Ammonia Storm: Unmasking a Rare Urea Cycle Disorder in Adulthood

Ammonia Storm: Unmasking a Rare Urea Cycle Disorder in Adulthood | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Ammonia Storm: Unmasking a Rare Urea Cycle Disorder in Adulthood Vikram Vikhe, Md. Hassan Shaik, Priya Khaire, Rahul Patil, Ahanaa Chakraborty This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9153576/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 14 You are reading this latest preprint version Abstract Background Hyperammonaemia is a medical emergency which is mostly associated with liver dysfunction. However, in the absence of hepatic disease, rare inborn errors of metabolism such as urea cycle disorders (UCDs) must be considered. While UCDs typically present in the neonatal period, partial enzyme deficiencies may remain clinically silent until adulthood and present abruptly with life-threatening hyperammonaemia encephalopathy. Among these, late-onset carbamoyl phosphate synthetase I (CPS-I) deficiency is exceedingly rare and often underdiagnosed. Case Presentation: We report a 32-year-old male who presented with acute onset altered sensorium progressing to coma over 12 hours. It was preceded by two to three episodes of vomiting the same day and history of febrile illness few days back. On admission, the patient had a Glasgow Coma Scale score of 7/15 and required endotracheal intubation with ventilatory support. Routine laboratory investigations, including liver and renal function tests, were within normal limits. Neuroimaging studies (CT and MRI brain) showed no abnormalities. Plasma ammonia was markedly elevated at 397 µg/dL and further increased to 804 µg/dL within 24 hours. Further metabolic evaluation revealed low plasma citrulline, elevated glutamine levels, and low urinary orotic acid, suggestive of CPS-I deficiency. A significant family history of consanguinity and unexplained neonatal death, further supported a genetic etiology.The patient underwent urgent haemodialysis for ammonia clearance and was treated with protein restriction, dextrose-based intravenous fluids, and ammonia-lowering agents including sodium benzoate. His neurological status improved progressively, allowing successful extubation after three days. He was later discharged on oral L-citrulline supplementation and dietary protein restriction. At two-week follow-up, he was clinically stable with normalized plasma ammonia levels. Conclusion This case highlights the importance of considering late-onset urea cycle disorders in adults presenting with unexplained hyperammonaemia encephalopathy. Early recognition and prompt aggressive management can be lifesaving and lead to complete neurological recovery. Hyperammonaemia Urea cycle disorder CPS-I deficiency adult onset Metabolic encephalopathy Figures Figure 1 INTRODUCTION Hyperammonemia is a serious metabolic condition characterized by elevated levels of ammonia in the blood and is mostly associated with acute or chronic liver dysfunction. Ammonia is a neurotoxin, and its accumulation can rapidly lead to cerebral edema, encephalopathy, seizures, coma, and death if not promptly recognized and treated [ 1 ]. In adult patients presenting with hyperammonemic encephalopathy and normal liver function tests, alternative etiologies must be actively explored, as delayed diagnosis can have catastrophic consequences. Urea cycle disorders (UCDs) are rare inborn errors of metabolism resulting from deficiencies of enzymes involved in ammonia detoxification through the urea cycle. These disorders classically present in the neonatal period with severe hyperammonemia; however, partial enzyme deficiencies may allow survival into adulthood with little or no symptoms until a metabolic stressor unmasks the condition [ 2 ], [ 3 ]. Such stressors include infections, fasting, increased protein intake, surgery, or certain medications, all of which can precipitate an acute hyperammonemic crisis [ 4 ]. Carbamoyl phosphate synthetase I (CPS-I) deficiency is one of the rarest urea cycle disorders and results from impaired conversion of ammonia to carbamoyl phosphate in hepatic mitochondria. Unlike ornithine transcarbamylase deficiency, CPS-I deficiency is not associated with elevated urinary orotic acid levels, a biochemical distinction that aids in diagnosis [ 5 ]. Late-onset CPS-I deficiency is particularly uncommon and poses a diagnostic challenge due to its nonspecific presentation and rarity in adult clinical practice [ 6 ]. Adult-onset UCDs are frequently misdiagnosed as toxic, infectious, psychiatric, or cerebrovascular conditions, leading to delays in appropriate management [7]. Neuroimaging is often normal in early stages, further