AP4S1 encodes the sigma-1 subunit of adaptor protein complex 4 (AP-4), a non-clathrin vesicle coat involved in protein trafficking from the trans-Golgi network to the endosomal-lysosomal system and basolateral membrane targeting in epithelial cells. AP-4 mediates cargo recognition through tyrosine-based sorting signals and controls asymmetric protein localization in neurons. Biallelic loss-of-function variants in AP4S1 cause spastic paraplegia type 52 (SPG52), a childhood-onset hereditary spastic paraplegia characterized by global developmental delay, intellectual disability (moderate to severe), progressive lower-limb spasticity evolving to tetraplegia, and intractable epilepsy in approximately two-thirds of patients 1. Core neuroimaging features include thin corpus callosum (90%), ventriculomegaly (65%), and white-matter abnormalities (68%) 1. Disease typically manifests before age one with delayed motor milestones and speech delay; mean diagnosis occurs at 10.2 years 1. Seizures appearing before age three are associated with worse motor outcomes 1. SPG52 shares a common phenotype with other AP-4 subunit deficiencies (SPG47, SPG50, SPG51), termed 'AP-4 deficiency syndrome' 1. Mechanistically, AP4S1 mutations disrupt AP-4 complex assembly and endosomal trafficking 2. Plasma neurofilament light chain elevation serves as a biomarker of neuroaxonal damage in AP-4-associated hereditary spastic paraplegia 3. Notably, heterozygous carriers show no increased neurological manifestations 4, indicating autosomal recessive inheritance with complete penetrance in biallelic disease.