Amyotrophic lateral sclerosis (ALS) is clinically characterized by stiff muscles and progressive motor dysfunction. Hexanucleotide repeat expansion in intron of the C9ORF72 gene is the most common cause of ALS accounting for 37.6% of familial ALS and 21.1% of sporadic ALS. The cover illustrates that the hexanucleotide repeat expansion in C9ORF72 results in a freezing phenotype in ALS models. Recent advances cover the role of C9ORF72 in disease pathology and the attempts in therapeutics using animal models, which may melt the ice to free the frozen muscles and broadens the avenue to overcome ALS. (Cover image provided by Ms. Xiying Wang)