Paeds · genetics-dysmorphology-and-metabolism

Urea-cycle disorders and hyperammonaemia

Also known as Urea cycle disorders · UCD · Hyperammonaemia of metabolic origin · Ornithine transcarbamylase deficiency · OTC deficiency · Carbamoyl phosphate synthetase 1 deficiency

A fellowship approach to the urea cycle disorders: recognise hyperammonaemia as a time-critical metabolic emergency that mimics sepsis in the neonate and presents with bizarre behaviour or coma in the older child, treat on suspicion with calorie loading, nitrogen scavengers and dialysis before the enzyme diagnosis returns, confirm with plasma amino acids and urinary orotic acid, and lock in long-term protein-restricted medical and — for severe forms — transplant-based management.

high12 referencesUpdated 13 July 202621 min readVerification in progress

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Red flags

Any neonate who is well at birth then deteriorates after 24–72 hours of feeds with lethargy, poor feeding, vomiting, hyperventilation or seizures — measure ammoniaRespiratory alkalosis or a mixed acid-base picture with encephalopathy in a neonate — a classic clue to a urea cycle disorderAn acutely encephalopathic child with 'sepsis' cultures that remain negative, or recurrent vomiting and ataxia after a protein load or intercurrent illnessAltered behaviour, confusion, ataxia or coma after surgery, infection, fasting, valproate or high protein intake in a previously well child or adolescentA child labelled 'cerebral palsy' with progressive spastic diplegia, seizures and developmental delay — arginase deficiency mimics cerebral palsyUnexplained cerebral oedema, raised intracranial pressure or an unexplained neonatal death in the familyMaternal illness in pregnancy (hyperemesis, confusion) or a family history consistent with X-linked OTC deficiency — affected males, carrier females

Life stages

neonateinfanttoddlerpreschoolschool-ageadolescentyoung-adult-transition

Care settings

nicued-acutepicuoutpatientrural-remotetelehealth

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written-only

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Neonatal hyperammonaemia as a metabolic emergencyInitial investigation of the sick neonate with a possible inborn error of metabolismPrinciples of acute hyperammonaemia managementBiochemistry and classification of the six urea cycle enzyme/transporter deficienciesNitrogen scavengers, dialysis thresholds and long-term metabolic managementLiver transplantation and emerging gene therapy for severe urea cycle disordersRecognising and stabilising a neonatal hyperammonaemic crisisInterpreting plasma amino acids and urinary orotic acidCounselling a family on an X-linked OTC deficiency diagnosisAcute case of a neonate with encephalopathy and a rising ammoniaLong case of a child surviving an OTC deficiency crisis discussing neurodevelopmental outcome and transplantationMetabolic emergencies in the neonate and infantInvestigation of the acutely unwell childSafeguarding and family implications of inherited metabolic diseaseUrea cycle biochemistry and the six deficienciesAcute and long-term management of hyperammonaemiaGenetics and counselling of urea cycle disordersResuscitation of the metabolic collapseCommunicating a life-limiting inherited metabolic diagnosis to parentsInborn errors of metabolism presenting in the neonateHyperammonaemia diagnosis and emergency managementArginase deficiency and the cerebral palsy mimicUrea cycle disordersAcute hyperammonaemic encephalopathyMultidisciplinary care of inherited metabolic diseaseUrea cycle disorders and hyperammonaemiaNeonatal metabolic emergency managementLong-term outcomes and liver transplantation in UCD

Your progress

Saved locally on this device.

Practise this topic

Target exams

RACP General PaediatricsRACP DWERACP DCE

Red flags

Life stages

neonateinfanttoddlerpreschoolschool-ageadolescentyoung-adult-transition

Care settings

nicued-acutepicuoutpatientrural-remotetelehealth

Clinical exam formats

written-only

Board mappings

The fellowship answer

A urea cycle disorder is a metabolic emergency until proven otherwise, and the window to protect the brain is measured in hours. The urea cycle converts neurotoxic ammonia into excretable urea; a defect in any of its six enzymes or transporters — most commonly X-linked ornithine transcarbamylase (OTC) deficiency — causes ammonia to accumulate, cross the blood–brain barrier, and produce cerebral oedema that becomes irreversible. Treat on suspicion: stop protein, calorie-load to switch off catabolism, give nitrogen scavengers and arginine, and move to haemofiltration if ammonia exceeds the threshold. Confirm the diagnosis with plasma amino acids, urinary orotic acid and molecular testing, then lock in long-term protein-restricted medical management and, for severe forms, liver transplantation. [1] [4]

The fellowship mark goes to the candidate who thinks in three layers at once. The first layer is the child in front of you: an encephalopathic neonate or a confused older child, where the immediate question is not "what is the enzyme defect" but "what is the ammonia and how fast is it rising". The second is the biochemistry: a cycle that sits half in the mitochondrion and half in the cytosol, with each block producing a recognisable pattern of accumulating metabolites. The third is the family: an X-linked diagnosis in OTC deficiency obliges carrier testing of the mother and sisters and reproductive counselling, because the recurrence risk and the carrier phenotype change lives. [1] [3]

Paediatrics Fellowship Pro

You have read the opening of this topic. The complete unit — every section and its primary-source references — is part of the Paediatrics Fellowship fellowship atlas.

