Specific gait changes in prodromal hereditary spastic paraplegia type 4 - preSPG4 study

Background In hereditary spastic paraplegia type 4 (SPG4), subclinical gait changes might occur years before patients realize gait disturbances. The prodromal phase of neurodegenerative disease is of particular interest to halt disease progression by future interventions before impairment has manifested. Objectives Identification of specific movement abnormalities before manifestation of gait impairment and quantification of disease progression in the prodromal phase. Methods 70 subjects participated in gait assessment, including 30 prodromal SPAST mutation carriers, 17 patients with mild-to-moderate manifest SPG4, and 23 healthy controls. Gait was assessed by an infrared-camera-based motion capture system to analyze features like range of motion and continuous angle trajectories. Those features were correlated with disease severity as assessed by the Spastic Paraplegia Rating Scale (SPRS) and neurofilament light chain (NfL) as a fluid biomarker indicating neurodegeneration. Results Compared to healthy controls, we found an altered gait pattern in prodromal mutation carriers during the swing phase in segmental angles of the lower leg (p<0.05) and foot (p<0.01), and in heel ground clearance (p<0.01). Furthermore, ranges of motion of segmental angles were reduced for foot (p<0.001) and lower leg (p<0.01). These changes occurred in prodromal mutation carriers without quantified leg spasticity in clinical examination. Gait features correlated with NfL levels and SPRS score. Conclusion Gait analysis can quantify changes in prodromal and mild-to-moderate manifest SPG4 patients. Thus, gait features constitute promising motor biomarkers characterizing the subclinical progression of spastic gait and might help to evaluate interventions in early disease stages.