complicating diagnosis [8]. Measurement of plasma ammonia levels, therefore, plays a crucial role in the early identification of metabolic encephalopathy and should be considered in all adults with unexplained altered sensorium [9]. Early recognition and aggressive management—including ammonia-lowering therapies, hemodialysis, and long-term dietary modifications—are essential to prevent irreversible neurological damage and improve outcomes [10]. We report a rare case of late-onset partial CPS-I deficiency presenting as acute hyperammonemic encephalopathy in an adult, emphasizing the importance of maintaining a high index of suspicion for urea cycle disorders in similar clinical scenarios. CASE PRESENTATION A 32-year-old male was brought to the emergency department by family members with complaints of progressive alteration in sensorium over the preceding 12 hours. The patient was reportedly well earlier in the day. At approximately 9:00 AM, he developed mild drowsiness but remained oriented and communicative. Over the next 5–6 hours, his level of consciousness deteriorated progressively, with reduced verbal responsiveness, and by around 5:00 PM, he became unresponsive. This episode was associated with a single event of urinary incontinence. There was no history suggestive of seizure activity, head trauma, fall, alcohol intake, or exposure to toxins. The patient had three episodes of vomiting earlier the same day. The vomitus was non-projectile, non-bilious, non-blood stained, and contained food particles. A history of fever with loose stools was present three days prior to admission, lasting approximately five to six days, which resolved following treatment with oral antibiotics. There was no history of headache, visual disturbances, focal neurological deficits, or similar episodes in the past. His past medical and surgical history was unremarkable, and he had no known comorbidities. Personal history revealed a mixed diet with normal appetite, sleep, bowel, and bladder habits. There was no history of substance abuse. Family history was significant for the death of a female sibling at three to four days of life due to an unknown cause. The patient’s younger brother was healthy. There was a history of consanguineous marriage between his parents. On examination at presentation, the patient was afebrile and hemodynamically stable. Neurological assessment revealed a Glasgow Coma Scale (GCS) score of E2 V2 M3 (7/15). Pupils were equal and reactive to light, and there were no signs of meningeal irritation or focal neurological deficits. Plantar responses were flexor bilaterally. There were no clinical stigmata of chronic liver disease such as jaundice, spider nevi, palmar erythema, or ascites. Respiratory, cardiovascular, and abdominal examinations were unremarkable. In view of the low GCS and risk of airway compromise, the patient was electively intubated and placed on mechanical ventilatory support. Initial laboratory investigations, including complete blood count, renal function tests, liver function tests, serum electrolytes, calcium, magnesium, phosphorus, urine routine microscopy, hepatitis B surface antigen, and anti-hepatitis C virus antibodies, were within normal limits, effectively excluding hepatic, renal, and infective etiologies.A urine toxicology panel was also sent which came out as normal.Plasma ammonia levels sent at admission came markedly elevated at 397 µg/dL. Non-contrast computed tomography of the brain was normal. Magnetic resonance imaging of the brain with contrast showed no parenchymal or meningeal abnormalities. Despite supportive management, repeat plasma ammonia levels after 24 hours increased to 804 µg/dL. Given the rapidly rising plasma ammonia levels, an urgent nephrology consultation was obtained, following which the patient underwent one session of hemodialysis. The patient showed significant neurological improvement and was successfully extubated after three days. Chest radiograph (posteroanterior view) was unremarkable. Ultrasonography of the abdomen and pelvis revealed mild free fluid in the pelvis, with no other abnormalities. Electroencephalography was normal. Given the severe hyperammonemia in the absence of liver dysfunction, further metabolic investigations were pursued. Plasma and urine quantitative amino acid analysis demonstrated low plasma citrulline levels with elevated glutamine levels. Urinary orotic acid levels were low, findings consistent with carbamoyl phosphate synthetase I(CPS-1)deficiency. Genetic testing for CPS-I mutation could not be performed due to financial constraints. He was managed with a protein-restricted diet, dextrose-containing intravenous fluids to prevent catabolism, and