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Urea cycle disorders: Clinical features and diagnosis

Urea cycle disorders: Clinical features and diagnosis
Brendan Lee, MD, PhD
Section Editor:
Sihoun Hahn, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Mar 2023. | This topic last updated: Jun 14, 2022.

INTRODUCTION — The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (figure 1). Deficiency of an enzyme in the pathway causes a urea cycle disorder (UCD). The UCDs [1] are:

Carbamyl phosphate synthetase I (CPSI) deficiency (MIM #237300)

Ornithine transcarbamylase (OTC) deficiency (MIM #311250)

Argininosuccinate synthetase (ASS) deficiency [2] (also known as classic citrullinemia or type I citrullinemia [CTLN1] MIM #215700)

Argininosuccinate lyase (ASL) deficiency [3] (also known as argininosuccinic aciduria, MIM #207900)

N-acetyl glutamate synthetase (NAGS) deficiency (MIM#237310)

Arginase deficiency [4] (MIM #207800)

UCDs, except for arginase deficiency, result in hyperammonemia and life-threatening metabolic decompensations in infancy. Survivors of the metabolic decompensation frequently have severe neurologic injury. Prompt recognition and treatment are needed to improve outcome.

An overview of the clinical features and diagnosis of UCDs is presented here. The management of UCDs is discussed separately. A general overview of inborn errors of metabolism is also presented separately. (See "Urea cycle disorders: Management" and "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

EPIDEMIOLOGY — UCDs occur in approximately 1 in 8200 live births in the United States [5]. The incidence of UCDs among the offspring of employees of a large Saudi company in the Eastern Province of Saudi Arabia was 1 in 14,285 live births. However, this incidence is suspected to be an underestimation since patients were evaluated based upon clinical manifestations and/or family history rather than newborn screening [6]. UCDs appear to be less common in Finland, with a reported incidence of 1 in 39,000 live births. In a longitudinal study of 614 individuals performed by the Urea Cycle Disorders Consortium (UCDC) of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network, the overall calculated prevalence of UCDs was 1 in 35,000, with two-thirds presenting with initial symptoms after the newborn period [7]. The mortality rate was 24 percent in neonatal-onset cases and 11 percent in late-onset cases.

PATHOGENESIS — The urea cycle converts nitrogen from peripheral (muscle) and enteral sources (protein ingestion) into urea that is water soluble and can be excreted. Two moles of nitrogen, one from ammonia and one from aspartate, are converted to urea in each cycle (figure 1). Ammonia nitrogen derives from circulating amino acids, mostly glutamine and alanine. Aspartate is a substrate for argininosuccinic acid synthesis.

Deficiencies in the first four enzymes of the cycle (carbamyl phosphate synthetase I [CPSI], ornithine transcarbamylase [OTC], argininosuccinate synthetase [ASS], or argininosuccinate lyase [ASL]) or in N-acetyl glutamate synthetase (NAGS), the enzyme involved in production of the cofactor N-acetylglutamate, result in accumulations of ammonia and the precursor metabolites [8]. Primary mitochondrial disease secondarily may affect urea cycle activity because CPSI, NAGS, and OTC are located in mitochondria. Hyperammonemia is rare or usually not as severe in arginase deficiency [9].

GENETICS — The inheritance pattern of the UCDs is autosomal recessive, with the exception of ornithine transcarbamylase (OTC) deficiency (which is X linked). Thus, the recurrence risk for parents of an affected child (except OTC deficiency) is 25 percent.

Because inheritance of OTC deficiency is X linked, all female offspring of a male OTC-deficient parent will carry an OTC pathogenic variant, and 50 percent of all offspring (male and female) from a female OTC-deficient parent will carry the pathogenic variant. Hemizygous males usually are more severely affected than are heterozygous females. Approximately 10 percent of female carriers become symptomatic. The clinical severity in affected females depends upon the pattern of X inactivation in the liver (also known as lyonization) and ranges from asymptomatic to almost as severe as in that of an affected male [10-12].

CLINICAL FEATURES — The majority of affected patients present in early childhood, although those with a partial enzyme deficiency may become symptomatic later in childhood or as adults. Frequent vomiting and poor appetite with food refusal and protein aversion are common features in patients with UCD [13].

