Effectiveness of L-serine supplementation in children with a GRIN2B loss-of-function mutation: Rationale and protocol for single patient (n-of-1) multiple cross-over trials

Rationale: Loss-of-function (LoF) mutations in GRIN2B result in neurologic abnormalities due to N-methyl-D-aspartate receptor (NMDAR) dysfunction. Affected persons present with various symptoms, including intellectual developmental disability (IDD), hypotonia, communication deficits, motor impairment, complex behavior, seizures, sleep disorders and gastrointestinal disturbance. Recently, in vitro experiments showed that D-serine mitigates function to GluN2B (mutation)-containing NMDARs. 11 previous case reports are published on (experimental) L-serine treatment of patients between 1.5 and 12 years old with GRIN2B missense or null mutations, some of whom showed notable improvement in motor and cognitive performance, communication, behavior and abnormalities on electro encephalography (EEG). Our objective is to further evaluate the effectiveness of L-serine for GRIN2B-related neurodevelopmental disorder (GRIN2B-NDD), using an n-of-1 trial design, increasing the level of evidence. Methods/design: These n-of-1 trials, consisting of 2 cycles of 6 months, will be performed to evaluate the effect of L-serine compared to placebo in 4 patients with a GRIN2B LoF mutation. The aggregation of multiple n-of-1 trials will provide an estimate of the average treatment effects. The primary outcome is the Perceive-Recall-Plan-Perform of Task Analysis, assessing developmental skills. Secondary outcomes include Goal Attainment Scaling, seizure log books, EEGs, sleep log books, the irritability subscale of the Aberrant Behavior Checklist, the Bristol Stool Scale and the Pediatric Quality of Life Inventory. Conclusion: This study employs an innovative methodological approach to evaluate the effectiveness of L-serine for patients with a GRIN2B LoF mutation. The results will establish a foundation for implementing L-serine as a disease-modifying treatment in GRIN2B-NDD

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

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 subunit-containing 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-containing NMDARs. Initial reports of GRIN2B-NDD patients LoF variants, treated with l-serine using different regimens, showed varying effects on motor and cognitive performance, communication, behavior and EEG. Here, this novel treatment using a standardized protocol with an innovative developmental outcome measure 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 12 months. 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-serine without adverse effects. In one patient, improvement in psychomotor development and cognitive functioning was observed after 12 months (PRPP mastery score 10% at baseline, 78% at twelve months). In the most severe clinically affected patient no significant objective improvement in validated outcomes was 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

Corrigendum to “Effectiveness of L-serine supplementation in children with a GRIN2B loss-of-function mutation: Rationale and protocol for single patient (n-of-1) multiple cross-over trials” [Contemp. Clin. Trials Commun. 36 (2023)/ DOI: 10.1016/j.conctc.2023.101233] (Contemporary Clinical Trials Communications (2023) 36, (S2451865423001795), (10.1016/j.conctc.2023.101233))

The authors regret the need for the following corrigendum: In table 1, the amino acid change for the patient is listed incorrectly. It should be p.(Arg696Leu) instead of p.(Arg820Leu). The authors would like to apologise for any inconvenience caused