Urea cycle disorders: Clinical features and

diagnosis
Author: Brendan Lee, MD, PhD
Section Editor: Sihoun Hahn, MD, PhD
Deputy Editor: Elizabeth TePas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Mar 2022. | This topic last updated: Jun 21, 2021.

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' 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

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".)

SUMMARY
● 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.)

● Ornithine transcarbamylase (OTC) deficiency is X linked. The other UCDs

are autosomal recessive. (See 'Genetics' above.)

● 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.)

● 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.)

● 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.)

● 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 'Laboratory findings' above.)

● 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.)

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