The goal of this clinical study is to find out whether L-serine dietary supplementation helps improve overall clinical functioning in children and young adults (2-30 years) with GRIN-related neurodevelopmental disorders (GRIN-NDD) caused by loss-of-function (LoF) variants in GRIN1, GRIN2A, GRIN2B, or GRIN2D. It will also assess the safety and tolerability of L-serine.
The main questions it aims to answer are:
Does L-serine improve overall clinical status, measured mainly by the Clinical Global Impression-Severity (CGI-S) score?
Does L-serine improve behaviour, cognition, adaptive functioning, motor skills, sleep, and (in those with epilepsy) seizure frequency and EEG findings?
What side effects or medical problems occur during L-serine compared with placebo?
Do neurophysiological measures (including TMS-EMG/TMS-EEG) change with treatment and potentially act as biomarkers of response?
Researchers will compare L-serine to a placebo (maltodextrin powder with similar appearance/texture) using a randomised, double-blind, placebo-controlled "n-of-1" approach, where each participant receives both treatments in alternating periods. Results from multiple single-patient trials will then be combined (aggregated) to estimate the overall treatment effect across the study population.
Participants will:
Complete a 4-week baseline period with assessments (and seizure diary use where applicable)
Receive L-serine and placebo in alternating 3-month periods within each cycle (minimum 2 cycles, up to 4 cycles; each cycle lasts 6 months)
Take the assigned study product by mouth 3 times per day at 500 mg/kg/day (maximum 30 g/day for participants ≥60 kg)
Have the first 7 days of each 3-month period treated as washout, with data from that week not analysed
Attend regular clinic visits for clinical exams, safety labs, and standardized assessments of global status, behaviour/cognition, motor function, and sleep
If they have epilepsy: keep a seizure diary and undergo EEG assessments after each treatment period
In some sites (Italy and France): undergo TMS-based neurophysiology testing
Optionally, a subset may join a cellular biomarker substudy (blood collection to generate iPSC-derived neuronal models and organoids) to explore treatment effects in variant-specific lab models.
Clinical diagnosis of a GRIN-related neurodevelopmental disorder (GRIN-NDD)
Presence of a pathogenic or likely pathogenic loss-of-function (LoF) variant in GRIN1, GRIN2A, GRIN2B, or GRIN2D
Parent(s), caregiver(s), or legally authorised representative(s) have been informed of the nature of the study and have provided written informed consent.
Participants who are able to do so have provided written informed consent or assent, according to local regulations and cognitive capacity.
Age younger than 2 years at screening.
Known hypersensitivity or intolerance to L-serine, placebo, or any excipients used in the study formulations.
Presence of a clinically significant unstable medical condition (other than epilepsy) that, in the investigator's judgement, may place the participant at increased risk or interfere with study participation.
Any other significant disease or disorder that may compromise participant safety, affect study outcomes, or impair the participant's ability to complete the study procedures.
Crossover
L-serine
Dietary supplementL-serine supplementation is administered as an oral powder for solution and used as an add-on intervention to participants' existing standard of care. L-serine is a naturally occurring amino acid and is classified as a food for special medical purposes. In this study, L-serine is used to increase the availability of its enantiomer D-serine, an endogenous co-agonist of the N-methyl-D-aspartate receptor (NMDAR), with the aim of enhancing NMDAR-mediated neurotransmission in individuals with GRIN-related neurodevelopmental disorders caused by loss-of-function variants. The intervention is delivered using a randomised, double-blind, placebo-controlled n-of-1 design, in which each participant receives both L-serine and placebo in alternating treatment periods. L-serine and placebo are identical in appearance, packaging, and method of administration to maintain blinding. Treatment allocation within each cycle is determined by a computer-generated randomisation schedule managed by unblinded s
Maltodextrin (Placebo)
Other interventionPlacebo is administered as an oral powder for solution and serves as the comparator to L-serine supplementation. The placebo consists primarily of maltodextrin, a readily digestible carbohydrate that is commonly used as an inert control substance in clinical studies. It is classified as a food-grade product and contains no active amino acids or pharmacologically active ingredients. The placebo is formulated to be indistinguishable from L-serine with respect to appearance, texture, solubility, and method of administration, in order to maintain blinding of participants, caregivers, investigators, and study staff. Packaging, labelling, and dosing instructions are identical to those used for the active intervention. The placebo is administered orally in three divided daily doses, following the same dosing schedule and duration as the active intervention within the randomised, double-blind, n-of-1 trial design. Each placebo treatment period lasts three months, with the first seven days de
Change in Clinical Global Impression - Severity (CGI-S) score
The Clinical Global Impression - Severity (CGI-S) scale is a clinician-rated measure of overall illness severity. The primary outcome is the within-subject difference in CGI-S score comparing L-serine supplementation with placebo, assessed at the end of each treatment period relative to baseline. Lower CGI-S scores indicate less severe overall clinical status.
Number of adverse events
Safety and tolerability will be assessed through the collection of adverse events (AEs), serious adverse events (SAEs), clinical examinations, vital signs, body weight, neurological examinations, and laboratory parameters during L-serine and placebo periods.
Change in Clinical Global Impression - Improvement (CGI-I) score
The CGI-I is a clinician-rated measure of overall improvement or worsening compared with baseline. Changes in CGI-I scores will be compared between L-serine and placebo treatment periods within subjects.
Change in behavioural functioning
Behavioural changes will be assessed using age-appropriate standardized instruments (Child Behavior Checklist \[CBCL\] or Adult Behavior Checklist \[ABCL\]). Scores obtained at the end of each treatment period will be compared with baseline and between L-serine and placebo periods.
Change in adaptive functioning
Adaptive functioning will be assessed using standardized measures (Vineland Adaptive Behavior Scales \[VABS\] or Adaptive Behaviour Assessment System, Third Edition \[ABAS-3\], as appropriate). Changes from baseline will be compared between treatment conditions.
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