C9orf72 repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis.

ABSTRACT

In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69). Only individuals who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [95% CI 1.97-9.14], p<0.001) and an increased hazard (HR= 4.77 [95% CI 2.33-9.79], p<0.001) for developing secondary symptoms in those with a C9orf72 expansion compared to those without. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary symptoms. These data highlight the need for clinician vigilance to detect the onset of secondary motor and cognitive-behavioral symptoms in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.