Clinical Characteristics

Severity of a urea cycle disorder is influenced by the position of the non-functional protein in the urea cycle pathway (see Figure 1) and the clinical consequences of the pathogenic variant.

Severe deficiency or total absence of activity of any of the first four enzymes in the pathway (CPS1, OTC, ASS, and ASL) or the cofactor producer (NAGS) results in the accumulation of blood ammonia concentration and other precursor metabolites during the first few days of life. Because there is no effective secondary in vivo clearance system for ammonia, complete disruption of this pathway results in the rapid ex utero increase of blood ammonia concentration and development of related clinical manifestations.

Neonates with a urea cycle disorder appear normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma due to hyperammonemia. Because neonates are often discharged from the hospital within two days after birth, the manifestations of a urea cycle disorder often develop when the newborn is at home and may not be recognized in a timely manner by the family and/or primary care physician.

The typical initial manifestations in a newborn with hyperammonemia are nonspecific [Raina et al 2020] and include the following:

• Failure to feed and vomiting
• Loss of thermoregulation with a low core temperature
• Irritability
• Somnolence

Manifestations progress from somnolence to lethargy and coma.

• Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brain stem.
• About 50% of neonates with severe hyperammonemia may have seizures, some without overt clinical manifestations. Seizures are common in acute hyperammonemia and may result from cerebral damage. Subclinical seizures are common in acute hyperammonemic episodes, especially in neonates; their effects on cerebral metabolism in an otherwise compromised state should be addressed. These seizures may be seen during the rise of blood glutamine concentration even before blood ammonia concentrations peak [Wiwattanadittakul et al 2018].
• Hyperventilation, secondary to the effects of hyperammonemia on the brain stem, is a common early finding with hyperammonemia that results in respiratory alkalosis [Martin-Hernandez et al 2014]. Metabolic acidosis with an increased anion gap is typically not present in individuals with a urea cycle disorder.
• Hypoventilation and respiratory arrest follow as pressure on the brain stem increases.

When urea cycle enzyme defects are partial (i.e., some residual enzyme activity is present), neonatal hyperammonemia is typically averted. Instead, hyperammonemic episodes may first occur at almost any age due to illness, stress (e.g., surgery, prolonged fasting, the peripartum period), or excessive protein intake.

• Manifestations of hyperammonemia may be different from those in neonates. Although clinical manifestations vary somewhat depending on the specific urea cycle disorder, hyperammonemia may result in loss of appetite, vomiting, lethargy, and neurobehavioral/psychiatric manifestations that can include sleep disorders, delusions, hallucinations, and/or psychosis.
• Correct diagnosis of the manifestations of recurrent mild episodes of hyperammonemia may be delayed for months or years.
• Children and adults, in whom cranial sutures are typically closed, are at a higher risk for rapid neurologic deterioration due to the cerebral edema that results from increased blood ammonia concentration.
• Acute liver failure may also be a presenting feature [Bigot et al 2017].
• Some individuals with "mild" or apparently "asymptomatic" OTC deficiency, most often women, may in fact display neurocognitive or neurofunctional differences without evidence of elevated ammonia or elevated glutamine [Sen et al 2021].

Defects in the final enzyme in the pathway (ARG1) cause hyperargininemia, a more subtle disorder involving neurologic manifestations and, less frequently, neonatal hyperammonemia (see Arginase Deficiency).

Defects in the two amino acid transporters (ORNT1 and citrin) may cause hyperammonemia. However, ORNT1 deficiency (see Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome) may also present with chronic liver dysfunction. Citrin deficiency typically only presents with hyperammonemia in adolescents or adults; however, it may present in infants as neonatal intrahepatic cholestasis and in older children as poor weight gain and/or poor linear growth. Unlike all other urea cycle disorders, citrin deficiency is treated with a high-protein, high-fat, low-carbohydrate diet.

Neurologic aspects of urea cycle disorders. Neurologic involvement is both common and central to the clinical presentation of urea cycle disorders, with findings that range from acute, life-threatening encephalopathy to long-term neurodevelopmental disabilities.

