Editors' note: The underacknowledged PPA-ALS: A unique clinicopathologic subtype with strong heritability

Abstract

As many as 10%–15% of patients with frontotemporal dementia (FTD) are known to have concomitant amyotrophic lateral sclerosis (ALS), and this association is mainly with the behavioral variant of FTD. However, some patients with primary progressive aphasia (PPA) have also developed ALS. In their observational cohort of 130 patients with semantic variant (n = 64) or nonfluent variant (n = 66) PPA, Tan and colleagues sought to better characterize the relationship between PPA and ALS. Of the included patients with PPA, 12% were ultimately diagnosed with ALS. A large proportion of these patients exhibited a strong family history (57% of patients with PPA-ALS), and all autopsied patients demonstrated TDP-43 inclusions on histopathology. Gazulla et al. reflected on their experience with 1 family, 6 members of which met clinical criteria for primary lateral sclerosis-plus—only later to develop a nonfluent aphasia and dementia. Although the condition observed by Gazulla et al. followed an autosomal dominant pattern with complete penetrance, whole exome sequencing failed to identify a genetic predisposition in this family. Because the cases reported by Gazulla et al. were derived from a single family without a clear genetic etiology, and their motor neuron disease appears clinically distinct from the PPA-ALS pathology confirmed in the present study, the investigators believe these 2 cohorts to have unique neurodegenerative conditions. In conclusion, Tan et al. encourage clinicians to be mindful of the association between ALS and all FTD phenotypes. As many as 10%–15% of patients with frontotemporal dementia (FTD) are known to have concomitant amyotrophic lateral sclerosis (ALS), and this association is mainly with the behavioral variant of FTD. However, some patients with primary progressive aphasia (PPA) have also developed ALS. In their observational cohort of 130 patients with semantic variant (n = 64) or nonfluent variant (n = 66) PPA, Tan and colleagues sought to better characterize the relationship between PPA and ALS. Of the included patients with PPA, 12% were ultimately diagnosed with ALS. A large proportion of these patients exhibited a strong family history (57% of patients with PPA-ALS), and all autopsied patients demonstrated TDP-43 inclusions on histopathology. Gazulla et al. reflected on their experience with 1 family, 6 members of which met clinical criteria for primary lateral sclerosis-plus—only later to develop a nonfluent aphasia and dementia. Although the condition observed by Gazulla et al. followed an autosomal dominant pattern with complete penetrance, whole exome sequencing failed to identify a genetic predisposition in this family. Because the cases reported by Gazulla et al. were derived from a single family without a clear genetic etiology, and their motor neuron disease appears clinically distinct from the PPA-ALS pathology confirmed in the present study, the investigators believe these 2 cohorts to have unique neurodegenerative conditions. In conclusion, Tan et al. encourage clinicians to be mindful of the association between ALS and all FTD phenotypes.