Signs and symptoms of hyperammonemia
due to NAGS deficiency

The brain is the main organ affected by hyperammonemia caused by NAGS deficiency (NAGSD) or other inherited metabolic urea cycle disorders (UCDs). Most signs and symptoms are neurological in origin.1

Review emergency management
instructions for hyperammonemic crisis

Symptoms in Neonates (Days 1-28)

Common neonatal symptoms of hyperammonemia,
which may be caused by NAGS deficiency, include:

Neurological Presentations

  • Altered level of consciousness (from somnolence to lethargy to coma), mimicking encephalitis or drug intoxication2
  • Acute encephalopathy2
  • Seizures (generally not isolated but along with altered level of consciousness)2,3
  • Hypotonia4
  • Multiorgan failure2
  • Peripheral circulatory failure2
  • Respiratory distress, hyperventilation2/respiratory alkalosis4
  • Sepsis-like picture**,2,4 including temperature instability,2 hypo- or hyperthermia1

Gastrointestinal Presentations*

  • Vomiting,2,3 progressive poor appetite2 or poor feeding1,3

Additional considerations

  • Newborns with NAGSD typically appear normal at birth because the maternal urea cycle clears surplus nitrogen from the fetus.1
  • Ammonia level increases can occur as early as 24 hours after birth due to postnatal catabolism.1
  • Neonatal presentations can be especially dangerous when hyperammonemia begins to develop after hospital discharge.
  • As ammonia levels build up, cerebral edema, respiratory arrest, lethargy, coma, irreversible brain damage, and death can quickly follow earlier symptoms.1,4-6

*Gastrointestinal symptoms are neurological in origin.1

**Septicemia, generally accompanied by metabolic acidosis, is the most common differential diagnosis. Presence of respiratory alkalosis should trigger an immediate evaluation of ammonia levels. Confirmed septicemia does not exclude a primary hyperammonemic defect.1

Symptoms in Infants, Children, and Adults

Common symptoms of hyperammonemia in infants, children, and adults
which may be caused by NAGS deficiency, include:

  • Neurological Presentations

    Confusion,2,3 lethargy,2 dizziness2

    Migraine-like headaches, tremor, ataxia, dysarthria2

    Intellectual/learning disabilities,2 neurodevelopmental delay2,4

    Seizures1

    Coma7

  • Gastrointestinal Presentations

    Abdominal pain,2 nausea,3,4 vomiting2,4

    Protein aversion, self-selected low-protein diet2

    Failure to thrive2

    Hepatomegaly, elevated liver enzymes2

  • Psychiatric Presentations

    Hyperactivity, mood alteration, behavioral changes, aggressiveness,2 combativeness3

Additional considerations

  • Hyperammonemia can occur for the first time at any age and is an emergency situation.1 Individuals with partial NAGS deficiency may develop symptoms early in life or well into adulthood.
  • Severe symptoms may develop suddenly in someone who was previously healthy.1 Or less severe, chronic symptoms may occur for years.6
  • Symptoms tend to develop with increased catabolic stress caused by infection, starvation, surgery, or trauma, for example.4 Symptoms also tend to be episodic2 and neurological in origin.1

Stressors

Adding stress to the urea cycle process can trigger symptoms of hyperammonemia in individuals with NAGS deficiency.4 Knowledge of these triggers can aid in diagnosis as well as prevention and management of hyperammonemic episodes.

Stressors include:

  • Infections2,4

  • Fever2

  • Vomiting2

  • Gastrointestinal or internal bleeding2

  • Decreased energy
    or protein intake

    (due to fasting pre-surgery, for example)2

    or protein aversion4


  • Surgery under general anesthesia2

  • Chemotherapy or high-dose glucocorticoids2

  • Certain medications

    (mainly valproate and

    L-asparaginase/pegaspargase)2

  • Unusual protein load

    (e.g., due to a barbecue,
    parenteral nutrition)2

  • Prolonged or intense physical exercise2

Laboratory expertise is critical

Misdiagnoses of urea cycle disorders may occur. Testing should be done by hospitals and laboratories that can provide ongoing metabolic investigation and monitoring with speed and accuracy.