intravenous sodium benzoate. He was discharged on oral L-citrulline supplementation and dietary protein restriction. At two-week follow-up, the patient remained asymptomatic with normalized plasma ammonia levels. Figure 1 DISCUSSION Hyperammonemia in adults is most frequently associated with hepatic dysfunction; however, when liver function tests are normal, alternative, and often rare etiologies must be considered. Urea cycle disorders (UCDs) represent an important but underrecognized cause of non-hepatic hyperammonemia in adults and are associated with significant morbidity and mortality if not promptly diagnosed and treated [ 1 ], [ 2 ]. The present case highlights a rare instance of late-onset carbamoyl phosphate synthetase I (CPS-I) deficiency presenting as acute hyperammonemic encephalopathy in adulthood. UCDs are inherited metabolic disorders caused by deficiencies of enzymes involved in ammonia detoxification. CPS-I deficiency affects the first and rate-limiting step of the urea cycle and is typically associated with severe neonatal hyperammonemia. However, partial enzyme deficiencies may allow individuals to remain asymptomatic until a metabolic stressor precipitates an acute crisis [ 3 ]. In the present case, the antecedent febrile illness with gastrointestinal symptoms likely induced a catabolic state, leading to increased ammonia production and unmasking the underlying enzymatic defect. Clinical manifestations of hyperammonemia are largely neurological and nonspecific, ranging from mild confusion to coma and cerebral oedema [ 4 ]. Neuroimaging findings may be normal in the early stages, as observed in this patient, which can delay diagnosis [ 5 ]. Therefore, measurement of plasma ammonia levels is critical and should be included in the evaluation of any adult presenting with unexplained altered sensorium [ 6 ]. The markedly elevated ammonia levels in the absence of liver disease were key diagnostic clues in this case. Biochemical profiling plays a pivotal role in differentiating among UCD subtypes. The combination of low plasma citrulline, elevated glutamine levels, and low urinary orotic acid strongly suggested CPS-I deficiency and helped distinguish it from ornithine transcarbamylase deficiency, the most common UCD presenting in adults [7], [8]. Although genetic confirmation could not be obtained due to financial constraints, the biochemical pattern and clinical presentation were highly supportive of the diagnosis. Management of acute hyperammonemia requires rapid reduction of ammonia levels to prevent irreversible neurological damage. Hemodialysis remains the most effective modality for rapid ammonia clearance in severe cases [9]. Adjunctive therapies, including ammonia scavengers such as sodium benzoate, caloric supplementation to prevent catabolism, and dietary protein restriction, are essential components of both acute and long-term management [10]. Early intervention in this case resulted in complete neurological recovery. This case underscores the importance of maintaining a high index of suspicion for late-onset UCDs in adults with unexplained hyperammonemic encephalopathy. CONCLUSION This case highlights a rare presentation of late-onset carbamoyl phosphate synthetase I deficiency manifesting as acute hyperammonemic encephalopathy in adulthood. In patients presenting with unexplained altered sensorium and markedly elevated ammonia levels in the absence of liver disease, urea cycle disorders should be strongly considered. Early recognition, prompt metabolic evaluation, and aggressive ammonia-lowering interventions, including hemodialysis, are critical to prevent irreversible neurological damage. Long-term dietary modification and appropriate supplementation play a key role in preventing recurrence. Awareness of this rare but treatable condition can significantly improve patient outcomes and reduce mortality. Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE - -Not applicable CONSENT FOR PUBLICATION/CONSENT TO PUBLISH- -Written Informed consent has been taken from the patient for the publication of this case report AVAILABILITY OF DATA AND MATERIALS - -Not applicable. COMPETING INTERESTS- The authors declare that they have no competing interests. FUNDING- There is no funding involved in this case report. CLINICAL TRIAL NUMBER- Not Applicable. AUTHORS’S CONTRIBUTIONS- 1.PK-Conceptualized the case report, did the initial clinical assessment, and helped in drafting the original manuscript. 2.MHS-As the corresponding author, did the literature review and performed critical revisions of the manuscript. 3.RP-supervised the management and treatment protocols, including the coordination of the urgent hemodialysis. 