biostudies-literatureSwanson MADickens Family FoundationNKH CrusadersJoseph's GoalBarnett FamilyMaud & Vic FoundationNational Institutes of HealthLes Petits BourdonsLucas John FoundationUniversity of Colorado FoundationMadi's Mission NKH FundBrodyn's FriendsWilliam R Hummel Research FundMedical Research CouncilNational Health and Medical Research CouncilNora Jane Almany FoundationNIH HHSe70137https://www.ebi.ac.uk/biostudies/studies/S-EPMC12848846biostudies-literatureUnknown49(1)Nonketotic hyperglycinemia is a severe neonatal epileptic encephalopathy caused by deficient glycine cleavage enzyme activity, for which currently no effective treatment exists. Incomplete understanding of brain biochemistry represents a major knowledge gap to develop new treatments. We examined the biochemistry in blood, liver, cortex, hippocampus, and cerebellum of a mouse model homozygous for the Gldc variant p.Ala394Val. Glycine was increased in all compartments and caused increased brain neurotoxic metabolites guanidinoacetate and methylglyoxal, and also N-acetylglycine and cystathionine. The glycine extruding transporter Slc6a20 was increased. There was reduced one-carbon folate charging with secondarily reduced methionine in the cortex, and reduced alternative one-carbon donors L-seJournal of inherited metabolic diseaseA Nonketotic Hyperglycinemia Mouse Shows Wide-Ranging Biochemical Consequences of Elevated Glycine, Reduced Folate One-Carbon Charging, and Serine Deficiency.PMC12848846200973220160301140906W00500XS10 OD028538‐01A1S10 OD028538-01A1Binard RWood TGreene NDEJiang HAnderson-Lehman LLin XArning EKolora LDMichael BVan Hove RAWong FReisdorph RLancaster SFriederich MWMolino RVan Hove JLKLeung KYDoenges KAChristians UMichel CRStroud DASwanson MASnyder MHock DHMacLean KNfalseA Nonketotic Hyperglycinemia Mouse Shows Wide-Ranging Biochemical Consequences of Elevated Glycine, Reduced Folate One-Carbon Charging, and Serine Deficiency.Nonketotic hyperglycinemia is a severe neonatal epileptic encephalopathy caused by deficient glycine cleavage enzyme activity, for which currently no effective treatment exists. Incomplete understanding of brain biochemistry represents a major knowledge gap to develop new treatments. We examined the biochemistry in blood, liver, cortex, hippocampus, and cerebellum of a mouse model homozygous for the Gldc variant p.Ala394Val. Glycine was increased in all compartments and caused increased brain neurotoxic metabolites guanidinoacetate and methylglyoxal, and also N-acetylglycine and cystathionine. The glycine extruding transporter Slc6a20 was increased. There was reduced one-carbon folate charging with secondarily reduced methionine in the cortex, and reduced alternative one-carbon donors L-se2026-01-01T00:00:00Z2026 Jan2026-06-14T05:47:07.348Z2026-06-14T03:09:16.948ZS-EPMC128488464160318710.1002/jimd.70137