Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is contained within the SPT complex. This evidence concerns the gene AGXT and amyotrophic lateral sclerosis.