Acute neurologic considerations include:

• Cerebral edema. Acutely elevated ammonia concentration leads to increased glutamine content in astrocytes, causing them to swell [Braissant et al 2013]. This can result in cerebral edema, increased intracranial pressure, and risk of brain herniation. Initially, hyperventilation and respiratory alkalosis may occur, followed by hypoventilation and apnea.
• Seizures. Both convulsive and subclinical seizures are common in acute hyperammonemia and may even occur after ammonia concentrations have normalized [Wiwattanadittakul et al 2018, Chanvanichtrakool et al 2024]. Although interburst interval duration on EEG correlates with the degree of hyperammonemia, it occasionally may result from cerebral dysfunction from other brain pathology; thus, continuous EEG monitoring may be valuable in managing individuals with hyperammonemia.

Long-term neurologic considerations include:

• Cognitive abilities. Neuropsychological deficits in urea cycle disorders are common, particularly in motor/performance domains. Although adults generally show worse performance involvement than younger individuals, it is unclear if this is due to age-related decline or better care for younger individuals. Mean scores on tests of development, intelligence, and adaptive behavior by urea cycle disorder type and by age category are reviewed in Waisbren et al [2016] (full text) and Waisbren et al [2019] (full text). The cognitive deficits can range from mild impairment in executive function, working memory, attention, and fine motor skills in individuals with a urea cycle disorder with non-neonatal mild disease to profound intellectual disability and spastic quadriplegia in those with severe neonatal-onset hyperammonemia [Sen et al 2022]. In fact, some individuals with OTC deficiency who are considered to be "asymptomatic" actually exhibit subtle deficits affecting working memory and cognitive flexibility despite having normal blood ammonia concentrations [Sen et al 2024].
• Seizure disorders. Both absence and overt seizure disorders are common in urea cycle disorders [Waisbren et al 2019, Kido et al 2021, Sen et al 2022] and may develop even in the absence of a prior overt hyperammonemic episode, especially in individuals with ASL deficiency [Waisbren et al 2019].
• Behavioral and psychiatric comorbidities. Attention-deficit/hyperactivity disorder and behaviors associated with autism spectrum disorder are common as well as anxiety, depression, social difficulties, and, in some instances, psychosis [Waisbren et al 2019]. These need to be assessed in all individuals with a urea cycle disorder.

Biochemical Testing

Elevated Ammonia in the Newborn

An elevated blood ammonia concentration in a newborn is highly suggestive of an inherited metabolic disorder, including a urea cycle disorder.

The following may be helpful in determining the likelihood of a urea cycle disorder:

• Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder.
• Metabolic acidosis with a wide anion gap often suggests a cause other than a urea cycle disorder, such as an organic acidemia. However, septic newborns who have a urea cycle disorder can present with metabolic acidosis.

Elevated blood ammonia concentration in a newborn should also prompt consideration of additional investigations: quantitative analysis of plasma amino acids and urine organic acids and acylcarnitines.

Respiratory alkalosis and/or an unusually low blood urea nitrogen (BUN) concentration are often the first identified non-NBS laboratory abnormality seen in acutely ill newborns with a urea cycle disorder. These laboratory abnormalities, in addition to the clinical manifestations described in Section 1, should prompt measurement of blood ammonia concentration, as blood ammonia concentration of 150 μmol/L or higher in a newborn associated with a normal anion gap and a normal blood glucose concentration is a strong indication of a urea cycle disorder [Häberle et al 2019]. Conversely, a markedly elevated BUN would not suggest the diagnosis of a urea cycle disorder.

Figure 2 highlights the use of the following recommended diagnostic tests if a primary urea cycle disorder is suspected.

Figure 2.

Testing used in the diagnosis of urea cycle disorders * If DNA testing is not informative, enzymatic testing is available for these disorders (see Evaluation Strategies).

