Disorders affecting the glutamate receptor of the N-methyl-D-aspartate receptor (NMDAR) type are associated with neurodevelopmental disorders (NDDs), epilepsy syndromes, as well as cognitive and motor impairments. In individuals with pathogenic variants in the genes GRIN2A and GRIN2B that result in loss of function, improvements in behavior, epilepsy, and other aspects of development have been reported following supplementation with the amino acid L-serine. L-serine acts via its enantiomer D-serine as a co-agonist at the NMDAR. Recent animal studies also demonstrate the efficacy of L-serine supplementation in developmental disorders caused by pathogenic variants in STXBP1 and other monogenic NDDs. Consequently, some individuals are already being treated in individualized therapeutic attempts. 

1. Retrospective analysis of published data and existing treatment data from patient registries (GRIN registry (GRIN2A/B), STXBP1 registry, TIRCON registry (WDR45)) regarding L-serine supplementation in these monogenic NDDs.
2. Development of a generic digital N-of-1 platform for the standardized implementation of future N-of-1 strategies in rare diseases.
3. Preparation of a prospective clinical study on dietary L-serine supplementation in the context of multiple N-of-1 trials in individuals with monogenic NDDs, including the development of a study protocol, ethics application, and study plan. 

In a first phase, a retrospective analysis of existing patient and treatment data for the aforementioned monogenic NDDs will be conducted, focusing on prior dietary supplementation with L-serine. In a second phase, a prospective, randomized, double-blind, placebo-controlled study will be designed to evaluate the tolerability and efficacy of dietary L-serine supplementation compared to placebo.

Due to the low prevalence of the described variants and the heterogeneity of the patient cohort, the study will be designed as a series of independent N-of-1 trials with randomized and blinded treatment blocks. In this design, each individual serves as their own control across predefined “on” and “off” phases, during which L-serine or placebo is administered. For this purpose, a digital platform will be developed to enable standardized and systematic data collection and to serve as a generic tool for future N-of-1 therapeutic evaluations. REDCap will be used as the database, and descriptive statistical analyses will be performed using R. 

The outcome of the doctoral project will be an initial retrospective assessment of L-serine supplementation on behavior, cognition, and epilepsy in monogenic neurodevelopmental disorders (NDDs). A further outcome will be the planning of a prospective interventional study, including the collection of initial data on the safety of L-serine administration.