Hereditary spastic paraplegia: from decades of therapy to future innovations

Hereditary spastic paraplegia (HSP) groups rare, clinically and genetically heterogeneous neurodegenerative disorders, characterized by progressive lower-limb spasticity and weakness. Over the past decades, diagnostic strategies have evolved from pure clinical assessment to the integration of molecular tools, with next-generation and long-read sequencing (LRS) substantially increasing diagnostic yield and refining genotype-phenotype correlations. Neuroimaging provides complementary information, especially in specific subtypes such as SPG11 and SPG15, supporting diagnosis and guiding testing. Treatment has historically focused on symptomatic care, including physiotherapy, antispastic agents, and botulinum toxin, with dalfampridine explored for gait improvement in selected patients. More recently, research has expanded into disease-modifying avenues, such as drug repurposing (e.g., statins in SPG5, menatetrenone in ALS2) and early gene-based interventions in ultra-rare subtypes. At the same time, advances in technology, ranging from quantitative imaging and digital gait analysis to induced pluripotent stem cell models and artificial intelligence, are beginning to influence both clinical management and trial design. This review traces the trajectory of HSP care from its historical foundations to present standards and emerging innovations, outlining how technological progress is shaping realistic prospects for future therapeutic strategies.