4.VV-Provided overall supervision, validated the final diagnostic findings and gave final approval for the version to be published. 5.AC-Assisted in data collection, prepared the pedigree chart, and performed the final technical editing of the manuscript. ACKNOWLEDGEMENTS- -Not Applicable. References Machado MC, Pinheiro da Silva F. Hyperammonemia due to urea cycle disorders: a potentially fatal condition in the intensive care setting. Journal of Intensive Care [Internet]. 2014 Mar 13;2(1). Available from: http://dx.doi.org/10.1186/2052-0492-2-22 Waisbren SE, Gropman AL, Batshaw ML. Improving long term outcomes in urea cycle disorders‐report from the Urea Cycle Disorders Consortium. Journal of Inherited Metabolic Disease [Internet]. 2016 May 23;39(4):573–84. Available from: http://dx.doi.org/10.1007/s10545-016-9942-0 Wells DL, Thomas JB, Sacks GS, Zouhary LA. Late-onset urea cycle disorder in adulthood unmasked by severe malnutrition. Nutrition [Internet]. 2014 Jul;30(7–8):943–7. Available from: http://dx.doi.org/10.1016/j.nut.2013.12.011 Choi DE, Lee KW, Shin YT, Na KR. Hyperammonemia in a Patient with Late-Onset Ornithine Carbamoyltransferase Deficiency. Journal of Korean Medical Science [Internet]. 2012;27(5):556. Available from: http://dx.doi.org/10.3346/jkms.2012.27.5.556 Ishikawa R, Sugimoto T, Abe T, Ohno N, Tazuma T, Giga M, et al. A 36-year-old Man with Repeated Short-term Transient Hyperammonemia and Impaired Consciousness with a Confirmed Carbamoyl Phosphate Synthase 1 Gene Monoallelic Mutation. Internal Medicine [Internet]. 2022 May 1;61(9):1387–92. Available from: http://dx.doi.org/10.2169/internalmedicine.7961-21 Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, et al. Unmasked Adult-Onset Urea Cycle Disorders in the Critical Care Setting. Critical Care Clinics [Internet]. 2005 Oct;21(4):S1–8. Available from: http://dx.doi.org/10.1016/j.ccc.2005.05.002. Kölker, A. Garcia Cazorla, et al., “The phenotypic spectrum of organic acidurias and urea cycle disorders,” J. Inherit. Metab. Dis., 2015. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. Journal of Inherited Metabolic Disease [Internet]. 2007 Nov;30(6):865–79. Available from: http://dx.doi.org/10.1007/s10545-007-0709-5 R. N. Siddiqui, J. C. Baker, E. O. Shpizen, et al., “Adult-Onset Ornithine Transcarbamylase Deficiency Presenting as Severe Hyperammonemia,” Ann. Intern. Med. Case Reports, 2023. N. Summar and M. Tuchman, “Diagnosis, management, and outcome in urea cycle disorders,” Mol. Genet. Metab., 2014. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 05 Apr, 2026 Reviews received at journal 03 Apr, 2026 Reviewers agreed at journal 03 Apr, 2026 Reviewers agreed at journal 01 Apr, 2026 Reviews received at journal 31 Mar, 2026 Reviewers agreed at journal 31 Mar, 2026 Reviewers agreed at journal 31 Mar, 2026 Reviewers agreed at journal 30 Mar, 2026 Reviewers agreed at journal 30 Mar, 2026 Reviewers invited by journal 30 Mar, 2026 Editor assigned by journal 30 Mar, 2026 Editor invited by journal 30 Mar, 2026 Submission checks completed at journal 28 Mar, 2026 First submitted to journal 28 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9153576","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":615503295,"identity":"6f7e38dd-5690-4ccf-ae07-71b56e02c9e6","order_by":0,"name":"Vikram Vikhe","email":"","orcid":"","institution":"Dr. D.Y. Patil Vidyapeeth, Pune","correspondingAuthor":false,"prefix":"","firstName":"Vikram","middleName":"","lastName":"Vikhe","suffix":""},{"id":615503297,"identity":"a6e17e83-a628-4136-b711-f38ce611e073","order_by":1,"name":"Md. 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Ammonia is a neurotoxin, and its accumulation can rapidly lead to cerebral edema, encephalopathy, seizures, coma, and death if not promptly recognized and treated [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In adult patients presenting with hyperammonemic encephalopathy and normal liver function tests, alternative etiologies must be actively explored, as delayed diagnosis can have catastrophic consequences. Urea cycle disorders (UCDs) are rare inborn errors of metabolism resulting from deficiencies of enzymes involved in ammonia detoxification through the urea cycle. These disorders classically present in the neonatal period with severe hyperammonemia; however, partial enzyme deficiencies may allow survival into adulthood with little or no symptoms until a metabolic stressor unmasks the condition [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Such stressors include infections, fasting, increased protein intake, surgery, or certain medications, all of which can precipitate an acute hyperammonemic crisis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCarbamoyl