Urea Cycle Disorders

Urea cycle disorders (UCDs) are caused by genetic defects and result in deficiencies of enzymes and transporters of the urea cycle. As a result of the defects, individuals are unable to rid the body of nitrogen waste. Common symptoms include vomiting, lethargy, seizures, and respiratory alkalosis. Most defects are autosomal recessive and definitive diagnosis is by molecular genetic testing. Treatment aims to reduce ammonia concentration in plasma. In less severe cases, acute episodes can be prevented through dietary restriction of protein. Untreated disease may lead to seizures, coma, or death.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Urea cycle disorders (UCDs) are a group of syndromes resulting from genetic mutations, which cause deficiencies in enzymes and amino acid transporters of the urea cycle, resulting in the accumulation of nitrogenous waste products.

Epidemiology

  • Incidence: 
    • Globally: 1 per 35,000 live births
    • United States: 1 per 8,200 live births
    • Higher in individuals with partial defects
    • Difficult to quantify: Prevalence data is difficult to track.
  • Annual incidence: approximately 113 new cases in the United States and 149 in Europe
  • Symptomatic in the newborn period: approximately 26% of cases
  • Only 2 UCDs are currently detected by newborn screening in the United States.

Etiology

All UCDs stem from genetic abnormalities, which cause deficiencies in enzymes important to the urea cycle:

  • Carbamyl phosphate synthetase I (CPSI) deficiency 
  • N-acetylglutamate synthetase (NAGS) deficiency 
  • Ornithine transcarbamylase (OTC) deficiency 
  • Arginase deficiency
  • Argininosuccinate synthetase (ASS) deficiency (classic/type I citrullinemia) 
  • Argininosuccinate lyase (ASL) deficiency (argininosuccinic aciduria)

All UCDs are inherited as autosomal recessive traits except OTC deficiency (X-linked recessive trait).

Pathophysiology

Normal physiology of urea cycle:

  • Produces amino acids: arginine, ornithine, and citrulline
  • Mechanism for nitrogen clearance via protein breakdown (catabolism)
  • Protein catabolism results in ammonia production.
  • Ammonia is converted to urea.

Impairment of the urea cycle in the liver causes hyperammonemia (ammonia accumulation in the blood). Depending on the severity and age at manifestation, ammonia may cause neurotoxic effects on the brain.

Urea cycle

Schematic diagram of the urea cycle: The blue square indicates the feeder reaction.

Image by Lecturio.

Clinical Presentation

Neonatal period

  • In the case of severe disorder, symptoms typically appear after the 1st 24 hours of life.
  • Symptoms appear after feeding.
  • Commonly misdiagnosed as Reye syndrome or sepsis
  • Symptoms:
    • Irritability
    • Refusal to feed
    • Vomiting
    • Lethargy
    • Seizures
    • Floppiness
    • Respiratory alkalosis
    • Coma

Childhood

  • Mild/moderate cases of UCD present in early childhood. 
  • If the condition remains undiagnosed, hyperammonemia may occur leading to coma and death.
  • Symptoms:
    • Failure to thrive
    • Excessive crying
    • Agitation
    • Self-injurious behaviors
    • Refusal to eat high-protein foods
    • Lethargy
    • Delirium

Adulthood

  • Individuals with mild deficiencies may not be diagnosed during childhood.
  • Symptoms in mild cases may be observed following an episode of viral illness, excessive exercise, drug use (e.g., valproic acid), or childbirth.
  • Symptoms:
    • Slurred speech
    • Disorientation
    • Confusion
    • Agitation
    • Delirium
    • Lethargy
    • Stroke-like symptoms
    • Psychiatric issues like bipolar disorder and schizophrenia

