AP4S1 encodes the σ1 subunit of adaptor protein complex 4 (AP-4), a vesicle coat component involved in cargo selection and protein trafficking 12. AP-4 mediates non-clathrin-associated vesicle formation from the trans-Golgi network (TGN) and regulates protein sorting to endosomal-lysosomal compartments, basolateral membranes in epithelial cells, and somatodendritic regions in neurons. Functionally, AP4S1 loss-of-function mutations cause disruption of AP-4 complex assembly and loss of recruitment of accessory proteins to membranes 3. Biallelic AP4S1 mutations cause spastic paraplegia 52 (SPG52), part of the "AP-4 deficiency syndrome"—a complex childhood-onset hereditary spastic paraplegia characterized by early developmental delay, severe intellectual disability, progressive lower limb spasticity evolving to tetraplegia, postnatal microcephaly (83%), and intractable epilepsy (66%) 4. Neuroimaging reveals thin corpus callosum (90%), ventriculomegaly (65%), and white-matter abnormalities (68%). A zebrafish ap4s1 truncation model demonstrates motor impairment, neurodevelopmental delay, and distal axonal degeneration 5. Elevated plasma neurofilament light chain levels serve as a biomarker of neuroaxonal damage 6. Critically, heterozygous AP4S1 variants are not associated with neurological phenotypes 7, confirming autosomal recessive inheritance. AP-4 deficiency syndrome represents the most common syndromic intellectual disability in consanguineous populations 8.