In a large cohort of UCD patients from multiple centers (n = 260), only 34 percent presented during the neonatal period (<30 days of age) [14]. Of the remaining patients, the first episode of hyperammonemia was reported at 31 days to 2 years of age in 18 percent, >2 to 12 years of age in 28 percent, and >12 years of age in 20 percent. The median age at presentation was two years (range one day to 53 years). The most common presenting symptoms in this cohort were neurologic (decreased level of consciousness, altered mental status, abnormal motor function, seizures) and gastrointestinal (vomiting, poor feeding, diarrhea, nausea, constipation).

Typical presentation — Severe defects typically present in term newborns who appear well for the first 24 to 48 hours after birth. The infant becomes symptomatic after feeding has started because human milk or infant formula provides a protein load. Initial signs include somnolence, inability to maintain normal body temperature, and poor feeding, usually followed by vomiting, lethargy, and coma [15,16], a presentation that is identical to that of an infant with sepsis. However, the absence of risk factors for sepsis and a nondiagnostic sepsis evaluation should prompt consideration of a metabolic disorder [17].

A common early sign in newborns with hyperammonemia is central hyperventilation leading to respiratory alkalosis. Hyperventilation is thought to result from cerebral edema caused by the accumulation of ammonia, glutamine, and other metabolites [18]. Increasing cerebral edema also may result in abnormal posturing and progressive encephalopathy with hypoventilation and respiratory arrest. Approximately 50 percent of infants with severe hyperammonemia have seizures [5].

Affected patients have a lifelong risk of metabolic decompensation with intercurrent hyperammonemia. Metabolic decompensation usually occurs during episodes of increased catabolism, such as infections (eg, gastroenteritis, otitis media), fasting, surgery, or trauma.

The most common long-term risks are intellectual disability and developmental delay. A systematic review of 58 reports of cognitive abilities in 1649 persons with UCD found that 34 percent functioned in the range of intellectual disabilities [19]. Overall, patients with distal UCDs had poorer neurocognitive outcomes than those with proximal UCDs.

Atypical presentation — Patients who have partial enzyme deficiencies may have atypical presentations after the newborn period [10,11]. This delayed presentation is most commonly seen in patients with partial ornithine transcarbamylase (OTC) deficiency, such as female carriers, although it also occurs with partial activity of all urea cycle enzymes.

Some patients with partial urea cycle enzyme deficiency present with chronic vomiting, developmental delay, a seizure disorder, sleep disorders, or psychiatric illness [20-22]. Others may develop symptoms (eg, headache, anorexia, vomiting, lethargy, ataxia, behavioral abnormalities) following increased protein intake or during periods of catabolic stress (eg, viral illness, pregnancy) [10,11,23]. These patients tend to prefer vegetarian diets because dietary protein intake often is associated with headache. Still others present with laboratory abnormalities. There is emerging clinical evidence that UCDs may be complicated by hepatic dysfunction characterized by elevation of liver enzymes, coagulopathy, and histologic evidence of glycogenoses [24,25]. The cause of this and other anecdotally reported morbidities may relate to deficiency of downstream intermediates, such as arginine, and dysregulation of nitric oxide synthesis or other arginine-derived intermediates [26-28]. How this chronic liver injury may affect lifetime risk for developing malignancy such as hepatocellular carcinoma is unknown, but sporadic cases have been reported [29]. Metabolic stress secondary to surgery (eg, hyperammonemia post-bariatric surgery in females with OTC deficiency) can also lead to unmasking of previously minimally symptomatic persons [30].

In patients with partial urea cycle enzyme deficiency, hyperammonemia may be chronic or occur only during metabolic decompensations associated with catabolic stress [31,32]. The hyperammonemia is often less severe and the associated symptoms more subtle in patients with partial defects. It is important to consider a UCD in patients who have recurrent metabolic decompensations and to measure plasma ammonia concentration at the time of decompensation since ammonia may be normal during healthy periods [32]. (See 'Laboratory findings and neuroimaging' below.)

