Arginase Deficiency

Clinical characteristics.

Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms.

Diagnosis/testing.

The diagnosis of arginase deficiency is established in a proband with suggestive clinical and/or biochemical findings and confirmed by identification of biallelic pathogenic variants in ARG1 or, in limited instances, by failure to detect arginase enzyme activity (usually <1% of normal) in red blood cell extracts.

Management.

Treatment of manifestations: Management should closely mirror that for urea cycle disorders, except that individuals with arginase deficiency are not as likely to have episodes of hyperammonemia; if present, such episodes respond to conservative management (e.g., intravenous fluid administration). Treatment should involve a team coordinated by a metabolic specialist. Routine outpatient management includes restriction of dietary protein and consideration of oral nitrogen-scavenging drugs (in those who have chronic or recurrent hyperammonemia). Treatment of an acutely ill (comatose and encephalopathic) individual requires: rapid reduction of plasma ammonia concentration; use of pharmacologic agents (sodium benzoate and/or sodium phenylbutyrate/phenylacetate) to promote excretion of excess nitrogen through alternative pathways; and introduction of calories supplied by carbohydrates and fat to reduce catabolism and the amount of excess nitrogen in the diet while avoiding overhydration and resulting cerebral edema. Standard treatment for seizures, spasticity, developmental delay / intellectual disability, and joint contractures. In those with persistent hepatic synthetic function abnormalities, fresh-frozen plasma should be considered prior to surgical procedures. In the rare instance of progression to hepatic fibrosis and cirrhosis, liver transplantation can be considered.

Prevention of primary manifestations: Maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein and use of oral nitrogen-scavenging drugs as necessary to treat hyperammonemia. Liver transplantation eliminates hyperargininemia and presumably the risk for hyperammonemia but is rarely necessary in arginase deficiency.

Surveillance: Regular follow up at intervals determined by age and degree of metabolic stability. Assessment of metabolic control (plasma ammonia, amino acid profile, and nutritional labs) at least monthly for the first year of life and as determined by a metabolic specialist after the first year of life; guanidinoacetate and liver function tests every six to 12 months; monitoring of growth and developmental progress at each visit.

Agents/circumstances to avoid: Valproic acid (exacerbates hyperammonemia).

Evaluation of relatives at risk: Plasma quantitative amino acid analysis, molecular genetic testing (if the family-specific pathogenic variants are known), or enzymatic testing in all sibs (especially younger ones) of a proband to allow early diagnosis and treatment of those found to be affected.

Pregnancy management: In general, affected pregnant women should continue dietary protein restriction and ammonia-scavenging medications (after an appropriate benefit/risk calculation) based on their clinical course before pregnancy.

Other: Immunizations on the usual schedule; appropriate use of antipyretics as indicated (ibuprofen preferred over acetaminophen).

Genetic counseling.

Arginase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the ARG1 pathogenic variants in the family are known.

Suggestive Findings

Scenario 1. Abnormal newborn screening (NBS) result

• NBS for arginase deficiency is primarily based on quantification of the analyte arginine on dried blood spots.
• Arginine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see Preliminary laboratory findings below).
• If these studies support the diagnosis of arginase deficiency, additional testing is required to establish the diagnosis (see Establishing the Diagnosis).

Note: (1) Some infants with arginase deficiency may have follow-up arginine levels in the normal range, and thus infants who continue to have elevated arginine-to-ornithine ratios and arginine toward the upper limit of normal should undergo additional diagnostic testing (see Establishing the Diagnosis) [Author, personal observation]. (2) Arginase deficiency is currently a secondary condition on the Recommended Uniform Screening Panel. Thus, not all states will screen for and detect newborns with arginase deficiency.

Scenario 2. Symptomatic individual with either atypical findings or untreated arginase deficiency resulting from any of the following:

• NBS not performed
• False negative NBS result
• Caregivers not adherent to recommended treatment following a positive NBS result

Supportive but nonspecific clinical findings and preliminary laboratory findings can include the following.