phosphate synthetase I (CPS-I) deficiency is one of the rarest urea cycle disorders and results from impaired conversion of ammonia to carbamoyl phosphate in hepatic mitochondria. Unlike ornithine transcarbamylase deficiency, CPS-I deficiency is not associated with elevated urinary orotic acid levels, a biochemical distinction that aids in diagnosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Late-onset CPS-I deficiency is particularly uncommon and poses a diagnostic challenge due to its nonspecific presentation and rarity in adult clinical practice [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Adult-onset UCDs are frequently misdiagnosed as toxic, infectious, psychiatric, or cerebrovascular conditions, leading to delays in appropriate management [7]. Neuroimaging is often normal in early stages, further complicating diagnosis [8]. Measurement of plasma ammonia levels, therefore, plays a crucial role in the early identification of metabolic encephalopathy and should be considered in all adults with unexplained altered sensorium [9].\u003c/p\u003e \u003cp\u003eEarly recognition and aggressive management\u0026mdash;including ammonia-lowering therapies, hemodialysis, and long-term dietary modifications\u0026mdash;are essential to prevent irreversible neurological damage and improve outcomes [10]. We report a rare case of late-onset partial CPS-I deficiency presenting as acute hyperammonemic encephalopathy in an adult, emphasizing the importance of maintaining a high index of suspicion for urea cycle disorders in similar clinical scenarios.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eA 32-year-old male was brought to the emergency department by family members with complaints of progressive alteration in sensorium over the preceding 12 hours. The patient was reportedly well earlier in the day. At approximately 9:00 AM, he developed mild drowsiness but remained oriented and communicative. Over the next 5\u0026ndash;6 hours, his level of consciousness deteriorated progressively, with reduced verbal responsiveness, and by around 5:00 PM, he became unresponsive. This episode was associated with a single event of urinary incontinence. There was no history suggestive of seizure activity, head trauma, fall, alcohol intake, or exposure to toxins. The patient had three episodes of vomiting earlier the same day. The vomitus was non-projectile, non-bilious, non-blood stained, and contained food particles. A history of fever with loose stools was present three days prior to admission, lasting approximately five to six days, which resolved following treatment with oral antibiotics. There was no history of headache, visual disturbances, focal neurological deficits, or similar episodes in the past.\u003c/p\u003e \u003cp\u003eHis past medical and surgical history was unremarkable, and he had no known comorbidities. Personal history revealed a mixed diet with normal appetite, sleep, bowel, and bladder habits. There was no history of substance abuse. Family history was significant for the death of a female sibling at three to four days of life due to an unknown cause. The patient\u0026rsquo;s younger brother was healthy. There was a history of consanguineous marriage between his parents. On examination at presentation, the patient was afebrile and hemodynamically stable. Neurological assessment revealed a Glasgow Coma Scale (GCS) score of E2 V2 M3 (7/15). Pupils were equal and reactive to light, and there were no signs of meningeal irritation or focal neurological deficits. Plantar responses were flexor bilaterally. There were no clinical stigmata of chronic liver disease such as jaundice, spider nevi, palmar erythema, or ascites. Respiratory, cardiovascular, and abdominal examinations were unremarkable. In view of the low GCS and risk of airway compromise, the patient was electively intubated and placed on mechanical ventilatory support.\u003c/p\u003e \u003cp\u003eInitial laboratory investigations, including complete blood count, renal function tests, liver function tests, serum electrolytes, calcium, magnesium, phosphorus, urine routine microscopy, hepatitis B surface antigen, and anti-hepatitis C virus antibodies, were within normal limits, effectively excluding hepatic, renal, and infective etiologies.A urine toxicology panel was also sent which came out as normal.Plasma ammonia levels sent at admission came markedly elevated at 397 \u0026micro;g/dL. Non-contrast computed tomography of the brain was normal. Magnetic resonance imaging of the brain with contrast showed no parenchymal or meningeal abnormalities. Despite supportive management, repeat plasma ammonia levels after 24 hours increased to 804 \u0026micro;g/dL. Given the rapidly rising plasma ammonia levels, an urgent nephrology consultation was obtained, following which the patient underwent one session of hemodialysis. The patient showed significant neurological improvement and was successfully extubated after three days. Chest radiograph (posteroanterior view) was unremarkable. Ultrasonography of the abdomen and pelvis revealed mild free fluid in the pelvis, with no other abnormalities. Electroencephalography was normal.