PURA-Related Neurodevelopmental Disorder: A Comprehensive Clinical Review of Genetics, Phenotype, and Emerging Therapeutic Strategies

PURA-related neurodevelopmental disorder (PURA-NDD) is an ultra-rare genetic condition caused by heterozygous pathogenic variants in the PURA gene, leading to haploinsufficiency of the Pur-α protein, a critical regulator of neuronal development and RNA trafficking. The disorder is characterized by neonatal hypotonia, global developmental delay, intellectual disability, severely impaired speech, epilepsy, feeding difficulties, respiratory dysfunction, and multisystem involvement. Clinical presentation is heterogeneous, with variability in seizure burden, motor milestones, autonomic dysfunction, endocrine abnormalities, and musculoskeletal complications such as scoliosis. Diagnosis relies on molecular confirmation through genome-wide sequencing, with early recognition enabling anticipatory guidance and multidisciplinary management. Current treatment remains supportive and symptom-directed, focusing on seizure control, nutritional support, respiratory care, rehabilitative therapies, and management of associated comorbidities. Evidence for targeted interventions, including ketogenic diet, vagus nerve stimulation, and neuromuscular junction-modulating agents, remains limited to case-based and small-cohort data. Emerging disease-modifying strategies, including adeno-associated virus-mediated gene replacement, antisense oligonucleotide approaches, RNA-targeted therapies, and drug repurposing, are under preclinical investigation. Advances in animal models, epigenetic profiling, and global patient registries are refining genotype-phenotype correlations and informing future clinical trial design. This comprehensive clinical review synthesizes current evidence on the genetics, pathophysiology, clinical spectrum, diagnostic evaluation, management strategies, and evolving therapeutic landscape of PURA-NDD, highlighting practical considerations for clinicians and priorities for translational research.