Patients with arginase deficiency typically present in later infancy to the preschool years. The most common physical findings are spasticity, especially of the lower extremities, dystonia, and ataxia. A diagnosis of cerebral palsy is often suspected. Other presenting symptoms are similar to those with partial urea cycle defects.

LABORATORY FINDINGS AND NEUROIMAGING — The laboratory hallmark of a UCD is an elevated plasma ammonia concentration (>100 to 150 micromol/L). However, as previously noted, ammonia may only be abnormal during periods of decompensation in patients with partial defects. (See 'Atypical presentation' above.)

Ammonia — The plasma ammonia concentration can be measured in an arterial or venous blood sample. Measurement from a capillary blood sample is not reliable. Blood should be collected in chilled tubes with ammonia-free sodium heparin (green top) or ethylenediaminetetraacetic acid (EDTA; purple top), placed on ice, and delivered rapidly to the laboratory. Ammonia levels can be elevated falsely by hemolysis, delayed processing, and exposure to room temperature.

Normal values for ammonia concentration are often higher in newborns than in older children or adults. In newborns, levels are affected by gestational and postnatal age. In one study, the mean plasma ammonia concentration of healthy term infants at birth was 45±9 micromol/L; the upper limit of normal was 80 to 90 micromol/L [33]. Initial values in preterm infants less than 32 weeks gestation were higher (mean 71±26 micromol/L) but declined to term levels by seven days. Normal values in children older than one month and adults are less than 50 and 30 micromol/L, respectively.

Neuroimaging — Findings on neuroimaging are variable and depend upon the severity of the presentation and duration of hyperammonemia [34]. Imaging during acute presentation may show evidence of cerebral edema. Magnetic resonance imaging (MRI) of the brain in neonatal-onset cases with prolonged hyperammonemia may show findings similar to that of hypoxic ischemic encephalopathy or hepatic encephalopathy. As an example, neonatal ornithine transcarbamylase (OTC) deficiency with prolonged hyperammonemia may lead to chronic changes including cortical atrophy, white matter cystic changes, and hypomyelination. Reversible white matter lesions may be seen even in milder late-onset cases.

DIAGNOSIS — Ammonia levels should be measured in patients who present with typical clinical features of UCDs or who have a suggestive family history or an abnormal newborn screening test. If the plasma ammonia concentration is greater than 100 to 150 micromol/L, further testing is performed to establish a diagnosis. Mild elevations below this threshold should be interpreted in the context of the clinical course and followed to ensure resolution. Initial tests include arterial pH and carbon dioxide tension, serum lactate, serum glucose, serum electrolytes to calculate the anion gap, plasma amino acids, and urine organic acids and urine orotic acid. An elevated plasma ammonia concentration combined with normal blood glucose and anion gap strongly suggests a UCD. Additional plasma and urine should be frozen for future diagnostic tests. These samples may be useful to identify metabolic disorders in patients who have mild hyperammonemia and biochemical abnormalities during an acute illness and normal values when they appear well.

Additional testing is used to identify the specific enzyme deficiency, including enzyme analysis and molecular genetic testing.

Treatment should be initiated as soon as a UCD is suspected and should proceed concurrently with the diagnostic evaluation. (See "Urea cycle disorders: Management", section on 'Initial management of metabolic decompensation'.)

Plasma amino acid/urine orotic acid analyses — Quantitative plasma amino acid analysis is helpful to differentiate among UCDs (algorithm 1) [16]. Citrulline concentration is increased in argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) deficiencies; argininosuccinic acid is absent in the former and elevated in the latter.

Citrulline is absent or low in carbamyl phosphate synthetase I (CPSI), ornithine transcarbamylase (OTC), or N-acetyl glutamate synthetase (NAGS) deficiencies; arginine also is low, and glutamine is increased in these disorders. If citrulline is absent, urine orotic acid measurement may differentiate OTC and CPS deficiencies [15]. Orotic acid can be increased to more than 1000 micromol/mol creatinine (normal, 1 to 11 micromol/mol creatinine) in the former and is low in the latter.

Arginine is elevated three- to fourfold above the upper limit of normal in arginase deficiency [9].

