling AD. We obtained a high ratio (24.3%) of bvFTD diagnoses. Moreover, in other patients, prominent behavioral symptoms were highly frequent (71.4%). The MAPT H1/H2 haplotype and the APOE genotype did not modify onset age, disease duration, age at death or diagnosis.