Distinctive pattern of temporal atrophy in patients with frontotemporal dementia and the I383V variant in TARDBP

Introduction Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are closely related disorders, linked pathologically and genetically by the TAR DNA-binding protein-43 (TDP-43). Pathogenic variants in TARDBP encoding for TDP-43 have been described less frequently in FTD than in ALS, and clinicopathological studies are scarce.1 We previously observed a high frequency of the I383V variant in TARDBP in a Dutch cohort of FTD patients.2 Here, we provide further evidence for the pathogenicity of this variant and present its clinicopathological characteristics.

Methods We ascertained all FTD (n=13) and ALS patients (n=4) with the I383V variant (NM_007375.3: c.1147A>G, p.Ile383Val) in TARDBP from three university medical centres in the Netherlands (Amsterdam, Rotterdam and Utrecht), as identified by whole-exome or whole-genome sequencing in either clinical or research setting. Concurrent pathogenic variants in 20 other genes associated with ALS, FTD or other forms of dementia were excluded in all patients.

Brain imaging (CT or MRI) was available for all FTD patients. Quantitative assessment of volume loss across lobar brain regions was performed in those patients with T1-weighted MRI images of sufficient quality (n=5), and compared with a gender-matched/age-matched reference population.

Family histories were classified into adjusted Goldman categories, which were described previously.2 Additionally, we performed extensive genealogical research to investigate possible relatedness between the index patients.

Brain autopsy and routine immunohistochemistry was performed for two FTD patients by the Netherlands Brain Bank. One patient (4M) was reported previously as M008015-001.1 Detailed information on the genetic, neuroimaging, genealogical and pathological analyses can be found in the1.