Enzyme analysis — The diagnosis of a specific UCD can be confirmed by enzyme analysis of tissue samples, as follows:

Liver biopsy – CPSI, OTC, and NAGS deficiencies

Fibroblasts from skin biopsy – ASS and ASL deficiencies

Red blood cells – Arginase deficiency

Enzyme activity must be interpreted carefully. Measured enzyme activity does not always correlate with residual in vivo activity or with phenotypic severity, because most in vitro assays are performed with excess substrate and in cell-free extracts. In addition, in the X-linked disorder OTC deficiency, the level of OTC activity measured in a liver biopsy may be normal in an affected female, depending upon the pattern of X inactivation in the liver. Liver tissue, obtained by open or needle punch biopsy, can be used to test all enzymes affected in the UCDs when DNA testing is negative. Unfortunately, the availability of enzymatic testing has diminishing as DNA sequencing approaches have largely replaced biochemical testing as first-line diagnostic studies. The lack of enzyme testing is problematic since DNA testing is not 100 percent sensitive or specific: the former due to mutation in noncoding or regulatory regions and the latter due to the findings of difficult-to-interpret variants of uncertain significance.

Specialized testing — Special techniques available in a research setting may be useful to detect abnormalities in patients with UCDs, especially those with partial enzyme deficiencies who have normal laboratory values during asymptomatic periods.

The measurement of urinary excretion of orotic acid after administration of allopurinol is one such technique that was used to detect women who were carriers of a mutant OTC allele [35,36]. However, mild cases may have minimal elevations, and increased excretion may occur in mitochondrial disease, limiting the specificity of this test [37-39]. With the wide availability of DNA testing, provocative testing (eg, with oral protein loads) should be avoided. (See 'DNA mutation analysis' below.)

The use of isotopes in vivo is another specialized technique that can be employed to assess altered urea cycle activity [39,40]. In one report, stable isotopes were used to measure rates of total body urea synthesis and nitrogen flux (which assesses urea cycle activity); these studies detected patients with complete and partial enzyme deficiencies and asymptomatic carriers, and results correlated with clinical severity [40].

DNA mutation analysis — DNA sequencing-based mutation testing is clinically available for all genes of the urea cycle and is increasingly used as a first-line approach for diagnosis. DNA testing for OTC deficiency should be considered in patients with a suspected UCD, especially if the plasma amino acid pattern is not diagnostic, because OTC deficiency is the most common UCD. More than 150 pathogenic variants, most of which are single-base substitutions, have been reported [41]. However, microdeletion of part, or all, of the OTC gene may lead to false-negative results on DNA sequencing. Hence, array comparative genomic hybridization (aCGH) or chromosome microarray analysis to detect microdeletions of the gene is indicated when initial DNA sequencing is negative [42].

An increasingly effective alternative to targeted DNA mutation analysis is the application of next-generation DNA sequencing for clinical whole-exome analysis, which has the potential to identify variants in most, if not all, coding genes [43]. In so doing, all of the UCD genes as well as other gene variants that may cause hyperammonemia can be detected. Next-generation DNA sequencing is increasingly replacing other methodologies in the initial diagnostic work-up because of the high sensitivity of this approach. However, sequencing may miss small single or multi-exon deletions; therefore, aCGH designed with single exon resolution should be performed in conjunction with DNA sequencing [42]. Detection of a pathogenic variant in an asymptomatic patient may preclude the need for a liver biopsy to confirm the diagnosis. Failure to detect a pathogenic variant does not exclude the diagnosis, irrespective of the technology used for testing. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics".)

Prenatal testing — Prenatal testing can be performed for all the UCDs by DNA analysis if the pathogenic variant is known [44]; if an extended sibship is available, linkage analysis can be used, although it has limited sensitivity and specificity. The carrier status of both parents should be confirmed prior to prenatal DNA testing.

If the molecular genetic studies are not informative, prenatal diagnosis may be determined by biochemical testing, although the clinical availability of such biochemical tests has diminished in the genetic testing era. ASS and ASL enzyme activity can be measured directly in amniocytes and chorionic villus cells. Elevated citrulline and argininosuccinic acid can be measured in amniotic fluid. CPSI and OTC can be measured in fetal liver. The clinical phenotype of females with OTC deficiency cannot be predicted, due to random inactivation of the X chromosome. Genetic counseling should be considered.

