Following earlier human studies implicating this pathway in ALS by GWAS association to the SARM1 chromosomal locus and loss of potential SARM1 regulator STMN2 in human induced pluripotent stem cell (hiPSC)-derived motor neurons (Fogh et al., 2014; van Rheenen et al., 2016; Klim et al., 2019; Melamed et al., 2019), recent work has revealed that human SARM1 variant alleles that hyperactivate SARM1 NADase function and enhance neuronal vulnerability are enriched in patients with sporadic ALS, hereditary spastic paraplegia and other motor nerve disorders (Bloom et al., 2021; Gilley et al., 2021). This evidence concerns the gene STMN2 and hereditary spastic paraplegia.