\u003c/p\u003e \u003cp\u003eGiven the severe hyperammonemia in the absence of liver dysfunction, further metabolic investigations were pursued. Plasma and urine quantitative amino acid analysis demonstrated low plasma citrulline levels with elevated glutamine levels. Urinary orotic acid levels were low, findings consistent with carbamoyl phosphate synthetase I(CPS-1)deficiency. Genetic testing for CPS-I mutation could not be performed due to financial constraints. He was managed with a protein-restricted diet, dextrose-containing intravenous fluids to prevent catabolism, and intravenous sodium benzoate. He was discharged on oral L-citrulline supplementation and dietary protein restriction. At two-week follow-up, the patient remained asymptomatic with normalized plasma ammonia levels.\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eHyperammonemia in adults is most frequently associated with hepatic dysfunction; however, when liver function tests are normal, alternative, and often rare etiologies must be considered. Urea cycle disorders (UCDs) represent an important but underrecognized cause of non-hepatic hyperammonemia in adults and are associated with significant morbidity and mortality if not promptly diagnosed and treated [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The present case highlights a rare instance of late-onset carbamoyl phosphate synthetase I (CPS-I) deficiency presenting as acute hyperammonemic encephalopathy in adulthood. UCDs are inherited metabolic disorders caused by deficiencies of enzymes involved in ammonia detoxification. CPS-I deficiency affects the first and rate-limiting step of the urea cycle and is typically associated with severe neonatal hyperammonemia. However, partial enzyme deficiencies may allow individuals to remain asymptomatic until a metabolic stressor precipitates an acute crisis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In the present case, the antecedent febrile illness with gastrointestinal symptoms likely induced a catabolic state, leading to increased ammonia production and unmasking the underlying enzymatic defect.\u003c/p\u003e \u003cp\u003eClinical manifestations of hyperammonemia are largely neurological and nonspecific, ranging from mild confusion to coma and cerebral oedema [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Neuroimaging findings may be normal in the early stages, as observed in this patient, which can delay diagnosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, measurement of plasma ammonia levels is critical and should be included in the evaluation of any adult presenting with unexplained altered sensorium [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The markedly elevated ammonia levels in the absence of liver disease were key diagnostic clues in this case. Biochemical profiling plays a pivotal role in differentiating among UCD subtypes. The combination of low plasma citrulline, elevated glutamine levels, and low urinary orotic acid strongly suggested CPS-I deficiency and helped distinguish it from ornithine transcarbamylase deficiency, the most common UCD presenting in adults [7], [8]. Although genetic confirmation could not be obtained due to financial constraints, the biochemical pattern and clinical presentation were highly supportive of the diagnosis.\u003c/p\u003e \u003cp\u003eManagement of acute hyperammonemia requires rapid reduction of ammonia levels to prevent irreversible neurological damage. Hemodialysis remains the most effective modality for rapid ammonia clearance in severe cases [9]. Adjunctive therapies, including ammonia scavengers such as sodium benzoate, caloric supplementation to prevent catabolism, and dietary protein restriction, are essential components of both acute and long-term management [10]. Early intervention in this case resulted in complete neurological recovery. This case underscores the importance of maintaining a high index of suspicion for late-onset UCDs in adults with unexplained hyperammonemic encephalopathy.