Newborn screening — Testing for UCDs and other inborn errors of metabolism by tandem mass spectrometry is now included in most newborn screening programs [45-47]. (See "Newborn screening".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of neonatal hyperammonemia includes a limited number of disorders that are primarily caused by genetic defects, as discussed below [15]. Distinguishing features of UCDs include very high ammonia levels, which can be greater than 1000 micromol/L, in contrast to other etiologies in which ammonia rarely is higher than 200 to 300 micromol/L [17]. Other findings that suggest a UCD are normal blood glucose, normal anion gap, and respiratory alkalosis.

Primary genetic causes of hyperammonemia include organic acidemias, fatty acid oxidation defects, and disorders of pyruvate metabolism [48].

Hyperammonemia in organic acidemias results from inhibition of one of the urea cycle enzymes, most likely carbamyl phosphate synthetase I (CPSI) [48]. Patients with these disorders typically have metabolic acidosis and/or ketotic hypoglycemia. (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Organic acidemias: An overview and specific defects" and "Approach to hypoglycemia in infants and children".)

Fatty oxidation defects can cause hyperammonemia, but affected children typically have nonketotic hypoglycemia and present later in infancy. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders".)

In disorders of pyruvate metabolism, lactic acidemia usually accompanies the elevated ammonia concentration. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

Additional genetic causes of hyperammonemia include the following:

Hyperornithinemia, hyperammonemia, homocitrullinemia (HHH syndrome, MIM #238970) is a rare cause of hyperammonemia. It is caused by impaired transport of ornithine, a basic amino acid, across the inner mitochondrial membrane [49,50], which leads to functional impairment of the urea cycle and elevated plasma concentrations of ornithine, ammonia, and citrulline (figure 1). Affected newborns typically present with lethargy, muscular hypotonia, and seizures. If untreated, death occurs within the first few days. The majority of survivors have pyramidal tract signs, with spastic paraparesis [49,51]. Most have myoclonic seizures, ataxia, and intellectual disability. A milder form of the disorder has been reported in adults, who become symptomatic following protein-rich meals [49,50].

Citrin deficiency or citrullinemia type II (neonatal onset MIM #605814, adult onset MIM #603471) is caused by defective aspartate transport between the mitochondria and the cytosol [52]. This defective transport leads to insufficient substrate for argininosuccinate synthetase (ASS) and secondary functional deficiency of ASS activity. Patients may present in the neonatal period with hepatitis and/or intrahepatic cholestasis, or they may present in adulthood with recurrent hyperammonemia and neuropsychiatric symptoms [53,54]. Paradoxically, patients respond to a carbohydrate-restricted high-protein diet. Serum citrulline levels may be mildly elevated, and threonine levels are elevated out of proportion of changes in serine levels.

Lysinuric protein intolerance (hyperlysinuria, dibasic aminoaciduria II, MIM #222700) can present with postprandial hyperammonemia, hepatomegaly, short stature, and/or osteoporosis [55]. It is caused by impaired amino acid transport, particularly of dibasic amino acids, leading to increased urinary excretion of lysine, ornithine, and arginine. The clinical features are highly variable. Supplementation with citrulline is effective in ameliorating some symptoms of the condition.

Hyperammonemia due to carbonic anhydrase VA deficiency (MIM #615751) can present with elevated ammonia, hypoglycemia, increased serum alanine and lactate, and mixed metabolic acidosis and respiratory alkalosis. Recessive pathogenic variants in this enzyme (CA5A) lead to decreased delivery of bicarbonate substrate to multiple mitochondria enzymes. In the urea cycle, bicarbonate is required for carbamyl phosphate synthesis by the CPSI enzyme. In the families reported to date, the course has been relatively benign after initial presentation [56]. Treatment with carglumic acid should relieve at least the urea cycle component of this condition.