Clinical findings

• Slowing of linear growth at age one to three years
• Development of spasticity in the lower extremities
• Plateauing of cognitive development
• Loss of developmental milestones
• Seizures

Preliminary laboratory findings

• Plasma quantitative amino acid analysis. Elevation of plasma arginine concentration three- to fourfold the upper limit of normal is highly suggestive of the diagnosis. Plasma arginine elevation is the primary means of ascertainment.
  Note: Up to twofold the upper limit of normal may be seen in infants who do not have arginase deficiency and who are otherwise normal.
• Plasma ammonia concentration. Elevation of plasma ammonia concentration may be intermittent. Acute hyperammonemia (plasma ammonia concentration >150 µmol/L) is uncommon.
• Urinary orotic acid concentration. Although urinary orotic acid concentration is often elevated, it is not a primary screen for this disorder.

Note: Because elevations of these metabolites individually are not entirely specific to arginase deficiency, follow-up testing is required to establish or rule out the diagnosis of arginase deficiency (see Establishing the Diagnosis).

Establishing the Diagnosis

The diagnosis of arginase deficiency is established in a proband with suggestive clinical and/or biochemical findings and confirmed by identification of biallelic pathogenic (or likely pathogenic) variants in ARG1 (see Table 1) or, in limited instances, by failure to detect arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Because of its relatively high sensitivity, ARG1 molecular genetic testing is the preferred confirmatory test for arginase deficiency.

Note: (1) Enzyme assay can be helpful if two pathogenic variants are not found on molecular genetic testing. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (3) Identification of biallelic ARG1 variants of uncertain significance (or of one known ARG1 pathogenic variant and one ARG1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular Genetic Testing Approaches

Scenario 1. Abnormal newborn screening (NBS) result. When NBS results and other laboratory findings suggest the diagnosis of arginase deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of ARG1 detects missense, nonsense, and splice site variants and small intragenic deletions/insertions; depending on the method used, exon or whole-gene deletions/duplications may not be detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  Note: In individuals of French Canadian ancestry, the c.57+1G>A founder variant may be tested for first.
• A multigene panel that includes ARG1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Scenario 2. Symptomatic individual with atypical findings or untreated arginase deficiency (resulting from NBS not performed or false negative NBS result):

• If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see Scenario 1).
• When the diagnosis of arginase deficiency has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Arginase Deficiency

Clinical Description

To date, more than 260 individuals with arginase deficiency have been identified [Uchino et al 1995; De Deyn et al 1997; Crombez & Cederbaum 2005; Schlune et al 2015; Huemer et al 2016; Therrell et al 2017; Diez-Fernandez et al 2018; Chandra et al 2019; Author, personal observation]. The following description of the phenotypic features associated with this condition is based primarily on individuals with severe disease. It should be noted that a phenotypic spectrum exists, and mildly affected individuals exhibit less severe features. Individuals treated from birth (as a result either of newborn screening or of having an affected older sib) appear to have minimal symptoms [Cederbaum et al 2004].

Growth and feeding. Most commonly, growth at birth and through early childhood is normal.

• At age one to three years, linear growth slows and eventually the majority of affected children demonstrate growth deficiency, which persists if arginase deficiency goes untreated.
• Microcephaly is common and is congenital in some cases.
• Feeding issues may develop, leading to inadequate nutrition. Some require a supplemental feeding tube.

Cognitive development. Initially, cognitive development in infancy and early childhood is normal.

• Starting at age one to three years, previously normal cognitive development slows or stops and the child begins to lose developmental milestones.
• If untreated, arginase deficiency usually progresses to severe intellectual disability with accompanying neurologic findings (see Neurologic features below).
• Full scale IQ in adults is in the 70s, and about half are able to live independently, though they experience significant memory and fine motor deficits [Waisbren et al 2016]. Mildly affected individuals and those treated early in life may be able to hold a job.
• Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures.

Neurologic features. In untreated individuals, progressive neurologic signs typically include the development of severe spasticity with loss of ambulation and complete loss of bowel and bladder control.

