Evidence for effect of l-serine, a novel therapy for GRIN2B-related neurodevelopmental disorder

Abstract

Rationale: To date, causal therapy is potentially available for GRIN2B-related neurodevelopmental disorder (NDD) due to loss-of-function (LoF) variants in GRIN2B, resulting in dysfunction of the GluN2B subunitcontaining N-methyl-D-aspartate receptor (NMDAR). Recently, in vitro experiments showed that high doses of NMDAR co-agonist D-serine has the potential to boost the activity in GluN2B LoF variant-containingNMDARs. Initial reports of GRIN2B-NDD patients LoF variants, treated with L-serine using different regimens, showed varying effects onmotor and cognitive performance, communication, behavior and EEG. Here, this novel treatment using a standardized protocolwith an innovative developmental outcomemeasure is explored further in an open-label observational GRIN2B-NDD study. Methods: Initially, in vitro studies were conducted in order to functionally stratify two de novo GRIN2B variants present in two female patients (18 months and 4 years old). Functional studies showed that both variants are LoF, and thus the patients were treated experimentally according to an approved protocol with oral L-serine (500 mg/kg/day in 4 doses) for a period of 12months. Both patients showed a heterogeneous clinical phenotype, however overlapping symptoms were present: intellectual developmental disability (IDD), behavioral abnormalities and hypotonia. Outcome measures included laboratory tests, quality of life, sleep, irritability, stool, and performance skills, measured by, among others, the Perceive-Recall-Plan-Perform System of Task Analysis (PRPP-Assessment). Results: Both patients tolerated L-serinewithout adverse effects. In one patient, improvement in psychomotor development and cognitive functioning was observed after 12 months (PRPPmastery score 10% at baseline, 78% at twelvemonths). In the most severe clinically affected patient no significant objective improvement in validated outcomeswas observed. Caregivers of both patients reported subjective increase of alertness and improved communication skills. Conclusion: Our observational study confirms that L-serine supplementation is safe in patients with GRIN2B-NDD associated with LoF variants, and may accelerate psychomotor development and ameliorate cognitive performance in some but not all patients. The PRPP-Assessment, a promising instrument to evaluate everyday activities and enhance personalized and value-based care, was not performed in the severely affected patient, meaning that possible positive results may have been missed. To generate stronger evidence for effect of L-serine in GRIN2B-NDD, we will perform placebo-controlled n-of-1 trials.