ObjectiveTo investigate inflammatory cytokines in patients with motor neuron disease (MND) evaluating the putative contribution of amyotrophic lateral sclerosis (ALS)-causing gene variants.MethodsThis study is a retrospective case series with prospective follow-up (1994–2016) of 248 patients with MND, of whom 164 had ALS who were screened for mutations in the genes forSOD1andC9orf72. Paired CSF and plasma were collected at the diagnostic evaluation before treatment. A panel of cytokines were measured blindly via digital ELISA on the Simoa platform.ResultsTime from disease onset to death was longer for patients with ALS-causingSOD1mutations (mSOD1, n = 24) than those withC9orf72hexanucleotide repeat expansion (C9orf72HRE) ALS (n = 19;q= 0.001) and other ALS (OALS) (n = 119;q= 0.0008). Patients with OALS had higher CSF tumor necrosis factor alpha (TNF-α) compared with those with C9orf72HRE ALS (q= 0.014). Patients with C9orf72HRE ALS had higher CSF interferon alpha compared with those with OALS and mSOD1 ALS (q= 0.042 andq= 0.042). In patients with ALS, the survival was negatively correlated with plasma interleukin (IL) 10 (hazard ratio [HR] 1.17, 95% CI 1.05–1.30). Plasma TNF-α, IL-10, and TNF-related apoptosis-inducing ligand (TRAIL) (HR 1.01 [1.00–1.02], 1.15 [1.02–1.30], and 1.01 [1.00–1.01], respectively) of patients with OALS, plasma IL-1β (HR 5.90 [1.27–27.5]) of patients with C9orf72HRE ALS, and CSF TRAIL (10.5 [1.12–98.6]) of patients with mSOD1 ALS all correlated negatively with survival.ConclusionsDifferences in survival times in ALS subtypes were correlated with cytokine levels, suggesting specific immune responses related to ALS genetic variants.