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- Title
l-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy.
- Authors
Soto, David; Olivella, Mireia; Grau, Cristina; Armstrong, Judith; Alcon, Clara; Gasull, Xavier; Santos-Gómez, Ana; Locubiche, Sílvia; de Salazar, Macarena Gómez; García-Díaz, Roberto; Gratacòs-Batlle, Esther; Ramos-Vicente, David; Chu-Van, Emeline; Colsch, Benoit; Fernández-Dueñas, Víctor; Ciruela, Francisco; Bayés, Àlex; Sindreu, Carlos; López-Sala, Anna; García-Cazorla, Àngels
- Abstract
Treating NMDA receptor deficiency with a dietary supplement: Patients with Rett-like syndrome show impaired neuronal, motor, cognitive, and social development. Soto et al. studied the etiology and treatment of the disorder in a 5-year-old patient who had a mutation in GRIN2B, the gene encoding the NMDA receptor subunit GluN2B. Expressing this mutant in cultured neurons impaired both electrophysiological activity and dendritic morphology, but these features were improved with the application of the known NMDA receptor agonist, d-serine. d-Serine administration has some toxicity in rodents, but its stereoisomer l-serine is a natural, nonessential amino acid found in various foods. Adding l-serine powder to the patient's food or drink over the course of more than a year increased the amount of d-serine in the plasma and cerebrospinal fluid and markedly improved all neurodevelopment assessments, suggesting that this rather simple treatment might be extended to various patients with disorders associated with NMDA receptor deficiency. Autosomal dominant mutations 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.
- Subjects
METHYL aspartate receptors; AMPA receptors; MISSENSE mutation; CEREBROSPINAL fluid; DIETARY supplements; CEREBROSPINAL fluid examination
- Publication
Science Signaling, 2019, Vol 12, Issue 586, pN.PAG
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aaw0936