Recent work reveals that gain of function mutations in SPTLC1 and SPTLC2, which encode components of the SPT complex that catalyzes the initial, rate-limiting step of de novo ceramide and sphingolipid biosynthesis (Fan and Bergmann, 2010), cause juvenile ALS via increased sphingolipid biosynthesis (Lone et al., 2022; Lone et al., 2023; Syeda et al., 2024; Dohrn et al., 2024; Srivastava et al., 2023). Here, SPTLC2 is linked to amyotrophic lateral sclerosis.