About NAGS deficiency

In the United States, the incidence of urea cycle disorders (UCDs) is estimated to be 1 in every 35,000 births, or about 113 new patients per year across all age groups.1 NAGS deficiency, the rarest of the UCDs, is an autosomal recessive disorder.2

NAGS deficiency is the only inherited urea cycle disorder that can be specifically and effectively treated by a drug.2

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NAGS deficiency pathophysiology

The urea cycle

The urea cycle is the process by which the waste nitrogen (ammonium) that is produced by the catabolism of proteins is excreted as urea via the kidneys. Urea is produced primarily in the liver, which acts as the main ammonia detoxification center.3,4

The biochemical urea cycle pathway involves 5 catalytic enzmes and a cofactor producing enzyme: N-acetylglutamate synthase (NAGS), as well as 2 transporters: ornithine translocase and citrin.5

Enzymes of the urea cycle:

NAGS: N-acetylglutamate synthase (produces co-factor NAG)
CPS 1: carbamoyl phosphate synthetase 1
OTC: ornithine transcarbamylase
ASS: argininosuccinate synthetase
ASL: argininosuccinate lyase
ARG1: arginase

Disruption due to NAGS deficiency

The urea cycle involves many sequential steps:

  • The process begins with NAGS, which catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A.2,6
  • NAG then activates CPS 1, the first and rate-limiting enzyme of the urea cycle.2,6
  • In the absence of NAG, there is no activation of CPS 1 to trigger the urea cycle; thus, a deficiency of NAGS may result in hyperammonemia.2

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.7

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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 intoxication8
  • Acute encephalopathy8
  • Seizures (generally not isolated but along with altered level of consciousness)2,8
  • Hypotonia3
  • Multiorgan failure8
  • Peripheral circulatory failure8
  • Respiratory distress, hyperventilation/respiratory alkalosis3,8
  • Sepsis-like picture, including temperature instability, hypo- or hyperthermia3,7,8

Gastrointestinal Presentations

  • Vomiting, progressive poor appetite or poor feeding2,7,8

Additional considerations

  • Newborns with NAGSD typically appear normal at birth because the maternal urea cycle clears surplus nitrogen from the fetus.7
  • Plasma ammonia level increases can occur as early as 24 hours after birth due to postnatal catabolism.7
  • Neonatal presentations can be especially dangerous when hyperammonemia begins to develop after hospital discharge.
  • As plasma ammonia levels build up, cerebral edema, respiratory arrest, lethargy, coma, irreversible brain damage, and death can quickly follow earlier symptoms.1,3,4,7

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, lethargy, dizziness8,9

    Migraine-like headaches, tremor, ataxia, dysarthria8

    Intellectual/learning disabilities, neurodevelopmental delay3,8

    Seizures7

    Coma6

  • Gastrointestinal Presentations

    Abdominal pain, nausea, vomiting2,3,8

    Protein aversion, self-selected low-protein diet8

    Failure to thrive8

    Hepatomegaly, elevated liver enzymes8

  • Psychiatric Presentations

    Hyperactivity, mood alteration, behavioral changes, aggressiveness, combativeness2,8

Additional considerations

  • Hyperammonemia can occur for the first time at any age and is an emergency situation. Individuals with partial NAGS deficiency may develop symptoms early in life or well into adulthood.7
  • Severe symptoms may develop suddenly in someone who was previously healthy. Or less severe, chronic symptoms may occur for years.4,7
  • Symptoms tend to develop with increased catabolic stress caused by infection, starvation, surgery, or trauma, for example. Symptoms also tend to be episodic and neurological in origin.2,3,7

Triggers

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.

Triggers include:2,4


  • Infections


  • Fever


  • Vomiting


  • Gastrointestinal or internal bleeding


  • Decrease energy or protein intake (e.g., due to fasting pre-surgery) or protein aversion



  • Surgery under general anesthesia


  • Chemotherapy or high-dose glucocorticoids


  • Certain medications (mainly valproate and L-asparaginase/ pegaspargase)


  • Unusual protein load (e.g., due to a barbecue, parenteral nutrition)


  • Prolonged or intense physical exercise

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.3,7

Normal levels, according to the Association of Clinical Biochemistry, are:10

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

Important considerations:7

  • 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 acute hyperammonemia in patients with NAGS deficiency

In a hyperammonemic crisis, emergency management procedures should be followed:12

  • Contact a physician and medical team experienced in metabolic disorders for instructions, and arrange for emergency transport, if needed.
  • Initiate CARBAGLU treatment as soon as the diagnosis of NAGS deficiency is suspected, which may be as soon as at birth.
  • Administer CARBAGLU with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and protein restriction.

For a more comprehensive discussion of emergency management procedures, refer to the Urea Cycle Disorders Consortium.


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Additional biochemical investigations

The causes of hyperammonemia are diverse and include liver failure, infection, medications, and inborn errors of metabolism,11 such as NAGS deficiency. Therefore, once elevated plasma ammonia is confirmed, other laboratory investigations that are necessary for differential diagnosis should quickly follow.7,10

These investigations should include:7

  • Blood glucose
  • Blood gases
  • Plasma electrolytes
  • Plasma lactate
  • Liver 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:7,8

  • High plasma glutamine
  • Absent to low-normal plasma citrulline
  • Low plasma arginine
  • Normal urine orotic acid

NAGS deficiency vs. CPS 1 deficiency and OTC deficiency

The biochemical profile of NAGS deficiency is identical to the profile for CPS 1 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.2 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.5

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.3

REFERENCES

  1. Summar ML, Koelker A, Freedenberg D, Le Mons C, Haberle J, Lee H-S, Kirmse B, European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD), Urea Cycle Disorders Consortium (UCDC). The incidence of urea cycle disorders. Mol Genet Metab. 2013;110:179-180.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007;28:754-759.
  7. Haberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170:21-34.
  8. 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.
  9. Summar ML. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001;138(1 Suppl):S30-S39.
  10. 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 March 22, 2021.
  11. 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.
  12. CARBAGLU [Package Insert]. Lebanon, NJ: Recordati Rare Diseases; 2021
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