Abstract
Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR). This observation gave rise to the hypothesis of successfully treating GRIN-related disorders due to LoF variants with co-agonists of the NMDAR. In this respect, we describe a retrospectively collected series of ten individuals with GRIN2A- or GRIN2B-related disorders who were treated with L-serine, each within an independent n-of-1 trial. Our cohort comprises one individual with a LoF missense variant with clinical improvements confirming the above hypothesis and replicating a previous n-of-1 trial. A second individual with a GoF missense variant was erroneously treated with L-serine and experienced immediate temporary behavioral deterioration further supporting the supposed functional pathomechanism. Eight additional individuals with null variants (that had been interpreted as loss-of-function variants despite not being missense) again showed clinical improvements. Among all nine individuals with LoF missense or null variants, L-serine treatment was associated with improvements in behavior in eight (89%), in development in four (44%), and/or in EEG or seizure frequency in four (44%). None of these nine individuals experienced side effects or adverse findings in the context of L-serine treatment. In summary, we describe the first evidence that L-serine treatment may not only be associated with clinical improvements in GRIN-related disorders due to LoF missense but particularly also null variants.
Highlights
GRIN-related disorders comprise a spectrum of neurodevelopmental disorders related to pathogenic variants in one of the four currently known disease-associated GRIN genes, GRIN1, GRIN2A, GRIN2B, and GRIN2D – all encoding subunits of the N-methyl-D-aspartate receptor (NMDAR) [1,2,3,4]
By reporting on ten individuals that had been treated independently as individual treatment trials with L-serine, we here present the most comprehensive observational retrospective data collection on agonist therapy of GRINrelated neurodevelopmental disorders allowing for several conclusions
L-serine treatment in the context of a pathogenic GRIN2B GoF missense variant was associated with rapid behavioral deterioration in individual #3 followed by prompt and complete reversal after immediate stop of L-serine application
Summary
GRIN-related disorders comprise a spectrum of neurodevelopmental disorders related to pathogenic variants in one of the four currently known disease-associated GRIN genes, GRIN1, GRIN2A, GRIN2B, and GRIN2D – all encoding subunits of the N-methyl-D-aspartate receptor (NMDAR) [1,2,3,4]. Whereas GRIN2A and GRIN2B appear to be vulnerable to both missense and null variants [1, 2], heterozygous pathogenic variants in GRIN1 or GRIN2D currently solely comprise missense [5]. In line with this observation, carriers of GRIN2A or GRIN2B null variants tend to display a milder. Functional studies have shown that pathogenic missense variants can result in a gain or loss of NMDAR function or in mixed and more complex functional consequences [6]. This observation enabled precision medicine approaches leading to the application of antagonists or agonists of the NMDAR, depending on the presence of a molecularly confirmed gain or loss of NMDAR function [1, 7,8,9]
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