{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:54:20Z","timestamp":1777373660992,"version":"3.51.4"},"reference-count":105,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,10,11]],"date-time":"2019-10-11T00:00:00Z","timestamp":1570752000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Glutamate is involved in a variety of metabolic pathways. We reviewed the literature on genetic defects of enzymes that directly metabolise glutamate, leading to inborn errors of glutamate metabolism. Seventeen genetic defects of glutamate metabolising enzymes have been reported, of which three were only recently identified. These 17 defects affect the inter\u2010conversion of glutamine and glutamate, amino acid metabolism, ammonia detoxification, and glutathione metabolism. We provide an overview of the clinical and biochemical phenotypes of these rare defects in an effort to ease their recognition. By categorising these by biochemical pathway, we aim to create insight into the contributing role of deviant glutamate and glutamine levels to the pathophysiology. For those disorders involving the inter\u2010conversion of glutamine and glutamate, these deviant levels are postulated to play a pivotal pathophysiologic role. For the other IEM however\u2014with the exception of urea cycle defects\u2014abnormal glutamate and glutamine concentrations were rarely reported. To create insight into the clinical consequences of disturbed glutamate metabolism\u2014rather than individual glutamate and glutamine levels\u2014the prevalence of phenotypic abnormalities within the 17 IEM was compared to their prevalence within all Mendelian disorders and subsequently all disorders with metabolic abnormalities notated in the Human Phenotype Ontology (HPO) database. For this, a hierarchical database of all phenotypic abnormalities of the 17 defects in glutamate metabolism based on HPO was created. A neurologic phenotypic spectrum of developmental delay, ataxia, seizures, and hypotonia are common in the inborn errors of enzymes in glutamate metabolism. Additionally, ophthalmologic and skin abnormalities are often present, suggesting that disturbed glutamate homeostasis affects tissues of ectodermal origin: brain, eye, and skin. Reporting glutamate and glutamine concentrations in patients with inborn errors of glutamate metabolism would provide additional insight into the pathophysiology.<\/jats:p>","DOI":"10.1002\/jimd.12180","type":"journal-article","created":{"date-parts":[[2019,10,11]],"date-time":"2019-10-11T16:59:54Z","timestamp":1570813194000},"page":"200-215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Inborn errors of enzymes in glutamate metabolism"],"prefix":"10.1002","volume":"43","author":[{"given":"Lynne","family":"Rumping","sequence":"first","affiliation":[{"name":"Department of Genetics University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"},{"name":"Center for Molecular Medicine University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"},{"name":"Department of Pediatrics University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esmee","family":"Vringer","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roderick H. 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