Recognize the Signs of Urea Cycle Disorders and Hyperammonemia

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Overview of Hyperammonemia in Urea Cycle Disorders

What is a Urea Cycle Disorder?

The urea cycle, located in liver cells, is a series of biochemical steps that detoxify nitrogen (ammonia) in the body. Ammonia is the normal byproduct that results when protein from food is broken down into amino acids in the body, or the normal breakdown of musculoskeletal tissue. Urea cycle disorders (UCD) result in deficiencies in the urea cycle and its ability to detoxify ammonia. The result is an elevation of toxic ammonia levels in the blood, called hyperammonemia. Untreated, hyperammonemia can cause brain damage, coma and death.

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What are the symptoms?

Newborns with severe urea cycle disorders become catastrophically ill with symptoms that mimic sepsis -- failure to feed, lethargy, respiratory distress, seizures and ultimately coma.

Children and adults with milder (or partial) urea cycle enzyme deficiencies may go years without a diagnosis, until a trigger -- a high protein meal, viral illness, excessive exercise or calorie deficiency -- causes excessive ammonia to be produced in the body, resulting in critical elevations of blood ammonia levels.

The symptoms may be subtle and go unrecognized for years until a trigger results in catastrophic hyperammonemia. Children and adults with undiagnosed urea cycle disorders may experience only occasional subtle symptoms -- nausea, gastric distress, irritability, fatigue, lethargy -- or a spectrum of issues from mild to severe developmental delay, learning disabilities, hyperactivity, autism, seizures, behavioral abnormalities, psychiatric disturbances, mood changes, migraine-type headaches, cyclic vomiting.

RESOURCE: Recognizing Hyperammonemia

Newborns

Infants with a severe urea cycle disorder often initially appear normal but within 12-72 hours rapidly develop symptoms:

Refusal to feed Vomiting

Irritability progressing to lethargy

and somnolence

Hypothermia

Seizures

Hyperventilation leading to

respiratory alkalosis

Neurologic posturing

Coma

Hypoventilation with respiratory arrest  

Because newborns are usually discharged from the hospital within one to two days after birth, the symptoms of a urea cycle disorder may be subtle until the child is at home and may not be recognized in a timely manner by the family or medical professionals. Very early symptoms in an infant with hyperammonemia can be non-specific. Sepsis is often suspected. It is recommended that serum ammonia level be included in standard sepsis workup in order to quickly detect hyperammonemia in these infants.

Children and Adults

In children and adults with mild to moderate (partial) urea cycle enzyme deficiencies, the first recognized episode may be delayed for months or years. Although the symptoms vary, a hyperammonemic episode may be marked by a spectrum of symptoms:

Loss of appetite Vomiting
Lethargy Behavioral abnormalities
Agitation Sleep disorder
Confusion Delusions, hallucinations, psychosis
Bizarre/unusual behavior Stroke-like symptoms

Recommendations

1. Plasma ammonia measurement is a simple yet important screening in the ED for patients with unexplained stupor or delirium. Recognizing the symptoms of the disease is often delayed and/or mistaken.4

2. Although UCD is usually identified in early childhood, partial or mild forms may not be recognized until unmasked by an environmental trigger that can lead to catastrophic hyperammonemic crisis.14

3.  Altered consciousness should always lead to blood ammonia measurement.21

4.  Ornithine transcarbamylase deficiency should be suspected in adult patients who develop recurrent hyperammonemia and encephalopathy following bariatric surgery.5

5.  The diagnosis of NAGS or OTC deficiency should be considered in nonhepatic adult patients with hyperammonemic coma, particularly if they have a history of protein avoidance and neurological symptoms.13

Diagnosis/testing

The diagnosis of a urea cycle disorder is based on evaluation of clinical, biochemical, and molecular data including:

1) Plasma ammonia level: Sample must be placed immediately on ice and run STAT or false elevations can occur. Obtaining Accurate Ammonia Levels

2) Plasma quantitative amino acid analysis can be used to help diagnose a specific urea cycle disorder.

3) Urinary orotic acid is measured to distinguish CPSI deficiency and NAGS deficiency from OTC deficiency.

4) Molecular genetic testing.