Diagnosis

  • Screen ammonia level if:
    • Positive newborn screen
    • Presenting with clinical symptoms 
    • Positive 3-generation family history: Focus on relatives with neurologic issues.
  • Further workup to rule out UCD if:
    • Ammonia concentration in plasma ≥ 100–150 μmol/L
    • Normal anion gap
    • Normal plasma glucose concentration
  • Plasma amino acid concentrations:
    • Arginine:
      • ↑ Fourfold in arginase deficiency
      • ↓ CPSI deficiency
      • ↓ OTC deficiency
      • ↓ NAGS deficiency
    • Glutamine:
      • ↑ CPSI deficiency
      • ↑ OTC deficiency
      • ↑ NAGS deficiency
    • Citrulline:
      • ↑ ASS deficiency
      • ↑ ASL deficiency
      • ↓ CPSI deficiency
      • ↓ OTC deficiency
      • ↓ NAGS deficiency
    • Argininosuccinic acid:
      • Absent in ASS deficiency
      • ↑ ASL deficiency
  • Urine orotic acid:
    • ↑ OTC deficiency
    • ↓ CPSI deficiency
  • Molecular genetic testing:
    • Primary diagnostic method
    • Superior to enzyme activity as definitive testing method
  • Enzyme activity assay
  • Newborn screening: inconsistently performed in the United States

Management

Treatment should be tailored to the specific disorder:

Acute management

  • Physiologic stabilization:
    • Intravenous (IV) fluids
    • Cardiac vasopressors
  • Discontinuation of protein diet for 12–24 hours
  • To reduce ammonia concentration in plasma:
    • Dialysis
    • Hemofiltration
  • To excrete excess nitrogen through an alternative pathway to the urea cycle:
    • IV arginine hydrochloride
    • IV sodium benzoate
    • IV sodium phenylacetate 
  • Stable individuals: enteral nutrition with calories from glucose, fats, and essential amino acids (treats protein catabolic state)
  • Unstable individuals: total parenteral nutrition
  • Monitor with continuous EEG to detect subclinical seizures.

Continuing therapy after stabilization

  • Initiate enteral feeds with protein-free nutrition:
    • Specialty formula for infants
    • Supplement with mixed amino acids
  • Closely monitor daily protein intake: 
    • Sufficient for normal growth based on age
    • Transition to oral medication.
    • Closely follow serum level of essential amino acids.

Untreated hyperammonemia

Untreated hyperammonemia may cause:

  • Uremic encephalopathy 
  • Seizures 
  • Coma
  • Death

Differential Diagnosis

  • Fatty acid oxidation defects: genetic disorders resulting in failure of fatty acid transport into the mitochondria or metabolism by the mitochondria. Presentation is variable, but the most severe forms present only a few days after birth. Individuals present with low muscle tone, retinal degeneration, liver failure, cardiomyopathy, fatigue, and sudden death in more severe forms. Laboratory findings include hyperammonemia, hypoglycemia, and elevated liver function tests (AST/ALT). Diagnosis is usually through newborn screening.
  • Disorders of pyruvate metabolism: a group of inherited disorders caused by deficiencies of enzymes in the pyruvate metabolism pathway. Pyruvates are substrates created during protein and carbohydrate metabolism, which function as a cellular energy source. Depending on the severity, symptoms may present early in childhood or infancy and may include failure to thrive and/or seizures. Definitive diagnosis is obtained by enzyme analysis of cultured skin fibroblasts or DNA analysis.
  • Liver and biliary tract disease: caused by multiple etiologies including biliary atresia, acute liver failure, and cirrhosis of the liver. Failure of liver function may result in hyperammonemia, which mimicks the lab findings and symptoms of UCD.

References

  1. Ah Mew N., Simpson K.L., Gropman A.L., Lanpher B.C., Chapman K.A., Summar M.L. (2003). Urea Cycle Disorders Overview. In: Adam M.P., Ardinger H.H., Pagon R.A., et al., eds. GeneReviews. Seattle (WA): University of Washington, Seattle. https://pubmed.ncbi.nlm.nih.gov/20301396/
  2. Gardeitchik T., Humphrey M., Nation J., Boneh A. (2012). Early clinical manifestations and eating patterns in patients with urea cycle disorders. J Pediatr. 328-32. https://pubmed.ncbi.nlm.nih.gov/22424941/ 
  3. Summar M.L., Dobbelaere D., Brusilow S., Lee B. (2008). Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. https://pubmed.ncbi.nlm.nih.gov/18647279/ 
  4. Marshall L., Summar, M.L., Stefan Koelker, S., Debra Freedenberg, D., et al. (2013). The incidence of urea cycle disorders. Molecular Genetics and Metabolism, Volume 110, Issues 1–2. Pages 179–180. https://www.sciencedirect.com/science/article/pii/S1096719213002333

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details