L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy
Por:
Soto, D, Olivella, M, Grau, C, Armstrong, J, Alcon, C, Gasull, X, Santos-Gomez, A, Locubiche, S, de Salazar, MG, Garcia-Diaz, R, Gratacos-Batlle, E, Ramos-Vicente, D, Chu-Van, E, Colsch, B, Fernandez-Duenas, V, Ciruela, F, Bayes, A, Sindreu, C, Lopez-Sala, A, Garcia-Cazorla, A, Altafaj, X
Publicada:
18 jun 2019
Resumen:
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 GIuN2B 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 GIuN2B-containing NMDAR5. 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 NMDAR5. 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.
Filiaciones:
Soto, D:
Univ Barcelona, Dept Biomed, E-08036 Barcelona, Spain
Univ Barcelona, Inst Neurosci, E-08036 Barcelona, Spain
August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Olivella, M:
Cent Univ Catalonia, Univ Vic, Bioinfomat & Med Stat Grp, Vic 08500, Spain
Grau, C:
Univ Barcelona, Unit Neuropharmacol & Pain, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Spain
Armstrong, J:
Hosp St Joan Deu, Genet & Mol Med Serv, Barcelona 08950, Spain
CIBERER, Barcelona 08950, Spain
Alcon, C:
Univ Barcelona, Inst Neurosci, E-08036 Barcelona, Spain
Univ Barcelona, Dept Clin Fdn, E-08036 Barcelona, Spain
Gasull, X:
August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Univ Barcelona, Inst Neurosci, E-08036 Barcelona, Spain
Univ Barcelona, Dept Biomed, E-08036 Barcelona, Spain
Santos-Gomez, A:
Univ Barcelona, Unit Neuropharmacol & Pain, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Spain
Locubiche, S:
Univ Barcelona, Unit Neuropharmacol & Pain, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Spain
de Salazar, MG:
Univ Barcelona, Unit Neuropharmacol & Pain, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Spain
Garcia-Diaz, R:
August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Univ Barcelona, Inst Neurosci, E-08036 Barcelona, Spain
Univ Barcelona, Dept Biomed, E-08036 Barcelona, Spain
Univ Santiago de Cali, Grp Invest Quim & Biotecnol QUIBIO, Santiago De Cali 760035, Colombia
Gratacos-Batlle, E:
Univ Barcelona, Inst Neurosci, E-08036 Barcelona, Spain
August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Univ Barcelona, Dept Biomed, E-08036 Barcelona, Spain
Ramos-Vicente, D:
Autonomous Univ Barcelona, Bellaterra 08193, Spain
Biomed Res Inst St Pau IIB St Pau, Mol Physiol Synapse Lab, Barcelona 08026, Spain
Chu-Van, E:
Univ Paris Saclay, MetaboHUB, SPI, Lab Etud Metab Medicaments,CEA,INRA, F-91191 Gif Sur Yvette, France
Colsch, B:
Univ Paris Saclay, MetaboHUB, SPI, Lab Etud Metab Medicaments,CEA,INRA, F-91191 Gif Sur Yvette, France
Fernandez-Duenas, V:
Univ Barcelona, Unit Neuropharmacol & Pain, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Spain
Ciruela, F:
Univ Barcelona, Unit Neuropharmacol & Pain, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Spain
Bayes, A:
Biomed Res Inst St Pau IIB St Pau, Mol Physiol Synapse Lab, Barcelona 08026, Spain
Autonomous Univ Barcelona, Bellaterra 08193, Spain
Sindreu, C:
Univ Barcelona, Inst Neurosci, E-08036 Barcelona, Spain
Univ Barcelona, Dept Clin Fdn, E-08036 Barcelona, Spain
Lopez-Sala, A:
CIBERER, Barcelona 08950, Spain
Hosp St Joan Deu, Dept Neurol, Neurometab Unit, Barcelona 08950, Spain
Garcia-Cazorla, A:
CIBERER, Barcelona 08950, Spain
Hosp St Joan Deu, Genet & Mol Med Serv, Barcelona 08950, Spain
Hosp St Joan Deu, Dept Neurol, Neurometab Unit, Barcelona 08950, Spain
Altafaj, X:
Univ Barcelona, Unit Neuropharmacol & Pain, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Spain
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