GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil

Abstract

Background: Mutations in GRN (progranulin) and MAPT (microtubule-associated protein tau) are among the most frequent causes of monogenic frontotemporal dementia (FTD), but data on the frequency of these mutations in regions such as Latin America are still lacking.

Objective: We aimed to investigate the frequencies of GRN and MAPT mutations in FTD cohorts from 2 Brazilian dementia research centers, the University of Sao Paulo and the Federal University of Minas Gerais medical schools.

Methods: We included 76 probands diagnosed with behavioral-variant FTD (n=55), semantic-variant Primary Progressive Aphasia (PPA) (n=11), or nonfluent-variant PPA (n=10). Twenty-five percent of the cohort had at least 1 relative affected with FTD.

Results: Mutations in GRN were identified in 7 probands, and in MAPT, in 2 probands. We identified 3 novel GRN mutations (p.Q130X, p.317Afs*12, and p.K259Afs*23) in patients diagnosed with nonfluent-variant PPA or behavioral-variant FTD. Plasma progranulin levels were measured and a cutoff value of 70 ng/mL was found, with 100% sensitivity and specificity to detect null GRN mutations.

Conclusions: The frequency of GRN mutations was 9.6% and that of MAPT mutations was 7.1%. Among familial cases of FTD, the frequency of GRN mutations was 31.5% and that of MAPT mutations was 10.5%.

Figure 1

Neuroimaging of probands Brain MRI scans (A) Proband USP 58’s sister. Axial FLAIR images. White matter hyperintensities appear as atrophy in frontal, temporal and parietal regions progress. (B) Axial FLAIR images from proband USP 64 show global cortical atrophy with periventricular white matter hyperintensities. (C) Axial FLAIR images from Proband UFMG 18 show left anteromedial temporal lobe atrophy and subtle white matter hyperintensities.

Figure 2

Neuropathological findings in proband USP 63 Macroscopy (A-D): global cortical atrophy, predominantly in the frontal, temporal and parietal lobes. Atrophy is slightly more significant on the right hemisphere. Views: dorsal (A); ventral (B); lateral of right hemisphere (C); lateral of left hemisphere (D). Microscopy (E-F, 400x): Immunohistochemistry with antibodies against hyperphosphorylated TDP-43 showing neuronal cytoplasmic inclusions (red arrow) in the granule cell layer of the dentate gryus (E) and short dystrophic neurites (red arrow) in the entorhinal cortex (F).

Figure 3

Dot plot of plasma progranulin levels. FTD: frontotemporal dementia; GRN+: with null GRN mutations; GRN−: without null GRN mutations. Values shown as mean ± standard deviation (range) in ng/ml. Red dotted lines indicate the means.