• Spasticity. Between 80% and 90% of affected individuals develop spasticity of the lower extremities [Huemer et al 2016, Chandra et al 2019].
  • Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy.
  • Severe spasticity can lead to joint contractures and lordosis.
• Seizures occur in 60%-75% of affected individuals and are usually controlled easily by anti-seizure medication [Huemer et al 2016, Chandra et al 2019]. Generalized tonic-clonic seizures are the most common seizure type.
• Brain imaging often reveals cortical atrophy. Other parts of the nervous system including basal ganglia, cerebellum, medulla, and spinal cord are largely spared [De Deyn et al 1997].

Hyperammonemia. Unlike the other eight primary urea cycle disorders (see Urea Cycle Disorders Overview), arginase deficiency rarely results in elevated plasma ammonia concentration in the newborn period.

• Episodic hyperammonemia of variable degree may occur during illness but is rarely severe enough to be life threatening, although death has been reported.
• Hyperammonemia presents with vomiting, lethargy, and altered mental status but in some cases is asymptomatic and only recognized if blood ammonia is obtained during an acute illness.
• Older individuals may present with postoperative encephalopathy.

Liver disease. Hepatic dysfunction, if present, is usually mild, manifesting as transaminitis, prolonged coagulation time, and in some cases hepatomegaly. Affected individuals typically do not have bleeding problems from prolonged coagulation time. Rarely, neonatal cholestatic jaundice has been reported [Braga et al 1997, Gomes Martins et al 2010], and cirrhosis can occur. Some adults have developed hepatocellular carcinoma.

Other. Some affected females experience symptomatic hyperammonemia during menstrual cycles. These individuals may require abortive therapy (see Management, Prevention of Primary Manifestations).

Prognosis. While data are not available, the vast majority of affected individuals appear to survive and live long (albeit handicapped) lives.

Genotype-Phenotype Correlations

Genotype-phenotype correlations indicate that the amount of residual enzyme activity modulates the phenotype [Diez-Fernandez et al 2018]. Severe disease is associated with:

• Homozygosity or compound heterozygosity for predicted loss-of-function variants such as c.466-2A>G, c.77delA, c.263_266delAGAA, and c.647_648ins32;
• Missense changes such as p.Ile8Lys or p.Gly106Arg when homozygous or in combination with another severe allele.

Prevalence

Arginase deficiency is one of the rarest urea cycle defects. Its incidence has been estimated at between 1:350,000 and 1:1,000,000; the true incidence in nonrelated populations is unknown.

Arginase deficiency is pan ethnic but may be more common among French Canadians due to a pathogenic founder variant [Uchino et al 1995] (see Table 9).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with arginase deficiency, the following evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with Arginase Deficiency

Treatment of Manifestations

The management of individuals with arginase deficiency should closely mirror that described in the Urea Cycle Disorders Overview, with one caveat: individuals with arginase deficiency are less prone to episodes of hyperammonemia and when present, hyperammonemia is more likely to respond to conservative management such as intravenous fluid administration. However, the individual who is comatose and encephalopathic is at high risk for severe brain damage and should be treated accordingly. Arginine supplementation is obviously contraindicated.

Table 3.

Routine Outpatient Management in Individuals with Arginase Deficiency

Table 4.

Acute Outpatient Management in Individuals with Arginase Deficiency

Table 5.

Acute Inpatient Management in Individuals with Arginase Deficiency

Table 6.

Management of Other Complications in Individuals with Arginase Deficiency

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Prevention of Primary Manifestations

The treatment goal is maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein intake, supplementation with arginine-free essential amino acid formula, and use of nitrogen-scavenging drugs as needed to treat hyperammonemia. Liver transplantation eliminates hyperargininemia and presumably the risk for hyperammonemia but (in contrast to other urea cycle disorders) is rarely necessary in arginase deficiency; see also Table 3.

Prevention of Secondary Complications

Table 7.

Prevention of Secondary Manifestations in Individuals with Arginase Deficiency

Surveillance

Regular follow up at intervals determined by age and degree of metabolic stability is recommended (see Table 8).

Table 8.

Recommended Surveillance for Individuals with Arginase Deficiency

Agents/Circumstances to Avoid

Valproic acid should be avoided as it exacerbates hyperammonemia in urea cycle defects and other inborn errors of metabolism [Scaglia & Lee 2006].

