Diagnostic approaches and pharmacological treatments for nonketotic hyperglycinemia: a 30-year scoping review

Nonketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder of glycine metabolism characterized by highly heterogeneous neurometabolic manifestations. Despite its clinical severity, no standardized diagnostic or therapeutic pathways have been established. This scoping review synthesizes 30 years of scientific literature to map current diagnostic approaches and pharmacological treatments for NKH. A total of peer􀀔reviewed journal articles published between 1992 and 2022 were included; most (63%) were case reports. Diagnostic evaluation relied primarily on biochemical testing—plasma glycine concentrations of articles􀀐 and the cerebrospinal fluid􀀔to􀀔plasma glycine ratio followed by genetic confirmation (50%). Neuroimaging techniques were used as complementary tools (MRI 45%, MRS 25%). Treatment of NKH was predominantly pharmacological: sodium benzoate was the most frequently used agent (80% of the articles), and NMDA-receptor antagonists such as dextromethorphan (73%) and ketamine (43%) were frequently employed as adjunctive therapies. Diazepam and phenobarbital were commonly used for seizure control, but valproic acid was consistently contraindicated.􀀶verall, the findings show a growing consensus on biochemical and molecular diagnostic criteria but also reveal substantial gaps in the therapeutic evidence base. High-quality collaborative studies are urgently needed to establish standardized treatment algorithms and to develop targeted therapies to improve longterm neurological outcomes in NKH.