AP4B1 encodes the β1 subunit of adaptor protein complex 4 (AP-4), a heterotetrameric vesicle coat component critical for intracellular protein trafficking 1. AP-4 mediates cargo recognition and vesicle formation at the trans-Golgi network, directing proteins to the endosomal-lysosomal system and controlling basolateral membrane sorting in epithelial cells and somatodendritic localization in neurons 23. Bi-allelic loss-of-function variants in AP4B1 cause spastic paraplegia 47 (SPG47), characterized by early-onset (mean 0.8 years) developmental delay, spastic diplegia progressing to tetraplegia, severe intellectual disability, postnatal microcephaly (83%), and intractable epilepsy (66%) 4. Neuroimaging reveals thin corpus callosum (90%), ventriculomegaly, and white matter abnormalities 45. AP4B1 mutations predominantly cause frameshift or nonsense mutations with autosomal recessive inheritance, often in consanguineous families 4. Disease progression worsens significantly with early-onset epilepsy; by adolescence, 54% of patients become wheelchair-dependent 4. Mechanistically, AP-4 deficiency causes mislocation of cargo proteins like ATG9A and neurodegeneration affecting long CNS axons 6. Preclinical gene therapy using AAV9/hAP4B1 restored disease hallmarks in SPG47 mouse models with demonstrated safety in non-human primates 6.