L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy

David Soto, Mireia Olivella, Cristina Grau, Judith Armstrong, Clara Alcon, Xavier Gasull, Ana Santos-Gómez, Sílvia Locubiche, Macarena Gómez De Salazar, Roberto García-Díaz, Esther Gratacòs-Batlle, David Ramos-Vicente, Emeline Chu-Van, Benoit Colsch, Víctor Fernández-Dueñas, Francisco Ciruela, Àlex Bayés, Carlos Sindreu, Anna López-Sala, Àngels García-CazorlaXavier Altafaj

    Research output: Contribution to journalArticleResearch

    20 Citations (Scopus)


    © 2019 American Association for the Advancement of Science. All rights reserved. Autosomal dominantmutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-D-Aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-To-Threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist D-serine restored function to GluN2B(P553T)-containing NMDARs. L-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of D-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of L-serine dietary supplementation. Our data suggest that L-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.
    Original languageEnglish
    Article numbereaaw0936
    JournalScience Signaling
    Publication statusPublished - 18 Jun 2019


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