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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.\n                    <jats:italic>SPG4<\/jats:italic>\n                    \u2010HSP, the most common variant, is caused by mutations in the\n                    <jats:italic>SPAST<\/jats:italic>\n                    gene, which encodes spastin, a microtubule\u2010severing protein with membrane\u2010related properties. Significant progress has been made in developing preclinical models for\n                    <jats:italic>SPG4<\/jats:italic>\n                    \u2010HSP 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. \u00a9 2026 The Author(s).\n                    <jats:italic>Movement Disorders<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                  <\/jats:p>","DOI":"10.1002\/mds.70453","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:25:58Z","timestamp":1785558358000},"page":"2592-2605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>\n                      <i>SPG4<\/i>\n                    <\/scp>\n                    Hereditary Spastic Paraplegia: From Etiology to 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