TREATMENT INFORMATION

Treatment options for Urea Cycle Disorders

New England Consortium of Metabolic Programs Treatment Guidelines

Rare Diseases Clinical Research Network Urea Cycle Disorders Consortium

References

  1. Hainline B, Clay A.  Hyperammonemia in the ICU. Chest 2007;132;1368-1378
  2. Lien J,  Nyhan WL, Barshop BA. Fatal Initial Adult-Onset Presentation of Urea Cycle Defect. Arch Neurol. 2007; 64(12):1777-1779
  3. Aronson PL, Mistry RD. Ornithine transcarbamylase deficiency presenting as hepatitis. Ped Emerg Care. 2011 Jun;27(6):527-9
  4. Weng TI, Shih FF, Chen WJ, Unusual causes of hyperammonemia in the ED. Am J Emerg Med. 2004 Mar;22(2):105-7
  5. Hu, WT, Kantarci, OH, Merritt II, JL, McGrann , Dyck PJB, Lucchinetti CF, Tippmann-Peikert, M. Ornithine Transcarbamylase Deficiency Presenting as Encephalopathy During Adulthood Following Bariatric Surgery. Arch Neurol. 2007;64:126-128
  6. Fenves.  Fatal Hyperammonemic Encephalopathy After Gastric Bypass Surgery. Am J Med. 2008 Jan;121(1):e1-e2
  7. Enns, GM, O’Brien, WE, Kobyashi K, Shinzawa H, Pellegrino J. Postpartum “Psychosis” in Mild Argininosuccinate Synthetase Deficiency. Obstetrics and Gynecology, Vol. 105, No. 5, Part 2, May 2005
  8. Rimbaux S, Hommet C, Perrier D, Cottier JP, Legras A, Labarthe F, Lemarcis L, Autrer A, Maillot F. Adult onset ornithine transcarbamylase deficiency: an unusual cause of semantic disorders.  J. Neurol. Neurosurg. Psychiatry 2004;75;1073-1075
  9. Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith M,  Summar M. Urea Cycle Disorders: Clinical Presentation Outside the Newborn Period. Crit Care Clin 21 (2005) S9–S17
  10. Priester T, Khoo, TK, Fernandez-Perez E, Regner K, Tracy J, Mitchell S, Summar M, Babovic-Vuksanovic D. Hyperammonemia from a urea cycle disorder presenting in adulthood. Open Critical Care Medicine Journal. 2009;2;9-12
  11. Enns G, Packman S. Diagnosing inborn errors of metabolism in the newborn: clinical features. NeoReviews.  2001;2;183-190
  12. Barrueto F, Hack J. Hyperammonemia and coma without hepatic dysfunction induced by valproate therapy.  Academic Emergency Medicine. October 2001, Vol. 8, Issue 10, 999-1001
  13. Gaspari R, Arcangeli A, Mensi S, Schembri-Wismayer D, Tartaglione T, Antuzzi D, Conti G, Proletti R. Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma. Annals of Emergency Medicine. Jan 2003; Vol. 41, Issue 1;104-109
  14. Houston B, Reiss K, Merlo C. Healthy, but comatose. Am J Med. 2011 Apr;124(4):303-5.
  15. Summar M, Barr, F, Dawling S, Smith W, Lee B, Singh R, Rhead W, Sniderman-King L, Christman B. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 21 (2005) S1–S8
  16. Schmidt J, Kroeber K,  Irouschek A, Birkholz T, Schroth M, Albrecht S. Anesthetic management of patients with ornithine transcarbamylase deficiency.  Pediatric Anesthesia 2006 16: 333–337
  17. Scaglia F, Zheng Q, O’Brien W, Henry J, Rosenberger J, Reeds P, Lee B.  An Integrated Approach to the Diagnosis and Prospective Management of Partial Ornithine Transcarbamylase Deficiency. Pediatrics 2002;109;150-152
  18. Enns, GM. Neurologic Damage and Neurocognitive Dysfunction in Urea Cycle Disorders. Semin Pediatr Neurol 15:132–139
  19. Gropman A, Rigas A.  Neurometabolic disorders: urea cycle disorders, outcomes, development and treatment.  Pediatric Health (2008)2(6)
  20. Krivitzky L, Babikian T, Lee H,  Hattiangadi Thomas N, Burk-Paull K, Batshaw ML. Intellectual, Adaptive, and Behavioral Functioning in Children with Urea Cycle Disorders.  Pediatr Res. 2009 July ; 66(1): 96–101 
  21. Seashore, MR. What’s new in the urea cycle: new research and treatments. Grand Rounds Presentation. Yale University School of Medicine, Department of Genetics. June 2010
  22. Testai FD, Gorelick PB, Inherited Metabolic Disorders and Stroke Part 2 Homocystinuria, Organic Acidurias, and Urea Cycle Disorders. Arch Neurol/Vol 67 (No. 2), Feb 2010 148-153
  23. NIH Rare Diseases Clinical Research Network Urea Cycle Disorders Consortium http://rarediseasesnetwork.epi.usf.edu/ucdc/physicians/index.htm
  24. New England Consortium of Metabolic Programs http://newenglandconsortium.org/for-professionals/acute-illness-protocols/urea-cycle-disorders/ornithine-transcarbamylase-deficiency-otc/

 

 

 

 

Symptoms of Hyperammonemia

Newborns

Refusal to feed

Vomiting

Irritability

Lethargy/somnolence

Respiratory alkalosis

Hypoventilation/respiratory
   arrest

Hypothermia

Seizures

Neurologic posturing

Coma

Suspected sepsis

Children/Adults

Loss of appetite
Vomiting
Lethargy

Disorientation

Confusion
Agitation

Combativeness

Stroke-like symptoms
Behavioral abnormalities
Sleep disorder
Delusions, hallucinations, psychosis

Triggers for hyperammonemia in urea cycle disorders

High protein load or
supplements

Catabolic state

Steroid administration

Virus or infection

Excessive exercise

Gastric bypass surgery

Synposis and Diagnostic FlowChart


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