ALS4 is a juvenile form of autosomal dominant neuromuscular disease characterized by progressive degeneration of upper and lower motor neurons in the brain and spinal cord and results in progressive muscle weakness, muscle wasting, atrophy and spasticity.128 In contrast to the SETX mutations in AOA2 that cause loss of function, SETX mutations associated with ALS4 result in gain of function in SETX R-loop resolution activity leading to neurodegeneration.65,125,146,147 An increase in SETX-dependent R-loop resolution activity results in fewer R-loops in ALS4 patient cells. Here, SETX is linked to amyotrophic lateral sclerosis type 4.