References12Show ledger

[1]Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. Eur J Pediatr / J Inherit Metab Dis, 2019.PMID 30982989
[2]Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis, 2012.PMID 22642880
[3]Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr, 1996.PMID 8794176
[4]Alfadhel M, Mutairi FA, Makhseed N, Jasmi FA, Al-Thihli K, Al-Jishi E, et al. Guidelines for acute management of hyperammonemia in the Middle East region. Ther Clin Risk Manag, 2016.PMID 27099506
[5]Raina R, Bedoyan JK, Lichter-Konecki U, Jouvet P, Picca S, Mew NA, et al. Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy. Nat Rev Nephrol, 2020.PMID 32269302
[6]Kido J, Matsumoto S, Häberle J, Nakajima Y, Wada Y, Mochizuki N, et al. Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan. J Inherit Metab Dis, 2021.PMID 33840128
[7]Ah Mew N, Cnaan A, McCarter R, et al. Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium. Transl Sci Rare Dis, 2018.PMID 30613471
[8]Sin YY, Baron G, Schulze A, Funk CD. Arginase-1 deficiency. J Mol Med (Berl), 2015.PMID 26467175
[9]Singh RH, Bourdages MH, Kurtz A, et al. The efficacy of Carbamylglutamate impacts the nutritional management of patients with N-Acetylglutamate synthase deficiency. Orphanet J Rare Dis, 2024.PMID 38637895
[10]García Vega M, Andrade JD, Morais A, et al. Urea cycle disorders and indications for liver transplantation. Front Pediatr, 2023.PMID 36937980
[11]Posset R, Garbade SF, Gleich F, et al. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Genet Med, 2024.PMID 38054409
[12]Lo RS, Cromie GA, Tang M, et al. The functional impact of 1,570 individual amino acid substitutions in human OTC. Am J Hum Genet, 2023.PMID 37146589

Urea-cycle disorders and hyperammonaemia

Also known as Urea cycle disorders · UCD · Hyperammonaemia of metabolic origin · Ornithine transcarbamylase deficiency · OTC deficiency · Carbamoyl phosphate synthetase 1 deficiency

high12 referencesUpdated 13 July 202621 min readVerification in progress

Practise this topic

The fellowship answer

Paediatrics Fellowship Pro

You have read the opening of this topic. The complete unit — every section and its primary-source references — is part of the Paediatrics Fellowship fellowship atlas.

References12Show ledger

[1]Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. Eur J Pediatr / J Inherit Metab Dis, 2019.PMID 30982989
[2]Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis, 2012.PMID 22642880
[3]Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr, 1996.PMID 8794176
[4]Alfadhel M, Mutairi FA, Makhseed N, Jasmi FA, Al-Thihli K, Al-Jishi E, et al. Guidelines for acute management of hyperammonemia in the Middle East region. Ther Clin Risk Manag, 2016.PMID 27099506
[5]Raina R, Bedoyan JK, Lichter-Konecki U, Jouvet P, Picca S, Mew NA, et al. Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy. Nat Rev Nephrol, 2020.PMID 32269302
[6]Kido J, Matsumoto S, Häberle J, Nakajima Y, Wada Y, Mochizuki N, et al. Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan. J Inherit Metab Dis, 2021.PMID 33840128
[7]Ah Mew N, Cnaan A, McCarter R, et al. Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium. Transl Sci Rare Dis, 2018.PMID 30613471
[8]Sin YY, Baron G, Schulze A, Funk CD. Arginase-1 deficiency. J Mol Med (Berl), 2015.PMID 26467175
[9]Singh RH, Bourdages MH, Kurtz A, et al. The efficacy of Carbamylglutamate impacts the nutritional management of patients with N-Acetylglutamate synthase deficiency. Orphanet J Rare Dis, 2024.PMID 38637895
[10]García Vega M, Andrade JD, Morais A, et al. Urea cycle disorders and indications for liver transplantation. Front Pediatr, 2023.PMID 36937980
[11]Posset R, Garbade SF, Gleich F, et al. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Genet Med, 2024.PMID 38054409
[12]Lo RS, Cromie GA, Tang M, et al. The functional impact of 1,570 individual amino acid substitutions in human OTC. Am J Hum Genet, 2023.PMID 37146589