SPAST encodes spastin, a microtubule-severing AAA-ATPase essential for axonal organization and synaptic patterning. Spastin locally amplifies microtubule polymerization dynamics to enable precise presynaptic cargo delivery and synapse formation along axons 1. The protein is transcriptionally regulated by NRF1 and SOX11, while miR-96 and miR-182 negatively regulate SPAST expression, indicating that stoichiometric spastin levels are critical for proper function 2. SPAST mutations cause spastic paraplegia type 4 (SPG4), the most common hereditary spastic paraplegia, representing 9.2% of hereditary spastic paraplegia cases 3. Mutations typically follow autosomal dominant inheritance but can present as severe early-onset complicated forms with dystonia, epilepsy, and cognitive decline, particularly with the recurrent p.Arg499His variant 45. Emerging evidence indicates biallelic SPAST variants cause severe early-onset encephalopathy resembling cerebral palsy 6. Pathogenic mechanisms involve both haploinsufficiency and potential gain-of-function effects, with mutant spastin proteins potentially causing a second hit in vulnerable corticospinal tracts 7. Cellular dysfunction includes reduced spastin levels, mitochondrial fragmentation, and abnormal membrane morphology 6. SPAST variants are detected in approximately 26% of Mendelian disorders identified in cerebral palsy patients 8.