Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency

Abstract

Objective: GRIN-related disorders due to pathogenic variants in GRIN1, GRIN2A, GRIN2B, or GRIN2D genes are associated with altered N-methyl-D-aspartate receptor (NMDAR) function. Functional changes include gain (GoF) and loss of receptor function (LoF). Clinical reports describing the use of the NMDAR blocker memantine in GRIN-related disorders show a diverse and inconsistent spectrum of treatment responses. Methods: To evaluate clinical responses to memantine, we collected retrospective data on 34 individuals with GRIN variants, including 20 unpublished and 14 published cases. Variants were reclassified following American College of Medical Genetics and Genomics guidelines, and six in vitro functional assays were used to assess receptor function. We compared individuals with pathogenic GoF versus LoF in terms of associated clinical improvements, memantine sensitivity, and variant localization within the gene. Results: In 19 of the 34 variants, a pathogenic likely or possible GoF of the receptor was detected. Fourteen of 19 individuals (74%) benefited from memantine, comprising improvements in behavior (71%), development (50%), and seizure frequency (39%). Individuals with either LoF or a functionally indeterminate or no effect GRIN variant (15/34 individuals) showed significantly less benefit from memantine treatment but nevertheless rare adverse events (3/15). An increased distance of the variant from the memantine binding site was associated with a clinical benefit. Significance: Our retrospective observational study outlines the importance of correct classification of GRIN variants with regard to pathogenicity and functional consequence prior to applying memantine or other precision medicine approaches in clinical trials. Furthermore, the distance from a GoF variant to the memantine binding site correlated with a positive treatment response and may, at least in part, explain different degrees of therapeutic benefit.