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The study of the glutamatergic synapse using the same approach than classic neurotransmitter disorders is challenging due to the lack of biomarkers in the CSF. A metabolomic approach can provide both insight into their molecular basis and outline novel therapeutic alternatives. We have performed a semi\u2010targeted metabolomic analysis on CSF samples from 25 patients with neurogenetic disorders with an important expression in the glutamatergic synapse and 5 controls. Samples from patients diagnosed with MCP2, CDKL5\u2010, GRINpathies and STXBP1\u2010related encephalopathies were included. We have performed univariate (UVA) and multivariate statistical analysis (MVA), using Wilcoxon rank\u2010sum test, principal component analysis (PCA), and OPLS\u2010DA. By using the results of both analyses, we have identified the metabolites that were significantly altered and that were important in clustering the respective groups. On these, we performed pathway\u2010 and network\u2010based analyses to define which metabolic pathways were possibly altered in each pathology. We have observed alterations in the tryptophan and branched\u2010chain amino acid metabolism pathways, which interestingly converge on LAT1 transporter\u2010dependency to cross the blood\u2013brain barrier (BBB). Analysis of the expression of LAT1 transporter in brain samples from a mouse model of Rett syndrome (MECP2) revealed a decrease in the transporter expression, that was already noticeable at pre\u2010symptomatic stages. The study of the glutamatergic synapse from this perspective advances the understanding of their pathophysiology, shining light on an understudied feature as is their metabolic signature.<\/jats:p>","DOI":"10.1002\/jimd.12689","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T04:25:38Z","timestamp":1699331138000},"page":"551-569","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolic characterization of neurogenetic disorders involving glutamatergic neurotransmission"],"prefix":"10.1002","volume":"47","author":[{"given":"Sof\u00eda","family":"Illescas","sequence":"first","affiliation":[{"name":"Synaptic Metabolism and Personalized Therapies Lab, Institut de Recerca Sant Joan de D\u00e9u, Department of Neurology and MetabERN Esplugues de Llobregat  Barcelona 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