Hyperinsulinism hyperammonemia (#606762) can present with constant hyperammonemia and episodic hypoglycemia. Dominant pathogenic variants in glutamate dehydrogenase (GLUD1) lead to decreased allosteric inhibition of this enzyme by guanosine triphosphate (GTP) [57]. This leads to imbalance of allosteric activation of GLUD1 by leucine with consequent insulin secretion. The hyperammonemia derives from deficiency of glutamate, which is required for production of N-acetylglutamate in the urea cycle.

Transient hyperammonemia of the newborn (THAN) is an unusual cause of hyperammonemia. This condition may be distinguished from UCDs by its clinical features. In one report, patients with THAN had lower birth weight and gestational age, earlier presentation of hyperammonemia, and more respiratory distress than those with UCDs [58]. Patients do not suffer from long-term risk of hyperammonemia and can tolerate normal diet without drug therapy.

Causes of hyperammonemia that are not genetic include severe dehydration and liver failure. However, the plasma ammonia level typically is less than 100 to 200 micromol/L in dehydration and returns to normal with volume replacement. Hyperammonemia usually is seen late in the course of severe hepatocellular damage. Severe elevated hyperammonemia can also present with hepatic failure due to neonatal or perinatal herpes simplex virus infection, though the presentation is usually later in the first week of life or beyond [59]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Disseminated disease'.)

The differential diagnosis in older children and adults who present with hyperammonemia includes hepatic encephalopathy in patients with advanced liver failure, valproic acid poisoning, severe dehydration, and gastrointestinal bacterial overgrowth. Liver function test abnormalities are seen in patients with hepatic encephalopathy and in most patients with valproic acid poisoning. Ammonia elevations are mild in patients with dehydration and bacterial overgrowth. Levels 100 to 150 micromol/L or greater should prompt a workup for a UCD. (See "Hepatic encephalopathy: Pathogenesis" and "Valproic acid poisoning".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urea cycle disorders" and "Society guideline links: Inborn errors of metabolism".)


Overview – The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (figure 1). Deficiency of an enzyme in the pathway causes a urea cycle disorder (UCD). Prompt recognition and treatment are needed to improve outcome. (See 'Introduction' above.)

Genetics – Ornithine transcarbamylase (OTC) deficiency is X linked. The other UCDs are autosomal recessive. (See 'Genetics' above.)

Age at presentation – The majority of affected patients present in early childhood, although those with a partial enzyme deficiency may become symptomatic later in childhood or as adults. (See 'Clinical features' above.)

Typical presentation in newborns – In newborns, UCDs typically present after 24 to 48 hours of age. Clinical features include somnolence and poor feeding followed by lethargy, vomiting, and coma. Other features include central hyperventilation leading to initial respiratory alkalosis, hyperammonemia, and seizures. (See 'Typical presentation' above.)

Atypical presentation with partial enzyme deficiency – Patients with partial enzyme deficiency may present with chronic vomiting, developmental delay, seizure disorder, or psychiatric illness. Symptoms (eg, headache, vomiting, lethargy, ataxia) may be precipitated by increased protein intake or catabolic stress (eg, illness, menstruation, pregnancy). Arginase deficiency presents with more specific symptoms such as spastic diplegia, dystonia, or ataxia. (See 'Atypical presentation' above.)

Diagnosis – The initial laboratory evaluation for suspected UCD should include arterial pH and carbon dioxide; serum ammonia, lactate, glucose, electrolytes, and amino acids; and urine organic acids and orotic acid. Elevated plasma ammonia concentration combined with normal blood glucose and normal anion gap strongly suggests a UCD. Additional testing is necessary to establish the diagnosis and identify the specific enzyme deficiency. Increasingly, DNA sequencing (targeted or whole exome-based approaches) in conjunction with array comparative genomic hybridization (aCGH) is being used as noninvasive alternatives to enzyme analysis of tissue samples. (See 'Diagnosis' above and 'Laboratory findings and neuroimaging' above.)