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis case highlights a rare presentation of late-onset carbamoyl phosphate synthetase I deficiency manifesting as acute hyperammonemic encephalopathy in adulthood. In patients presenting with unexplained altered sensorium and markedly elevated ammonia levels in the absence of liver disease, urea cycle disorders should be strongly considered. Early recognition, prompt metabolic evaluation, and aggressive ammonia-lowering interventions, including hemodialysis, are critical to prevent irreversible neurological damage. Long-term dietary modification and appropriate supplementation play a key role in preventing recurrence. Awareness of this rare but treatable condition can significantly improve patient outcomes and reduce mortality.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u003c/strong\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION/CONSENT TO PUBLISH-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-Written Informed consent has been taken from the patient for the publication of this case report\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/strong\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no funding involved in this case report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCLINICAL TRIAL NUMBER-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORS\u0026rsquo;S CONTRIBUTIONS-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1.PK-Conceptualized the case report, did the initial clinical assessment, and helped in drafting the original manuscript.\u003c/p\u003e\n\u003cp\u003e2.MHS-As the corresponding author, did the literature review and performed critical revisions of the manuscript.\u003c/p\u003e\n\u003cp\u003e3.RP-supervised the management and treatment protocols, including the coordination of the urgent hemodialysis.\u003c/p\u003e\n\u003cp\u003e4.VV-Provided overall supervision, validated the final diagnostic findings and gave final approval for the version to be published.\u003c/p\u003e\n\u003cp\u003e5.AC-Assisted in data collection, prepared the pedigree chart, and performed the final technical editing of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS-\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-Not Applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMachado MC, Pinheiro da Silva F. Hyperammonemia due to urea cycle disorders: a potentially fatal condition in the intensive care setting. Journal of Intensive Care [Internet]. 2014 Mar 13;2(1). Available from: http://dx.doi.org/10.1186/2052-0492-2-22\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWaisbren SE, Gropman AL, Batshaw ML. Improving long term outcomes in urea cycle disorders‐report from the Urea Cycle Disorders Consortium. Journal of Inherited Metabolic Disease [Internet]. 2016 May 23;39(4):573\u0026ndash;84. Available from: http://dx.doi.org/10.1007/s10545-016-9942-0\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWells DL, Thomas JB, Sacks GS, Zouhary LA. Late-onset urea cycle disorder in adulthood unmasked by severe malnutrition. Nutrition [Internet]. 2014 Jul;30(7\u0026ndash;8):943\u0026ndash;7. Available from: http://dx.doi.org/10.1016/j.nut.2013.12.011\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChoi DE, Lee KW, Shin YT, Na KR. Hyperammonemia in a Patient with Late-Onset Ornithine Carbamoyltransferase Deficiency. Journal of Korean Medical Science [Internet]. 2012;27(5):556. Available from: http://dx.doi.org/10.3346/jkms.2012.27.5.556\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIshikawa R, Sugimoto T, Abe T, Ohno N, Tazuma T, Giga M, et al. A 36-year-old Man with Repeated Short-term Transient Hyperammonemia and Impaired Consciousness with a Confirmed \u0026amp;lt;i\u0026amp;gt;Carbamoyl Phosphate Synthase 1\u0026amp;lt;/i\u0026amp;gt; Gene Monoallelic Mutation. Internal Medicine [Internet]. 2022 May 1;61(9):1387\u0026ndash;92. Available from: http://dx.doi.org/10.2169/internalmedicine.7961-21\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSummar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, et al. Unmasked Adult-Onset Urea Cycle Disorders in the Critical Care Setting. Critical Care Clinics [Internet]. 2005 Oct;21(4):S1\u0026ndash;8. Available from: http://dx.doi.org/10.1016/j.ccc.2005.05.002.\u003c/li\u003e\n \u003cli\u003eK\u0026ouml;lker, A. Garcia Cazorla, et al., \u0026ldquo;The phenotypic spectrum of organic acidurias and urea cycle disorders,\u0026rdquo; J. Inherit. Metab. Dis., 2015.\u003c/li\u003e\n \u003cli\u003eGropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. Journal of Inherited Metabolic Disease [Internet]. 2007 Nov;30(6):865\u0026ndash;79. Available from: http://dx.doi.org/10.1007/s10545-007-0709-5\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eR. N. Siddiqui, J. C. Baker, E. O. Shpizen, et al., \u0026ldquo;Adult-Onset Ornithine Transcarbamylase Deficiency Presenting as Severe Hyperammonemia,\u0026rdquo; Ann. Intern. Med. Case Reports, 2023.