Testing for plasma ammonia levels

As soon as hyperammonemia is suspected, plasma ammonia levels should be tested.1,4

Normal levels, according to the Association of Clinical Biochemistry, are:8

  • Premature neonates: < 150 μmol/L
  • Term neonates: < 100 μmol/L
  • Infants: < 40 μmol/L
  • Adults: 11-32 μmol/L

Important considerations:1

  • Proper procedures for obtaining plasma ammonia levels must be followed in order to prevent measurement errors, including false high ammonia levels.
  • Low or slightly elevated ammonia levels should lead to retesting, particularly since ammonia concentrations can fluctuate and may not entirely correlate with already impaired brain function.
  • Management should be guided by the clinical condition of the patient, rather than solely ammonia concentrations.

Emergency management for hyperammonemic crisis

In a hyperammonemic crisis, emergency management procedures should be followed. Refer to the Urea Cycle Disorders Consortium for a complete list of emergency management guidelines, which include:

  • Administration of fluids, dextrose, and interlipids to mitigate catabolism and typical dehydration.
  • Administration of antibiotics plus a septic workup to treat potential triggering events or primary sepsis.
  • Complete protein restriction is recommended to be maintained for 24 to 48 hours.
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Additional biochemical investigations

The causes of hyperammonemia are diverse and include liver failure, infection, medications, and inborn errors of metabolism,9 such as NAGS deficiency. Therefore, once elevated plasma ammonia is confirmed, other laboratory investigations that are necessary for differential diagnosis should quickly follow.

These investigations should include:1

  • Blood glucose
  • Blood gases
  • Electrolytes
  • Lactate
  • Transaminases
  • Plasma amino acids
  • Blood or plasma acylcarnitines
  • Urine amino acids, organic acids, and orotic acid

Testing amino acids

Test results that may be helpful in diagnosing NAGS deficiency include: 1,2,10

  • Elevated plasma glutamine level

  • Low to normal plasma citrulline level

  • Low plasma arginine level

  • Low to normal urine orotic acid level

NAGS deficiency vs. CPS1 deficiency and OTC deficiency

The biochemical profile of NAGS deficiency is identical to the profile for CPS1 deficiency. Moreover, the biochemical profile of NAGS deficiency also approximates a diagnosis of ornithine transcarbamylase (OTC) deficiency, with one difference: urine orotic acid tends to be high in individuals with OTC deficiency.1

DNA test to confirm diagnosis of NAGSD

Final confirmation of NAGS deficiency should be established with molecular testing for the specific DNA mutation.3 For more information, consult the National Center for Biotechnology Information (NCBI) Genetic Testing Registry.

NAGS deficiency is an autosomal recessive disorder; thus, affected individuals carry a mutation in each of their NAGS alleles (each offspring has a 25% chance of inheriting the mutation from both parents), whereas heterozygous carriers are unaffected.11

Genetic testing is therefore important for siblings of individuals diagnosed with NAGS deficiency.

Treatment for hyperammonemia should not be delayed if a UCD is suspected. Cerebral edema occurs early with severe hyperammonemia, and delays in reducing the level of ammonia can lead to serious neurological complications including irreversible brain damage or death.4

References

  1. Haberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170:21-34.
  2. Haberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Sanjurjo Crespo P, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32.
  3. Ah Mew N, Caldovic L. N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment. Appl Clin Gen. 2011;4:127-135.
  4. Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013;40:3-9.
  5. Summar ML. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001;138(1 Suppl):S30-S39.
  6. Summar ML, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001;138(1 Suppl):S6-S10.
  7. Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007;28:754-759.
  8. Hawke L. Ammonia (plasma, blood). The Association for Clinical Biochemistry and Laboratory Medicine. http://www.acb.org.uk/whatwedo/science/amalc.aspx. Published 2012. Accessed December 4, 2017.
  9. Vergano SA, Crossette JM, Cusick FC, Desai BR, Deardorff MA, Sondheimer N. Improving surveillance for hyperammonemia in the newborn. Mol Genet Metab. 2013;110:102-105.
  10. Bachmann C. Inherited hyperammonemias. In: Blau N, Duran M, Blaskovics M, Gibson K, eds. Physician’s Guide to the Laboratory Diagnosis of Metabolic Disease. Berlin, Heidelberg, New York: Springer; 2003:261-276.
  11. Ah Mew N, Lanpher BC, Gropman A, Chapman KA, Simpson KL, Urea Cycle Disorders Consortium, Summar ML. Urea cycle disorders overview. In Pagon RA, Adam MP, Ardinger HH et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2017. http://www.ncbi.nlm.nih.gov/books/NBK1217. Revised June 22, 2017. Accessed December 4, 2017.
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