Background In Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) a length-dependent axonal degeneration in the cortico-spinal tract leads to progressing symptoms of hyperrefexia, muscle weakness, and spasticity of lower extremities. Even before the manifestation of spastic gait, in the prodromal phase, axonal degeneration leads to subtle gait changes. These gait changes - depicted by digital gait recording - are related to disease severity in prodromal and early-to-moderate manifest SPG4 participants. Methods We hypothesize that dysfunctional neuro-muscular mechanisms such as hyperrefexia and muscle weak- ness explain these disease severity-related gait changes of prodromal and early-to-moderate manifest SPG4 partici- pants. We test our hypothesis in computer simulation with a neuro-muscular model of human walking. We introduce neuro-muscular dysfunction by gradually increasing sensory-motor refex sensitivity based on increased velocity feedback and gradually increasing muscle weakness by reducing maximum isometric force. Results By increasing hyperrefexia of plantarfexor and dorsifexor muscles, we found gradual muscular and kin- ematic changes in neuro-musculoskeletal simulations that are comparable to subtle gait changes found in prodromal SPG4 participants. Conclusions Predicting kinematic changes of prodromal and early-to-moderate manifest SPG4 participants by grad- ual alterations of sensory-motor refex sensitivity allows us to link gait as a directly accessible performance marker to emerging neuro-muscular changes for early therapeutic interventions. Keywords Gait simulation, Spasticity, Hyperrefexia, Prodromal, SPG4, HSP, Movement disorder