Combined molecular characterization and dopa-responsive treatment in two patients with NR4A2-associated intellectual developmental disorder.

Introduction: Pathogenic variants in NR4A2 are associated with neurodevelopmental disorders including intellectual developmental disorder with language impairment and early-onset dopa-responsive dystonia-parkinsonism (IDLDP). Here we report two pediatric NR4A2-related cases presenting with global developmental delay, speech impairment, and intellectual disability.

Methods: Comprehensive genetic investigations including whole-exome sequencing revealed a de novo missense variant (c.994G>C, p.Val332Leu) in NR4A2 and a 2q23.3-q24.2 deletion encompassing NR4A2. Functional validation via RNA sequencing revealed that the missense variant induces pathogenic exon 4 skipping through aberrant splicing. Both patients exhibited marked clinical improvements in linguistic competence and motor function following levodopa therapy, initiated after confirmation of dopaminergic responsiveness. A systematic review of 19 reported NR4A2-related cases revealed substantial phenotypic heterogeneity, with three of them demonstrating favorable responses to dopaminergic treatment.

Results: Our findings underscore the diagnostic value of integrating molecular profiling with functional RNA analysis to resolve complex neurogenetic disorders. Levodopa therapy shows therapeutic potential for NR4A2-deficient patients with dopa-responsive features, especially in linguistic improvement. This study expands the understanding of NR4A2-associated pathogenesis and provides insights for the precision management of related neurodevelopmental conditions.