Skip to main content
Evidence-Based Supplement Research
Evidence-Based Supplement Research
Pillser
Search
Sign UpLog In

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

  • 2023-03
  • Molecular genetics and metabolism 138(3)
    • B den Hollander
    • A R J Veenvliet
    • M Rothuizen-Lindenschot
    • P van Essen
    • G Peters
    • A Santos-Gómez
    • M Olivella
    • X Altafaj
    • M M Brands
    • B A W Jacobs
    • C D van Karnebeek

Study Design

Type
Observational
Population
two female patients (18 months and 4 years old) with GRIN2B-related neurodevelopmental disorder (NDD) due to loss-of-function (LoF) variants
Methods
open-label observational study; oral l-serine (500 mg/kg/day in 4 doses) for a period of 12 months; in vitro functional studies first conducted
Blinding
Open-label
Duration
12 months

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.

Research Insights

  • L-Serine→Improved Cognitive Functioning

    improvement in psychomotor development and cognitive functioning was observed after 12 months (PRPP mastery score 10% at baseline, 78% at twelve months)

    Effect
    Beneficial
    Effect size
    Large
    Dose
    500 mg/kg/day in 4 doses
  • L-Serine→Improved Communication Skills

    Caregivers of both patients reported subjective increase of alertness and improved communication skills

    Effect
    Beneficial
    Effect size
    Small
    Dose
    500 mg/kg/day in 4 doses
  • L-Serine→Improved Psychomotor Development

    improvement in psychomotor development and cognitive functioning was observed after 12 months (PRPP mastery score 10% at baseline, 78% at twelve months)

    Effect
    Beneficial
    Effect size
    Large
    Dose
    500 mg/kg/day in 4 doses
  • L-Serine→Increased Energy Levels

    Caregivers of both patients reported subjective increase of alertness

    Effect
    Beneficial
    Effect size
    Small
    Dose
    500 mg/kg/day in 4 doses
Back to top