Semantic variant primary progressive aphasia with ANXA11 p.D40G

Abstract

Introduction: Pathogenic variants of annexin A11 (ANXA11) have been identified in patients with amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). We explored ANXA11 pathogenic variants in a Korean FTD cohort to investigate the prevalence and the role of ANXA11 variation in FTD.

Methods: We used next-generation sequencing (NGS) to search for pathogenic variants in ANXA11 in two nationwide FTD cohorts in Korea.

Results: We identified a pathogenic variant in ANXA11, c.119A > G (p.D40G), in six patients with semantic variant primary progressive aphasia (svPPA), representing 5.5% of the svPPA cohort (6/109), and representing 2.3% of the FTD cohort overall (6/259). Only one patient later developed features suggestive of ALS.

Discussion: This study links a rare variant in ANXA11 to a sporadic clinical syndrome in which specific TAR DNA-binding protein-43 (TDP-43) forms an obligate co-fibril with annexin A11. The variant, p.D40G, lies within the N-terminal portion of annexin A11's TDP-43 type C interacting domain, suggesting that genetic variation in that region may promote co-fibrillization.

Highlights: The pathogenic variant of annexin A11 (ANXA11I) is linked to frontotemporal dementia (FTD) syndrome. ANXA11 (p.D40G) may be one of the possible genetic causes of semantic variant primary progressive aphasia (svPPA). ANXA11 (p.D40G) may enhance heteromeric amyloid filaments of annexin A11 and TDP-43, promoting frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) type C.

Keywords: ANXA11; FTLD‐TDP type C; TDP‐43; annexin A11; clinical genetics; frontotemporal dementia (FTD); semantic variant primary progressive aphasia (svPPA).

FIGURE 1

Brain MRI images of cases with D40G of ANXA11. FLAIR axial and T1‐weighted coronal brain MR images of each patient showed bilateral anterior temporal atrophy (case 5), worse on the right (case 1, 2, 4, 6) or left (case 3). FLAIR, Fluid‐attenuated inversion recovery; MRI, magnetic resonance imaging.

FIGURE 2

¹⁸F‐FDG‐PET images. ¹⁸F‐FDG‐PET images revealed decreased glucose metabolism in the bilateral anterior temporal areas, worse on the right side (case 1, 4, 6) or the left side (case 3). The images of Case 1 and Case 4 were obtained from the Australian e‐Health Research Centre (https://aehrc.csiro.au/wileyonlinelibrary.com]). The images were quantified and correlated with a 3D surface image using CapAIBL (https://milxcloud.csiro.au/wileyonlinelibrary.com]). To quantify uptake in PET images, focal uptake values were divided by those of the cerebellum (reference region). After quantification, a z‐score map was created on the 3D surface image. The images of Case 1 were reprinted with permission from the European Journal of Neurology 2022;29:3124‐3126. 18F‐FDG‐PET, [18F]‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography; 3D, three‐dimensional; PET, positron emission tomography.