IntroductionSOD1was the first gene associated with both familial and sporadic forms of amyotrophic lateral sclerosis (ALS) and is the second most mutated gene in Caucasian ALS patients. Given their high clinical and molecular heterogeneity, a detailed characterization ofSOD1-ALS patients could improve knowledge about the natural history of this disease. Here, the authors aimed to provide a clinical and molecular description of a monocentric cohort ofSOD1-ALS patients.MethodsAmyotrophic lateral sclerosis (ALS) patients referring to the neurology unit of our center between 2008 and 2021 were clinically assessed and underwent molecular testing forSOD1. Segregation studies in available family members andin silicoanalysis were performed to sustain the pathogenicity of the identifiedSOD1variants.ResultsAmong the 576 patients in our cohort, we identified 19 individuals harboring a mutation inSOD1(3.3%), including 15 (78.9%) with a familial and four (21.1%) with a sporadic form. The spinal onset of the disease was observed in all patients, and survival was extremely variable, ranging from 8 months to over 30 years. Twelve differentSOD1missense variants were identified in our cohort, including one novel mutation (p.Pro67Leu).DiscussionIn the present series, we provided the first description of an Italian monocentric cohort ofSOD1-ALS patients, and we expanded the repertoire ofSOD1mutations. Our cohort presents several remarkable features, including variable expressivity in the same family, atypical presentation (ataxia, cognitive impairment, and other extra-motor symptoms), and different modes of inheritance of a given mutation in the same family. Given the recent authorization ofSOD1-directed antisense oligonucleotide for use inSOD1-ALS patients, we recommend prompt screening forSOD1mutations in novel ALS patients with familiar or sporadic presentations.