This paper evaluates the clinical and neurodevelopmental features associated with gain-of-function (GOF) variants in the GRIA2 (p.Gly792) and GRIA3 (p.Gly803) genes, contributing valuable insights into rare neurodevelopmental disorders linked to AMPA receptor abnormalities. The authors effectively compare the clinical profiles of the GRIA2 and GRIA3 cohorts, highlighting both shared features and distinctive characteristics, such as the higher prevalence of hypertonia and cerebral palsy in GRIA3 patients. This comparative approach enhances the specificity of genotype-phenotype correlations. The authors speculate on the shared functional consequences of the paralogous variants but do not provide direct functional analyses, and including experimental data or referencing existing functional studies would strengthen these conclusions.
Some points could be expanded:
1)The presence of gastrointestinal comorbidities in patients with GRIA2 and GRIA3 variants adds an important dimension to understanding these disorders, suggesting that AMPA receptor dysfunction may extend beyond the nervous system to peripheral systems like the GI tract. The observed GI symptom improvement with perampanel underscores the therapeutic potential for this AMPA antagonist to manage a wider range of symptoms in these patients.
2)Direct functional analyses of GRIA2 and GRIA3 GOF variants could confirm the hypothesized gain-of-function effects, illuminating potential therapeutic targets. For instance, analogous studies have examined GRID genes, identifying intolerance regions to variation in GRID1 and GRID2, which help clarify their functional consequences and typical receptor function in both health and disease (Hum Mol Genet. 2024 Feb 1;33(4):355-373. Allen et al.).
3)The findings have potential implications for precision treatment strategies. Specifically, the study supports perampanel as a targeted therapy for GOF GRIA-related epilepsy, highlighting its benefits beyond seizure management to include neurological and gastrointestinal symptoms. Notably, recent studies underscore perampanel's high safety and efficacy in patients with rare genetic epilepsies (Perampanel as precision therapy in rare genetic epilepsies, Nissenkorn A., Epilepsia 2023;64(4):866-874).