• Quantitative plasma amino acid analysis can be used to arrive at a tentative diagnosis. Note that as the liver is not fully mature at birth, affected newborns often have quite different blood amino acid concentrations from those of older children and adults.
• Urine amino acid analysis may be used to identify the presence of urine homocitrulline, observed in HHH syndrome (ORNT1 deficiency). Because the increased concentration of argininosuccinate in urine is more pronounced than that in plasma, the urine amino acid profile may be helpful when small peaks of argininosuccinate or its anhydrides are difficult to resolve on plasma amino acid analysis.

Some helpful hints [Häberle et al 2019]:

• Only the following urea cycle disorders have a specific biochemical pattern:
  • ARG1 deficiency: high plasma arginine concentration
  • ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
  • ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
  • Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
  • HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
  Note: Blood concentrations of glutamine and alanine that serve as storage forms of waste nitrogen are also frequently elevated.
• Urinary orotic acid concentration is used to distinguish OTC deficiency from CPS1 deficiency and NAGS deficiency based on the following findings:
  • Normal or low in CPS1 deficiency and NAGS deficiency
  • Significantly elevated in OTC deficiency
  Note: Urinary orotic acid concentration can be increased in citrullinemia type I as well as in ARG1 deficiency or ORNT1 deficiency due to insufficient substrate for the OTC enzyme. Orotic acid is thus increased due to excess carbamoyl-phosphate entering the de novo pyrimidine biosynthetic pathway instead. Other pyrimidines such as urinary orotidine and uracil may also be elevated [Alsharhan et al 2020].

Molecular Genetic Testing

Molecular genetic testing (i.e., DNA-based testing) is the primary method of diagnostic confirmation for all eight urea cycle disorders. Molecular testing has supplanted measurement of enzyme activity as the definitive diagnostic test. However, enzymatic testing remains available for ARG1 deficiency (see Enzyme Activity) and may be helpful if DNA-based investigations are not informative. While clinical testing for other enzymes was previously performed, there are no US-based laboratories currently offering this testing.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Enzyme Activity

If molecular testing is uninformative, ARG1 deficiency can be diagnosed by assay of enzyme activity in erythrocytes.

Treatment of Hyperammonemia

Acute care of an individual with a urea cycle disorder should be provided by a team coordinated by a metabolic specialist in a tertiary care center. It is critical to stabilize the individual before transfer to a tertiary care center.

One example of a protocol is: Neonate/Infant/Child with Hyperammonemia — New England Consortium of Metabolic Program.

Rapidly return plasma ammonia concentrations to normal physiologic levels. Given the toxic effects of increased plasma ammonia concentrations, a rapid reduction to normal physiologic levels is necessary even without a definitive diagnosis. Kidney replacement therapies (KRTs) can most rapidly reduce plasma ammonia concentration.

• Various KRT modalities have been used to treat hyperammonemia, each with their own advantages and disadvantages. As KRT is a higher-risk technical procedure, the choice of KRT modality should be primarily guided by the available institutional expertise and resources [Gupta et al 2016].
• Intermittent hemodialysis (iHD) has been used successfully for rapid reduction of plasma ammonia concentrations [Gupta et al 2016]. Post-iHD rebound hyperammonemia occurs because of the delayed shift of ammonia from body compartments into the blood. To minimize this effect, iHD can be used followed by continuous kidney replacement therapy (CKRT) (typically 24 hours) in an intensive care unit (ICU) in children needing significant reduction in blood ammonia concentration.
• High-dose CKRT has been shown to achieve ammonia clearance rates comparable to those seen with iHD [Spinale et al 2013]. Due to its feasibility and effectiveness, high-dose CKRT has become the preferred treatment modality in this population [Häberle et al 2019, Raina et al 2020]. CKRT offers significant advantages over iHD by minimizing cardiovascular complications and decreasing the risk of rebound hyperammonemia. Its continuous nature prevents drastic fluid and osmotic shifts, thereby minimizing the potential to worsen intracranial pressure, a critical factor in individuals with hyperammonemia [Raina et al 2020].
  Note: Because clearance with peritoneal dialysis is substantially lower than with hemodialysis, hemodialysis (if available) is typically preferred [Raina et al 2020].
• Another hybrid approach consisting of iHD or CKRT with extracorporeal membrane oxygenation (ECMO) presents an option for neonates with cardiorespiratory failure and severe hemodynamic instability. This combination addresses the limitations of limited catheter sizes and blood flow rates that hinder ammonia clearance in neonates. However, the method also carries an increased risk of bleeding and cerebrovascular events, particularly in low-birth-weight neonates.

