IRF2BPL mutations in rare childhood brain disorders: from genetics to pathophysiology

Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) is an ultra-rare, progressive neurological disorder, with more than 60 individuals described in the medical literature. It is caused by de novo mutations in the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene, leading to early-onset symptoms including seizures, developmental delays, intellectual disability, and other severe neurological impairments, typically beginning in infancy or early childhood. This review aims to consolidate and refine current knowledge on NEDAMSS, focusing on the molecular functions of IRF2BPL, the spectrum of clinical features, and underlying disease mechanisms. A comprehensive understanding of NEDAMSS is essential for guiding the development of targeted interventions and therapeutic strategies to improve patient outcomes. By integrating current findings, we focus both on the progress made and the gaps that remain in research, providing a foundation for future studies to advance diagnosis, treatment, and overall patient care. We reviewed the published literature through studies available up to 2025 to synthesize current knowledge on clinical features, genetics, and proposed disease mechanisms. Reported phenotypes show substantial heterogeneity, and current genotype-phenotype correlations remain limited by small cohorts and inconsistent reporting. Key next steps include standardized phenotyping, natural history studies, and biomarker development to enable trial-ready outcome measures and accelerate targeted therapy development.