\u003c/li\u003e\n \u003cli\u003eN. Summar and M. Tuchman, \u0026ldquo;Diagnosis, management, and outcome in urea cycle disorders,\u0026rdquo; Mol. Genet. Metab., 2014.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hyperammonaemia, Urea cycle disorder, CPS-I deficiency, adult onset, Metabolic encephalopathy","lastPublishedDoi":"10.21203/rs.3.rs-9153576/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9153576/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHyperammonaemia is a medical emergency which is mostly associated with liver dysfunction. However, in the absence of hepatic disease, rare inborn errors of metabolism such as urea cycle disorders (UCDs) must be considered. While UCDs typically present in the neonatal period, partial enzyme deficiencies may remain clinically silent until adulthood and present abruptly with life-threatening hyperammonaemia encephalopathy. Among these, late-onset carbamoyl phosphate synthetase I (CPS-I) deficiency is exceedingly rare and often underdiagnosed.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eWe report a 32-year-old male who presented with acute onset altered sensorium progressing to coma over 12 hours. It was preceded by two to three episodes of vomiting the same day and history of febrile illness few days back. On admission, the patient had a Glasgow Coma Scale score of 7/15 and required endotracheal intubation with ventilatory support. Routine laboratory investigations, including liver and renal function tests, were within normal limits. Neuroimaging studies (CT and MRI brain) showed no abnormalities. Plasma ammonia was markedly elevated at 397 \u0026micro;g/dL and further increased to 804 \u0026micro;g/dL within 24 hours. Further metabolic evaluation revealed low plasma citrulline, elevated glutamine levels, and low urinary orotic acid, suggestive of CPS-I deficiency. A significant family history of consanguinity and unexplained neonatal death, further supported a genetic etiology.The patient underwent urgent haemodialysis for ammonia clearance and was treated with protein restriction, dextrose-based intravenous fluids, and ammonia-lowering agents including sodium benzoate. His neurological status improved progressively, allowing successful extubation after three days. He was later discharged on oral L-citrulline supplementation and dietary protein restriction. At two-week follow-up, he was clinically stable with normalized plasma ammonia levels.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case highlights the importance of considering late-onset urea cycle disorders in adults presenting with unexplained hyperammonaemia encephalopathy. Early recognition and prompt aggressive management can be lifesaving and lead to complete neurological recovery.\u003c/p\u003e","manuscriptTitle":"Ammonia Storm: Unmasking a Rare Urea Cycle Disorder in Adulthood","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-02 07:19:09","doi":"10.21203/rs.3.rs-9153576/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-06T03:49:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-03T11:07:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"213490006142481835485252305095199189868","date":"2026-04-03T10:42:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178819505886140833269362570328978071569","date":"2026-04-02T01:18:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-31T20:11:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"147109160446720132809384291614826923056","date":"2026-03-31T19:19:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124603917943756343883292122781766119266","date":"2026-03-31T07:02:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286684531327737453565715058574558443289","date":"2026-03-31T01:46:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204349532368732805566411906379664035693","date":"2026-03-30T20:24:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-30T18:43:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-30T18:40:38+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-30T17:39:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-28T06:43:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-03-28T06:39:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ed95ad42-446b-453a-ba5f-c38336d7b066","owner":[],"postedDate":"April 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T14:58:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-02 07:19:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9153576","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9153576","identity":"rs-9153576","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}