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.