AP4M1 encodes the μ-subunit of adaptor protein complex 4 (AP-4), a non-clathrin coat component mediating vesicular transport from the trans-Golgi network (TGN) 1. AP4M1 specifically recognizes and binds tyrosine-based sorting signals on cargo proteins, directing proteins to the endosomal-lysosomal system and basolateral membranes in epithelial cells 1. AP-4 deficiency causes hereditary spastic paraplegia 50 (SPG50), an ultra-rare childhood-onset disorder characterized by progressive spastic paraplegia, developmental delay, intellectual disability, postnatal microcephaly (83%), and intractable epilepsy (66%) 2. Brain imaging reveals thin corpus callosum (90%), ventriculomegaly (65%), and white-matter abnormalities (68%) 2. SPG50 shares a common phenotype with other AP-4 subunit mutations (SPG47, SPG51, SPG52), termed 'AP-4 deficiency syndrome,' with onset typically before age 3 years and progressive motor decline, with 54% wheelchair-dependent by mean age 13.4 years 2. Biallelic loss-of-function variants cause disease, with over 70 unique variants identified 2. Recent clinical advances include intrathecal AAV9/AP4M1 gene therapy, which demonstrated safety and disease stabilization in preclinical studies and a phase 1 patient trial, offering promise for this previously untreatable condition 34.