Differential diagnosis – The differential diagnosis of neonatal hyperammonemia includes organic acidemias; fatty acid oxidation defects; disorders of pyruvate metabolism; hyperornithinemia, hyperammonemia, homocitrullinemia (HHH); lysinuric protein intolerance; carbonic anhydrase VA deficiency; hyperinsulinism hyperammonemia; transient hyperammonemia of the newborn; severe dehydration; and liver failure. Distinguishing features of UCD include the degree of elevation of plasma ammonia (typically >1000 micromol/L for those disorders early in the cycle [ie, OTC deficiency] compared with 200 to 300 micromol/L for other genetic causes as well as for UCDs later in the cycle [ie, argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) deficiency]), normal blood glucose, normal anion gap, and respiratory alkalosis. (See 'Differential diagnosis' above.)

  1. Gene Reviews: Urea Cycle Disorders Overview. (Accessed on June 14, 2011).
  2. Gene Reviews: Citrullinemia type 1. (Accessed on June 14, 2011).
  3. Gene Reviews: Argininosuccinate lyase deficiency. (Accessed on June 14, 2011).
  4. Gene Reviews: Arginase deficiency. (Accessed on June 14, 2011).
  5. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996; 43:127.
  6. Moammar H, Cheriyan G, Mathew R, Al-Sannaa N. Incidence and patterns of inborn errors of metabolism in the Eastern Province of Saudi Arabia, 1983-2008. Ann Saudi Med 2010; 30:271.
  7. Batshaw ML, Tuchman M, Summar M, et al. A longitudinal study of urea cycle disorders. Mol Genet Metab 2014; 113:127.
  8. Braissant O. Current concepts in the pathogenesis of urea cycle disorders. Mol Genet Metab 2010; 100 Suppl 1:S3.
  9. GeneReviews: Arginase Deficiency. (Accessed on September 21, 2011).
  10. Brusilow SW, Horwich AL. Urea cycle enzymes. In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1909.
  11. Leonard JV, Morris AA. Urea cycle disorders. Semin Neonatol 2002; 7:27.
  12. Maestri NE, Brusilow SW, Clissold DB, Bassett SS. Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 1996; 335:855.
  13. Gardeitchik T, Humphrey M, Nation J, Boneh A. Early clinical manifestations and eating patterns in patients with urea cycle disorders. J Pediatr 2012; 161:328.
  14. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr 2008; 97:1420.
  15. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998; 102:E69.
  16. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138:S30.
  17. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr 1999; 134:268.
  18. Butterworth RF. Effects of hyperammonaemia on brain function. J Inherit Metab Dis 1998; 21 Suppl 1:6.
  19. Waisbren SE, Stefanatos AK, Kok TMY, Ozturk-Hismi B. Neuropsychological attributes of urea cycle disorders: A systematic review of the literature. J Inherit Metab Dis 2019; 42:1176.
  20. Maestri NE, Lord C, Glynn M, et al. The phenotype of ostensibly healthy women who are carriers for ornithine transcarbamylase deficiency. Medicine (Baltimore) 1998; 77:389.
  21. Serrano M, Martins C, Pérez-Dueñas B, et al. Neuropsychiatric manifestations in late-onset urea cycle disorder patients. J Child Neurol 2010; 25:352.
  22. Sedel F, Baumann N, Turpin JC, et al. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis 2007; 30:631.
  23. Houston B, Reiss KA, Merlo C. Healthy, but comatose. Am J Med 2011; 124:303.
  24. Iorio R, Sepe A, Giannattasio A, et al. Hypertransaminasemia in childhood as a marker of genetic liver disorders. J Gastroenterol 2005; 40:820.
  25. Miles L, Heubi JE, Bove KE. Hepatocyte glycogen accumulation in patients undergoing dietary management of urea cycle defects mimics storage disease. J Pediatr Gastroenterol Nutr 2005; 40:471.
  26. Brunetti-Pierri N, Erez A, Shchelochkov O, et al. Systemic hypertension in two patients with ASL deficiency: a result of nitric oxide deficiency? Mol Genet Metab 2009; 98:195.
  27. Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet 2011; 157C:45.
  28. Erez A, Nagamani SC, Shchelochkov OA, et al. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med 2011; 17:1619.