Perform pharmacologic interventions to allow alternative pathway excretion of excessive nitrogen (see Table 4).

• Nitrogen scavenger therapy (sodium phenylacetate and sodium benzoate) is available as an intravenous infusion for acute management and an oral preparation for long-term maintenance.
  Note: Although sodium phenylacetate and sodium benzoate can be infused through a peripheral IV, central access is preferred. As both medications are sodium salts, reduction of sodium from other infused sources or at least monitoring of sodium is recommended.
• Deficient urea cycle intermediates need to be replaced depending on the diagnosis; these can include arginine (IV/oral/enteral) and/or citrulline (oral/enteral).
  Note: Continuous arginine hydrochloride (HCl) infusion requires central access as extravasation from a peripheral IV has on multiple occasions resulted in severe cutaneous necrosis. Infused arginine may also cause hypotension, as it is a precursor to nitric oxide [Mehta et al 1996].

Treat catabolic state with calories from glucose, fats, and essential amino acids. Nutritional support, outlined below, is essential to reverse catabolism and prevent further elevations in ammonia.

One hundred percent of estimated energy needs should be provided through non-protein sources (carbohydrate and fat) to reverse catabolism.

Initial elimination of protein from the diet should not exceed 24 hours and prolonged restriction (>48 hours) should be avoided, as depletion of essential amino acids results in protein catabolism and nitrogen release. Frequent (often daily if available) quantitative assessments of plasma amino acid concentrations can help optimize nutritional management, permitting the clinician to maintain adequate endogenous levels of essential amino acids without having to provide excess nitrogen. Maintenance of appropriate plasma concentrations of essential amino acids is necessary to reverse the typical catabolic state, because most acutely ill individuals either already present with essential amino acid deficiency or will quickly become deficient.

Reintroduction of protein depends on the individual's clinical state and age. The goal for total protein intake should be to meet the Dietary Recommended Intake for age, which may require a combination of natural protein and essential amino acid medical food. If dialysis has been utilized, reintroduction may be more rapid to prevent rebound hyperammonemia resulting from catabolism. If dialysis has not been utilized, reintroduction of protein (essential amino acids and/or natural protein) may need to start lower and be more gradual.

Although enteral nutrition is preferred, intravenous (total parenteral nutrition) is an option when the individual is so clinically unstable that adequate enteral intake is not possible.

The placement of a nasogastric/jejunal tube at admission is warranted for slow drip administration of solutions of essential amino acids and infant formulas and administration of medications and supplements such as N-carbamylglutamate (analog of N-acetylglutamate) and L-citrulline.

Multiple other strategies to address catabolism can be used, including low-dose continuous infusion of insulin with maintenance of adequate glucose delivery by providing continuous delivery of high-carbohydrate-containing fluids; however, caution is advised, since affected individuals are often exquisitely sensitive to either glucose or insulin.

Reduce the risk for neurologic damage

• Use intravenous fluids (≥10% dextrose with appropriate electrolytes) for physiologic stabilization.
• Consider the use of continuous bedside EEG to detect subclinical seizures. Note: Individuals in a coma may have subclinical seizures that are non-convulsive and, therefore, not apparent.

Note: In individuals with prolonged hyperammonemic coma and evidence of severe neurologic damage, the relative risks versus benefits of all the treatments discussed above should be considered on an individual basis.

Disorder-Specific Treatments

Mode of Inheritance

Ornithine transcarbamylase (OTC) deficiency is inherited in an X-linked manner.

