SPG4 Hereditary Spastic Paraplegia: From Etiology to Therapy.

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of heritable neurodegenerative disorders resulting from mutations in a wide variety of genes. HSP locomotor symptoms include lower limb weakness and spasticity that arise from progressive degeneration of corticospinal axons projecting from the motor cortex to the distal spinal cord. Ensuing gait defects typically lead to wheelchair dependence. Degeneration of other tracts can also occur, expanding the constellation of symptoms to potentially include urinary, fecal, and speech problems, as well as intellectual disability. SPG4-HSP, the most common variant, is caused by mutations in the SPAST gene, which encodes spastin, a microtubule-severing protein with membrane-related properties. Significant progress has been made in developing preclinical models for SPG4-HSP and in elucidating its mechanistic etiology. On this basis, progress is being made on developing a flexible therapeutic regimen for patients at all stages of disease progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.