Potential benefits of l-serine in children with GRIN2B loss-of-function variants: Randomized n-of-1 trials

GRIN2B-neurodevelopmental disorder (GRIN2B-NDD) is a rare genetic disorder caused by pathogenic variants in GRIN2B, leading to impaired N-methyl d-aspartate receptor (NMDAR) function. l-serine, a precursor to d-serine that modulates NMDAR activity, has shown therapeutic potential for GRIN2B loss-of-function (LoF) variants.

The efficacy of oral l-serine supplementation in 4 children with GRIN2B LoF variants were evaluated in the first double-blind, randomized, placebo-controlled, one-year n-of-1 trials. The trial consisted of 2 cycles of 6 months.

The Perceive, Recall, Plan, and Perform Assessment (PRPP-A) showed a significant improvement in Performance Mastery at 1.5 months (p = 0.0373), while 11 of 14 other PRPP-A measures showed mean differences that were numerically in the same direction toward a positive l-serine effect (not significant). Secondary outcomes varied across patients, for those with statistical group analysis, no significant difference were observed. Individual improvements were noted in information processing/adaptive function (n = 3/4), quality of life (n = 3/4), sleep (n = 1/2), irritability (n = 2/4), and language (n = 1/3), based on objective assessments and anecdotal parent reports.

These pioneering n-of-1 trials provide insights into l-serine's potential for GRIN2B-NDD, with improvements in two of four patients, though no clear distinguishing responder-characteristics were identified. Future trials should focus on refining patient selection, the use of multiple baseline designs, establishing a core outcome set and pooling treatment data to better understand patient-specific responses.