IRF2BPL is a single-exon transcriptional regulator and E3 ubiquitin ligase that plays critical roles in neuronal maintenance and development. Through ubiquitin-mediated protein degradation, IRF2BPL negatively regulates Wnt signaling by targeting FOSL2 and other pathway components, and this function is essential for axonal preservation and proper neuronal function 1. Heterozygous loss-of-function variants in IRF2BPL cause a spectrum of neurodevelopmental and neurodegenerative phenotypes collectively termed NEDAMSS (Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures) 2. Clinical manifestations include developmental delay, drug-resistant epilepsy, progressive myoclonus, dystonia, autism spectrum disorder, and seizure-related encephalopathies, with phenotypic heterogeneity correlating to variant type and location 3. Truncated variants sequester wild-type protein to the cytoplasm and cause aggregation, impairing mitochondrial function in patient-derived neural cells 2. Recent evidence suggests the copper chelator CuATSM rescues neuronal survival and restores mitochondrial function in both cellular and Drosophila models 4, and gene-editing approaches including base editors and prime editors represent emerging therapeutic avenues for this severe disorder 5.