The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics

Background The co-occurrence of the c.709-1G > A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. Methods and findings We compared clinical characteristics of 14 patients who carried the c.709-1G > A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G > A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T-patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked beta-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). Conclusions In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question. F.M., P.S.J. and S.E.L. receive funding from the Tau Consortium. F.C. receives funding from the Generalitat de Catalunya (grant 2014 SGR 866). P.S.J. receives funding from ISCIII (PI12/02288). This work was also supported by the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.