ANXA11 Mutations in the FTD Spectrum: A Novel Finding in a Patient With Semantic Variant Primary Progressive Aphasia

Abstract

Background: Semantic variant primary progressive aphasia (svPPA) is typically a sporadic disorder, and few cases have been linked to ANXA11 mutations. Comprehensive analyses of genetic mutations in svPPA are limited. Furthermore, the clinical and genetic distinctions between typical svPPA and right temporal variant frontotemporal dementia (rtvFTD) are poorly understood.

Methods: A 68-year-old patient with svPPA carrying a heterozygous ANXA11 c.119A>G (p.D40G) mutation underwent comprehensive neuropsychological, neuroimaging, and genetic assessments at baseline and at the one-year follow-up timepoint. Additionally, systematic reviews were conducted to identify reported cases of ANXA11 mutations in the FTD spectrum and the genetic mutations associated with svPPA. Clinical-genetic profiles of typical svPPA and rtvFTD were compared based on data from the literature.

Results: Thirty-two patients with ANXA11 mutations were identified, including 11 with pure FTD phenotypes and the majority exhibiting FTD-amyotrophic lateral sclerosis (ALS). Among 167 svPPA-related cases, MAPT, GRN, and C9ORF72 mutations were most frequently implicated; ANXA11 mutations were primarily identified in East Asian patients. Comparative analysis revealed overlapping age at onset, disease duration, sex distribution, and APOE ε4 allele frequencies between typical svPPA and rtvFTD but differing clinical presentations.

Conclusions: This study reports a case of typical svPPA in China associated with the ANXA11 p.D40G mutation without ALS-related features. Our findings highlight the importance of ANXA11 mutations in FTD pathogenesis.

Keywords: ANXA11 gene; D40G mutation; frontotemporal lobar degeneration; right temporal variant frontotemporal dementia; semantic variant primary progressive aphasia.

FIGURE 1

Brain MRI of the patient with ANXA11 mutation at the initial visit. Axial (upper two rows) and coronal (lower row) T1‐weighted images show prominent atrophy in the bilateral anterior temporal lobes with left‐predominant (arrow) and mild atrophy in the left frontal, parietal, and insular compared with the right side. R = right; L = left.

FIGURE 2

Sanger sequencing shows the ANXA11 c.119A>G (p.D40G) mutation.

FIGURE 3

Flow chart of the classification of enrolled svPPA participants. A total of 167 participants diagnosed with SD/svPPA were classified into four subtypes: Typical SD/svPPA (n = 128), rtvFTD (n = 19), svPPA‐ALS (n = 12), and svPPA‐related diseases (n = 8). SD, semantic dementia; svPPA, semantic variant of PPA; rtvFTD, right temporal variant FTD; ALS, amyotrophic lateral sclerosis.

FIGURE 4

Genetic analysis of the FTD‐ALS spectrum with ANXA11 mutations (n = 32) and the genetic spectrum of the SD/svPPA patients (n = 167). (A) Geographical distribution of ANXA11 variants related to FTD‐ALS spectrum patients previously reported. (B) Proportions of specific ANXA11 variants identified. (C) Proportions of clinical subtypes of ANXA11‐related cases categorized as FTD‐ALS and FTD. (D) Geographical distribution of reported svPPA cases. (E) Genetic mutations identified in svPPA patients.