In the most recent and largest genetic study on 139 PLS patients [53], likely pathogenic or pathogenic variants in genes related to ALS-FTD (C9Orf72; TBK1), HSP (SPAST; SPG7), and the ALS-HSP-Charcot-Marie-Tooth overlap (NEFL; SPG11) were found in 7% of the cohort, remarking upon the possible significant contribution of genetics in the diagnostic work-up of PLS (Figure 1). This evidence concerns the gene SPAST and amyotrophic lateral sclerosis.