Long-Term Phenotypic Evolution in GRIN2A-Related Disorders: Electroclinical and Genetic Insights from Two Families with Extended Follow-Up.

Abstract

Background: The GRIN2A gene and its product protein have been linked to a wide spectrum of neurodevelopmental disorders named GRIN2A-related disorders. Clinical presentation is highly variable and characteristically includes acquired cognitive, behavioral, and language impairment, as well as epilepsy, ranging from benign forms to severe epileptic encephalopathy. Recent genetic investigations have expanded the clinical spectrum of heterozygous GRIN2A variants, improving our understanding of genotype-phenotype correlations. However, there have been few long-term observational studies of patients affected by the genetically determined GRIN2A-related disease. Methods: To understand the long-term changes in clinical features, we described three patients from two Italian families, carrying variants in the GRIN2A gene. Results: After more than a decade of extensive electro-clinical follow-up, we observed a progressive cognitive decline associated with severe behavioral disturbances, despite clinical seizure control. The persistent presence of EEG epileptiform abnormalities over time suggests the need for a longitudinal neurophysiological study to monitor disease progression and evaluate the potential for anti-seizure medication discontinuation. Conclusions: Our study offers new insights into the natural progression of epilepsy in GRIN2A-related disorders, highlighting that a more detailed understanding of the phenotype and timely, personalized treatment could enhance the management and quality of life for both GRIN2A patients and their caregivers.