Also, in patients with amyotrophic lateral sclerosis 4 (ALS4), caused by mutations in senataxin, R-loops have been shown to block DNA methylation at gene promoters and inhibit DNA methyl-transferase-1 (DNMT1) activity leading to activation of the TGFb pathway (82). Here, TGFB1 is linked to amyotrophic lateral sclerosis type 4.