N-acetylglutamate synthase (NAGS) deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency, citrullinemia type I (ASS deficiency), argininosuccinate lyase (ASL) deficiency, arginase (ARG1) deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (ORNT1 deficiency), and citrin deficiency are inherited in an autosomal recessive manner.

Once the molecular and/or biochemical diagnosis of a specific urea cycle disorder has been established in an affected family member, genetic counseling for that condition is indicated.

X-Linked Inheritance – Risk to Family Members

See Ornithine Transcarbamylase Deficiency, Genetic Counseling.

Autosomal Recessive Inheritance – Risk to Family Members

Note: A basic view of autosomal recessive inheritance is provided below; genetic counseling issues specific to individual urea cycle disorders are not addressed.

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a pathogenic variant in a gene associated with autosomal recessive urea cycle disorders (i.e., ARG1, ASL, ASS1, CPS1, NAGS, SLC25A13, or SLC25A15).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a pathogenic variant associated with an autosomal recessive urea cycle disorder, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with an autosomal recessive urea cycle disorder are obligate heterozygotes (carriers) for a pathogenic variant in a urea cycle disorder-related gene.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The American College of Medical Genetics includes OTC deficiency and ASL deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [Gregg et al 2021].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the urea cycle disorder-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider the use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. If the familial variant(s) are known, molecular genetic prenatal testing of both male and female fetuses at risk may be performed via amniocentesis or chorionic villus sampling to allow prompt institution of appropriate treatment/surveillance before a metabolic crisis occurs after birth.

Newborn sib. Evaluations of a newborn sib include the following:

• Prompt evaluation of newborn screening results (if performed) and collection and rapid analysis of blood ammonia and amino acids; consider delivery at tertiary care center where such tests are available on-site.
• Molecular genetic testing if a molecular diagnosis has been established in an affected family member.
• If the familial causative pathogenic variant in the family is unknown, elevated ammonia level or a diagnostic pattern of abnormal plasma amino acids and urine orotic acid (see Figure 2) may confirm the diagnosis.

In general, for children with neonatal-onset disease, such testing cannot be performed rapidly enough to prevent a metabolic crisis. Therefore, preventive measures at birth should be instituted until the diagnosis can be ruled out.

Hospital delivery at a specialized center with rapid neonatal transfer is recommended for delivery of a fetus at risk for an early-onset urea cycle disorder. At-risk newborns should be administered intravenous glucose with electrolytes, protein-free feeds, and alternative pathway medications (e.g., sodium phenylbutyrate or sodium benzoate and L-arginine therapy) as well as either citrulline (for proximal urea cycle disorders [ASS deficiency and ASL deficiency]) or arginine (for distal urea cycle disorders [OTC deficiency, CPS1 deficiency, and NAGS deficiency]; not for ARG1 deficiency). Frequent ammonia monitoring and urgent amino acid analysis guide treatment. A detailed protocol is described in Häberle et al [2019].

Author Notes

Nicholas Ah Mew (gro.lanoitansnerdlihc@wemhan) is interested in hearing from clinicians treating families affected by urea cycle disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Additionally, contact Dr Ah Mew to inquire about review of variants of uncertain significance in urea cycle disorder-related genes.

Author History

Nicholas Ah Mew, MD (2014-present)
Kimberly A Chapman, MD, PhD; Children's National Health System (2011-2025)
Andrea Gropman, MD (2011-present)
Aadil Kakajiwala, MD (2025-present)
Brendan C Lanpher, MD; Mayo Clinic (2011-2025)
Uta Lichter-Konecki, MD, PhD; Columbia University (2011-2014)
Erin L MacLeod, PhD, RD (2025-present)
Kara L Simpson, MS, CGC (2014-present)
Marshall L Summar, MD; Children's National Health System (2003-2025)
Mendel Tuchman, MD; Children's National Medical Center (2003-2005)

Revision History

• 3 July 2025 (bp) Comprehensive update posted live
• 22 June 2017 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 11 August 2005 (me) Comprehensive update posted live
• 29 April 2003 (me) Overview posted live
• 29 January 2001 (mls) Original submission

Published Guidelines

• Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42:1192-230.

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