NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies

Int J Mol Sci. 2024 May 10;25(10):5198. doi: 10.3390/ijms25105198.

Abstract

The NR4A2 gene encodes an orphan transcription factor of the steroid-thyroid hormone-retinoid receptor superfamily. This review focuses on the clinical findings associated with the pathogenic variants so far reported, including three unreported cases. Also, its role in neurodegenerative diseases, such as Parkinson's or Alzheimer's disease, is examined, as well as a brief exploration on recent proposals to develop novel therapies for these neurological diseases based on small molecules that could modulate NR4A2 transcriptional activity. The main characteristic shared by all patients is mild to severe developmental delay/intellectual disability. Moderate to severe disorder of the expressive and receptive language is present in at least 42%, while neuro-psychiatric issues were reported in 53% of patients. Movement disorders, including dystonia, chorea or ataxia, are described in 37% patients, although probably underestimated because of its frequent onset in late adolescence-young adulthood. Finally, epilepsy was surprisingly present in 42% of patients, being drug-resistant in three of them. The age at onset varied widely, from five months to twenty-six years, as did the classification of epilepsy, which ranged from focal epilepsy to infantile spasms or Lennox-Gastaut syndrome. Accordingly, we propose that NR4A2 should be considered as a first-tier target gene for the genetic diagnosis of developmental and epileptic encephalopathy.

Keywords: Alzheimer’s disease; NR4A2; NURR1; dystonia; epilepsy; intellectual disability; language impairment; parkinsonism.

Publication types

  • Systematic Review
  • Review

MeSH terms

  • Developmental Disabilities / genetics
  • Developmental Disabilities / therapy
  • Epilepsy* / genetics
  • Humans
  • Intellectual Disability / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2* / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2* / metabolism

Substances

  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • NR4A2 protein, human

Grants and funding

This research was funded by Mutua Madrileña Foundation (FMM), grant number 2019/0144, and by Instituto de Salud Carlos III (ISCIII) through the project “PI22/00272”, co-funded by the European Union.