Evaluation of Relatives at Risk

Because the age of onset of arginase deficiency is delayed beyond the newborn period and the manifestations can vary, the genetic status of all sibs of a proband (especially the younger ones) should be clarified so that morbidity can be reduced by early diagnosis and treatment in those who are affected. Testing methods can include any one of the following:

• Plasma quantitative amino acid analysis
• Molecular genetic testing (if the family-specific ARG1 pathogenic variants are known)
• Analysis of enzymatic activity in red blood cells

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The authors are not aware of any instance in which pregnancy has been reported in a woman with arginase deficiency.

Therapies Under Investigation

A clinical trial for enzyme replacement therapy using pegylated synthetic human arginase I is currently under way (Clinical Trials Identifier NCT03921541).

A variety of genomic therapies are under investigation including mRNA therapy [Asrani et al 2018, Truong et al 2019], ARG1 gene editing [Lee et al 2016, Sin et al 2017], and viral-mediated gene therapy [Cantero et al 2016].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Other

Immunizations can be provided on the usual schedule.

Appropriate use of antipyretics is indicated. Ibuprofen is preferred over acetaminophen.

Mode of Inheritance

Arginase deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one ARG1 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has 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

• Although most severely affected individuals have not reproduced, those who are successfully treated are likely to be fertile.
• Unless an affected individual's reproductive partner also has arginase deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ARG1. Note: The rarity of the condition makes it unlikely that an unrelated reproductive partner of the proband whose ancestors do not come from a confined geographic area will be a carrier.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ARG1 pathogenic variant.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the ARG1 pathogenic variants in the family.

Biochemical genetic testing. The normal mean red blood cell arginase enzyme activity is 100 times the lower limit of detection. Thus, most obligate carriers have been easily distinguished from normal. However, in at least one instance, a mother who was an obligate carrier tested in the mid- to normal range.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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 under treatment for arginase deficiency, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. If both ARG1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Biochemical genetic testing. If molecular genetic testing is not possible, prenatal testing for pregnancies at 25% risk may be possible by measuring arginase enzyme activity in fetal red blood cells obtained by percutaneous umbilical blood sampling after 18 weeks' gestation [Hewson et al 2003, Korman et al 2004].

Neither amniocytes nor chorionic villous cells have arginase enzyme activity and thus are unsuitable for prenatal diagnosis using biochemical testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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

Molecular Pathogenesis

ARG1 encodes ARG1, which forms a homotrimer that requires manganese as a cofactor for catalytic activity and stability. Deficiency of arginase leads to accumulation of arginine and related, toxic compounds such as guanidinoacetate. The block in ureagenesis can lead to hyperammonemia although this is not common as arginase is the last (most distal) enzyme in the urea cycle.

Mechanism of disease causation. Loss-of-function variants cause arginase deficiency.

Table 9.

Notable ARG1 Pathogenic Variants

Author Notes

Angela Sun is a specialist in biochemical genetics and an Associate Professor of Pediatrics at the University of Washington and Seattle Children's Hospital.

Eric Crombez is a specialist in biochemical genetics. He was formerly co-director, with Dr Stephen Cederbaum, of the Urea Cycle Disorders Consortium site at UCLA and is now at Shire HGT in Cambridge, MA.

Derek Wong is Associate Clinical Professor of Pediatrics at UCLA. He is the Director of the Urea Cycle Disorders Consortium site at UCLA, and is the Head of Biochemical Genetics.

Author History

Stephen Cederbaum, MD; University of California Los Angeles (2004-2020)
Eric Crombez, MD (2004-present)
Angela Sun, MD (2020-present)
Derek Wong, MD (2004-present)

Revision History

• 28 May 2020 (ma) Comprehensive update posted live
• 28 August 2014 (me) Comprehensive update posted live
• 9 February 2012(me) Comprehensive update posted live
• 1 September 2009 (me) Comprehensive update posted live
• 13 February 2007 (me) Comprehensive update posted live
• 21 October 2004 (me) Review posted live
• 2 March 2004 (sc) Original submission

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