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.
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Target exams
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 ammonia
- Respiratory alkalosis or a mixed acid-base picture with encephalopathy in a neonate — a classic clue to a urea cycle disorder
- An acutely encephalopathic child with 'sepsis' cultures that remain negative, or recurrent vomiting and ataxia after a protein load or intercurrent illness
- Altered behaviour, confusion, ataxia or coma after surgery, infection, fasting, valproate or high protein intake in a previously well child or adolescent
- A child labelled 'cerebral palsy' with progressive spastic diplegia, seizures and developmental delay — arginase deficiency mimics cerebral palsy
- Unexplained cerebral oedema, raised intracranial pressure or an unexplained neonatal death in the family
- Maternal illness in pregnancy (hyperemesis, confusion) or a family history consistent with X-linked OTC deficiency — affected males, carrier females
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- Neonatal hyperammonaemia as a metabolic emergency
- Initial investigation of the sick neonate with a possible inborn error of metabolism
- Principles of acute hyperammonaemia management
- Biochemistry and classification of the six urea cycle enzyme/transporter deficiencies
- Nitrogen scavengers, dialysis thresholds and long-term metabolic management
- Liver transplantation and emerging gene therapy for severe urea cycle disorders
- Recognising and stabilising a neonatal hyperammonaemic crisis
- Interpreting plasma amino acids and urinary orotic acid
- Counselling a family on an X-linked OTC deficiency diagnosis
- Acute case of a neonate with encephalopathy and a rising ammonia
- Long case of a child surviving an OTC deficiency crisis discussing neurodevelopmental outcome and transplantation
- Metabolic emergencies in the neonate and infant
- Investigation of the acutely unwell child
- Safeguarding and family implications of inherited metabolic disease
- Urea cycle biochemistry and the six deficiencies
- Acute and long-term management of hyperammonaemia
- Genetics and counselling of urea cycle disorders
- Resuscitation of the metabolic collapse
- Communicating a life-limiting inherited metabolic diagnosis to parents
- Inborn errors of metabolism presenting in the neonate
- Hyperammonaemia diagnosis and emergency management
- Arginase deficiency and the cerebral palsy mimic
- Urea cycle disorders
- Acute hyperammonaemic encephalopathy
- Multidisciplinary care of inherited metabolic disease
- Urea cycle disorders and hyperammonaemia
- Neonatal metabolic emergency management
- Long-term outcomes and liver transplantation in UCD
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]
References12ShowHide
- [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