{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:57:22Z","timestamp":1790913442939,"version":"4.1.0"},"reference-count":79,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":154,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatrics International"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ammonia can easily cross the blood\u2013brain barrier in its non\u2010ionized form, leading to significant accumulation in the brain during severe hyperammonemia. Excess ammonia is highly toxic to the brain and can cause neurological dysfunctions, such as tremors, ataxia, seizures, coma, and even death. Hyperammonemia is often the primary manifestation of urea cycle disorders (UCDs), a group of inherited metabolic disorders characterized by impaired nitrogen detoxification due to dysfunctions in urea cycle\u2010related enzymes and transporters. Patients with complete deficiencies of urea cycle enzymes typically present with lethargy, hypothermia, anorexia, seizures, abnormal respiratory patterns (hyperventilation or hypoventilation), neurologic posturing, and coma, along with hyperammonemia within a few days after birth. This condition, classified as the neonatal\u2010onset type, frequently results in severe hyperammonemic encephalopathy (\u2265600\u2009\u03bcg\/dL [360\u2009\u03bcmol\/L]) at onset. Hyperammonemia with blood ammonia levels of 600\u2009\u03bcg\/dL (360\u2009\u03bcmol\/L) or higher causes significant brain damage. Therefore, at this threshold, hemodialysis is indicated to rapidly remove ammonia and mitigate its harmful effects on the brain. However, even when neonatal\u2010onset UCD patients undergo a combination of hemodialysis and liver transplantation at the onset of severe hyperammonemia (\u2265600\u2009\u03bcg\/dL [360\u2009\u03bcmol\/L]), the neuroprotective effects remain limited. This review aims to describe the pathophysiology of hyperammonemia and UCDs, the impact of hyperammonemia on the brain in UCDs, the role of current therapeutic strategies, and the challenges associated with future treatments for UCDs.<\/jats:p>","DOI":"10.1111\/ped.70121","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T07:00:19Z","timestamp":1749020419000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hyperammonemia in urea cycle disorders: A toxic metabolite for the brain"],"prefix":"10.1111","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1328-6696","authenticated-orcid":false,"given":"Jun","family":"Kido","sequence":"first","affiliation":[{"name":"Department of Pediatrics Faculty of Life Sciences, Kumamoto University  Kumamoto Japan"},{"name":"Department of Pediatrics Kumamoto University Hospital  Kumamoto 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