Urea Cycle Defects


Urea Cycle

Responsible for the metabolism and disposal of unneeded nitrogen from dietary consumption and skeletal muscle metabolism.  Ammonia (glutamine and alanine nitrogen derivative), aspartate and bicarbonate are converted to urea to excrete excess nitrogen.  Two atoms of nitrogen are converted to urea with each cycle.

Figure 1: Diagram of the urea cycle. 

1 L-ornithine
carbamoyl phosphate
3 L-citrulline
6 L-arginine
L-Asp L-aspartate
CPS-1 carbamoyl phosphate synthetase I
OTC Ornithine transcarbamoylase
ASS argininosuccinate synthetase
ASL argininosuccinate lyase
ARG1 arginase 1


Etiology of Urea Cycle Defects

Urea cycle defects result from a deficiency or total absence of the activity of any of the enzymes along the pathway, particularly carbamoyl phosphate synthetase I (CPSI), ornithine transcarbamylase (OTC), arginosuccinate synthase (ASS), arginosuccinate lyase (ASL), arginase (ARG) or a deficiency of the co-factor N-acetylglutamate (N-GAS).  Most are named for the amino acid substrate in excess: argininemia, citrullinemia, arginosuccinic aciduria.  OTC deficiency is most common urea cycle defect.  CPS1 deficiency is the most severe UCD. 


Clinical Features

Symptoms typically present in the first few days of life in severe or total enzyme deficit; in milder enzymatic defects, symptoms present after a trigger such as illness or stress.  Generally, the symptoms of a urea cycle defect reflect those of hyperammonemic encephalopathy (brain edema, metabolic dysregulation and neurotransmitter disturbance), with the exception of ARG deficiency

General:  Poor feeding, lethargy, behavioral changes

Vital Sign Changes:  Hypothermia, hyperventilation

Neurologic:  Neurologic posturing and muscle tone abnormalities.  In the late stages, symptoms might also include seizures, ataxia and coma.



Often the clinical appearance of urea cycle defects mimics that of other inborn errors of metabolism.  Often an initial work-up includes CBC with differential, urinalysis, blood gases, serum electrolytes, blood glucose, plasma ammonia, urine reducing substances, urine ketones if acidosis or hypoglycemia present, quantitative plasma and urine amino acids, urine organic acids and plasma lactate.

Urea Cycle Defect Tests:

  • Ammonia > 150 mol/L, normal anion gap, normal glucose
  • Quantitative amino acid analysis- differentiates specific enzymatic defects in the cycle based on accumulation of cycle precursors
  • Measurement of urinary orotic acid- low in CPS1 deficiency and elevated in OTC deficiency
  • Definitive diagnosis based on molecular genetic testing or measurement of enzyme activity

Hyperammonemia Differential (and how they can be excluded):

  • Pyruvate metabolism disorder- will also present with lactic aciduria and anion gap
  • Organic acidemia- may inhibit a urea cycle enzyme but will present with metabolic acidosis/ketotic hypoglycemia
  • Fatty oxidation defect- will also have nonketotic hypoglycemia
  • Transient hyperammonemia of newborn- clinically, it is typically pre-term infant with substantial respiratory distress
  • Liver failure (often 2/2 to perinatal HSV)- severe liver malfunction and elevated liver enzymes


Acute management of Urea Cycle Defect

  1. Respiratory management- if respiratory failure is ensuing, mechanical ventilation is indicated to decrease the metabolic demands of increased respiration
  2. Volume repletion- with care not to increase cerebral edema
  3. Restrict protein- This should not be continued for longer than 24-48 hours
  4. Provide energy source- IV glucose.  Calories given as carbohydrates or fat.
  5. Resolution of Hyperammonemia:
    1. Oral Neosporin and lactulose to prevent intestine bacterial production of ammonia in colon
    2. Dialysis or hemofiltration- Hemodialysis is preferred; Exchange transfusion clears only ammonia in vasculature and dialysis can create a catabolic state
  6. Alternative pathway for nitrogen metabolism:
    1. Replacement of arginine or citrulline (enzyme defect dependent)- enzyme deficiencies may render these essential amino acids and are needed to generate urea cycle intermediates.
    2. Nitrogen scavenger drugs- sodium benzoate and sodium phenylacetate will decrease ammonia production by diverting amino acids away from the urea cycle


Primary Prevention/Long-term management

  1. Dietary restrictions-  Limit protein consumption and use specialized formulations of amino acids
  2. Nitrogen metabolism- use of nitrogen scavenging drugs and replacement of arginine/citrulline
  3. Carbamyl glutamate (Carbaglu) to replace NAGS deficiency if normal CPSI function
  4. Liver transplant- indications include CPSI or OTC deficiency, ASL deficiency associated with cirrhosis or any UCD refractory to medical management
  5. Parental education- vital that parents be able to recognize the signs of hyperammonemia as well as the states (such as infection, dehydration) that might lead to increased catabolism

Of note, glucocorticoids and valproic acid should be used with caution in children with UCD due to their affects of increasing protein catabolism and decreasing urea cycle enzyme function, respectively.  Vaccines should be given, as they , are not associated with exacerbation of defect and should be given to children with UCD.



Acute recovery:  Outcomes are less severe if ammonia concentration remains <180 �mol/L and hyperammonemia lasts <24 hours.  Normal neurologic recovery is rarely seen if ammonia levels exceed 400 �mol/L or coma lasts longer than 72 hours. 

Long-term complications: Poor growth, developmental delay, intellectual disability, ADHD, seizure disorder, CP.


Genetic Counseling

Predominantly autosomal recessive disorders.  The only exception is OTC, which is X-linked.  Severity in female carrier of OTC deficiency is largely dependent on number of hepatocytes affected.  Only 15% of female carriers will have symptoms; these are often precipitated by increased stress on the urea cycle, i.e. increased protein intake, infection, extensive collagen breakdown (post-partum period), GI bleeding, surgery. 

Carrier testing is available for any of the disorders if the disease causing mutation in the family is known. 


Illinois Newborn Screen

The Illinois newborn screen tests for:  Argininemia, Citrullinemia, Arginosuccinic aciduria



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Gene Reviews: Urea Cycle Disorders Overview. (Accessed on September 14, 2011)

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