  29. Koo M, Lipshutz GS, Cederbaum SD, Lassman C. Biopsy-proven Hepatocellular Carcinoma in a 53-year-old Woman With Arginase Deficiency. Pediatr Dev Pathol 2017; 20:517.
  30. Hu WT, Kantarci OH, Merritt JL 2nd, et al. Ornithine transcarbamylase deficiency presenting as encephalopathy during adulthood following bariatric surgery. Arch Neurol 2007; 64:126.
  31. Arn PH, Hauser ER, Thomas GH, et al. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. A cause of postpartum coma. N Engl J Med 1990; 322:1652.
  32. Tuchman M, Yudkoff M. Blood levels of ammonia and nitrogen scavenging amino acids in patients with inherited hyperammonemia. Mol Genet Metab 1999; 66:10.
  33. Usmani SS, Cavaliere T, Casatelli J, Harper RG. Plasma ammonia levels in very low birth weight preterm infants. J Pediatr 1993; 123:797.
  34. Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab 2010; 100 Suppl 1:S20.
  35. Hauser ER, Finkelstein JE, Valle D, Brusilow SW. Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. N Engl J Med 1990; 322:1641.
  36. Burlina AB, Ferrari V, Dionisi-Vici C, et al. Allopurinol challenge test in children. J Inherit Metab Dis 1992; 15:707.
  37. Bonham JR, Guthrie P, Downing M, et al. The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease. J Inherit Metab Dis 1999; 22:174.
  38. Ahrens MJ, Berry SA, Whitley CB, et al. Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation. Am J Med Genet 1996; 66:311.
  39. Scaglia F, Zheng Q, O'Brien WE, et al. An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency. Pediatrics 2002; 109:150.
  40. Lee B, Yu H, Jahoor F, et al. In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. Proc Natl Acad Sci U S A 2000; 97:8021.
  41. McCullough BA, Yudkoff M, Batshaw ML, et al. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet 2000; 93:313.
  42. Shchelochkov OA, Li FY, Geraghty MT, et al. High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH. Mol Genet Metab 2009; 96:97.
  43. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12:745.
  44. Scaglia F, Brunetti-Pierri N, Kleppe S, et al. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr 2004; 134:2775S.
  45. Wilcken B. Expanded newborn screening: reducing harm, assessing benefit. J Inherit Metab Dis 2010; 33:S205.
  46. Cavicchi C, Malvagia S, la Marca G, et al. Hypocitrullinemia in expanded newborn screening by LC-MS/MS is not a reliable marker for ornithine transcarbamylase deficiency. J Pharm Biomed Anal 2009; 49:1292.
  47. Huang HP, Chu KL, Chien YH, et al. Tandem mass neonatal screening in Taiwan--report from one center. J Formos Med Assoc 2006; 105:882.
  48. Walser M, Stewart PM. Organic acidaemia and Hyperammonaemia: review. J Inherit Metab Dis 1981; 4:177.
  49. Salvi S, Santorelli FM, Bertini E, et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 2001; 57:911.
  50. Camacho JA, Obie C, Biery B, et al. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 1999; 22:151.
  51. Lemay JF, Lambert MA, Mitchell GA, et al. Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients. J Pediatr 1992; 121:725.
  52. Gene Reviews: Citrin deficiency. (Accessed on June 14, 2011).
  53. Tonini MC, Bignamini V, Mattioli M. Headache and neuropsychic disorders in the puerperium: a case report with suspected deficiency of urea cycle enzymes. Neurol Sci 2011; 32 Suppl 1:S157.
  54. Ko JM, Kim GH, Kim JH, et al. Six cases of citrin deficiency in Korea. Int J Mol Med 2007; 20:809.
  55. Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab 2012; 106:12.
  56. van Karnebeek CD, Sly WS, Ross CJ, et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet 2014; 94:453.
  57. Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998; 338:1352.
  58. Hudak ML, Jones MD Jr, Brusilow SW. Differentiation of transient hyperammonemia of the newborn and urea cycle enzyme defects by clinical presentation. J Pediatr 1985; 107:712.
  59. Barnes PM, Wheldon DB, Eggerding C, et al. Hyperammonaemia and disseminated herpes simplex infection in the neonatal period. Lancet 1982; 1:1362.
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