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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Three- to fourfold elevation of plasma arginine concentration above the upper limit of normal is highly suggestive of the diagnosis. Many if not most affected infants will be picked up with the current full-panel expanded newborn screening testing done in many states and countries. Most affected individuals have no detectable arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Molecular genetic testing of ARG1, the only gene known to be associated with arginase deficiency, is available clinically.
Management. Treatment of manifestations: Management should closely mirror that for urea cycle disorders, except that individuals with arginase deficiency are unlikely to have episodes of hyperammonemia, which (when present) are likely to respond to conservative management (e.g., intravenous fluid administration). Treatment should be by a team coordinated by a metabolic specialist. Treatment of an acutely ill (comatose and encephalopathic) individual requires rapid reduction of plasma ammonia concentration, use of pharmacologic agents (sodium benzoate or sodium phenylbutyrate) to allow excretion of excess nitrogen through alternative pathways, introduction of calories supplied by carbohydrates and fat to reduce catabolism and the amount of excess nitrogen in the diet, and physiologic stabilization with intravenous fluids and cardiac pressors as necessary while avoiding over-hydration and resulting cerebral edema. 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. Surveillance: regular follow-up at intervals determined by age and degree of metabolic stability. Agents/circumstances to avoid: valproic acid (exacerbates hyperammonemia). Testing of relatives at risk: plasma quantitative amino acid analysis in all sibs (especially younger ones) of a proband to allow early diagnosis and treatment of those found to be affected. Other: prompt treatment of acute intercurrent illnesses with special dietary intervention or hospitalization to minimize the effect of catabolism.
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 disease-causing mutations in the family are known.
Clinical findings are not specific, but the disorder may be suspected in instances of progressive loss of developmental milestones and spasticity.
For laboratories offering biochemical testing, see
.
Plasma arginine concentration. Elevation of plasma arginine concentration three- to fourfold above the upper limit of normal is highly suggestive of the diagnosis.
Note: Up to twofold elevations 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 >150µM) is uncommon.
Urinary orotic acid concentration. Urinary orotic acid concentration is often elevated but is not a primary screen for the disorder.
Red blood cell arginase enzyme activity. Arginase enzyme assay can be used to confirm the diagnosis.
Affected individuals. Most affected individuals have no detectable arginase enzyme activity (usually <1% of normal) in red blood cell extracts.
Note: (1) Although arginase is stable, a control sample should be obtained and treated identically if the cells are to be shipped to a distant site. (2) Arginase enzyme activity is reduced in liver as well as red blood cells, but arginase enzyme activity in liver is rarely measured because of the risks involved in liver biopsy and the ease of diagnosis from red blood cells.
Carriers. 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-normal range.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. ARG1 is the only gene associated with arginase deficiency.
Clinical testing. Sequence analysis of the ARG1 coding region has detected mutations in most affected individuals tested to date, but sample size is small and no statement about mutation detection rate can be made at this time [J Haberle, personal communication].
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Gene and Test Method | Test Availability |
|---|---|---|---|---|
| ARG1 | Sequence analysis | Sequence variants | Unknown | Clinical
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Establishing the diagnosis in a proband
Plasma arginine elevation is the primary means of ascertainment.
Until recently, red blood cell enzyme testing was the gold standard for diagnostic confirmation. Molecular genetic testing is now readily available and is an alternative to enzyme testing as the first-line confirmatory test. Enzyme assay remains the norm if two mutations are not found.
The degree of enzyme deficiency in red blood cells or the genotype cannot be used to establish disease severity or prognosis as they are but two of several factors involved in the outcome.
Carrier testing for at-risk relatives using molecular genetic testing requires prior identification of the disease-causing ARG1 mutations in the family.
Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies using molecular genetic testing require prior identification of the disease-causing mutations in the family.
No other phenotypes are known to be associated with mutations in ARG1.
Unlike any of 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, even in individuals with two null mutations. Episodic hyperammonemia of variable degree may occur but is rarely severe enough to be life threatening or to cause death. Hyperammonemia is often recognized only if blood ammonia or plasma amino acid concentrations are obtained during an acute illness. Although data are not available, it appears that more than 75% of affected individuals survive their disease and live long, albeit handicapped lives.
Most commonly, birth and early childhood are normal. At the age of one to three years, linear growth slows and spasticity begins to develop. Soon, previously normal cognitive development slows or stops and the child begins to lose developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe mental retardation.
Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures.
All affected individuals have growth deficiency.
Seizures are common and are usually controlled easily.
Other parts of the nervous system including basal ganglia, cerebellum, medulla, and spinal cord are largely spared [De Deyn et al 1997].
Older individuals may present with postoperative encephalopathy.
No genotype-phenotype correlations have been described.
Arginase deficiency is, along with N-acetylglutamate synthetase deficiency, thought to be the least common of the urea cycle defects. Its incidence has been estimated at between 1:350,000 and fewer than 1:1,000,000, but the true incidence in non-related populations is unknown.
Arginase deficiency may be more common in parts of Japan and among French Canadians.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Hyperammonemia. Arginase is the sixth and final enzyme of the eight known steps in the urea cycle. See Urea Cycle Disorders Overview for approaches to distinguish: (1) other causes of hyperammonemia from a urea cycle disorder and (2) the differences between the urea cycle disorders themselves.
Spasticity. Arginase deficiency may be misdiagnosed as static spastic diplegia (cerebral palsy). See Hereditary Spastic Paraplegia Overview. It should be noted that arginase deficiency is one of the few treatable causes of spastic diplegia [Prasad et al 1997].
ARG2. A second arginase gene is known (ARG2), but no human deficiency state has been identified and it is not clear that elevated plasma arginine would be a part of such a deficiency.
To establish the extent of disease in an individual diagnosed with arginase deficiency, the following evaluations are recommended:
Plasma ammonia concentration
Plasma arginine concentration
Developmental assessment
Complete neurologic evaluation
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.
Infants should be managed by a team coordinated by a metabolic specialist in a specialized center. In the acute phase, the mainstays of treatment are the following:
Rapidly reducing plasma ammonia concentration. The best way to reduce plasma ammonia concentration quickly is by dialysis; the faster the flow rate of dialysate, the faster the clearance of ammonia from the plasma. The method employed depends on the affected individual's circumstances and available resources. Fastest is use of pump-driven dialysis, in which an extracorporeal membrane oxygenation (ECMO) pump is used to drive a hemodialysis (HD) machine. Other methods are hemofiltration (both arteriovenous and venovenous), peritoneal dialysis, and continuous-drainage peritoneal dialysis. Dialysis can usually be discontinued when plasma ammonia concentration falls below 200 µmol/L. Affected individuals often experience a "rebound" hyperammonemia that may require further dialysis, although rarely is this level of intervention required in arginase deficiency.
Pharmacologic management to allow alternative pathway excretion of excess nitrogen. Blocking the production of ammonia and the need for ureagenesis is accomplished by diminishing catabolism with adequate non-protein calories and with a combination of the nitrogen scavenger drugs sodium phenylacetate and sodium benzoate. A loading dose of the drugs is followed by maintenance administration, initially intravenously and later orally when the individual is stable. Intravenous forms of these medications are now approved by the FDA and are generally available.
Reducing the amount of excess nitrogen in the diet and reducing catabolism through the introduction of calories supplied by carbohydrates and fat. In acutely ill individuals, calories should be provided as carbohydrate and fat, either intravenously as glucose and Intralipid® or orally as protein-free oral formula, such as Mead Johnson 80056® or Ross Formula ProPhree®; however, complete restriction of protein should not exceed 24-48 hours, because depletion of essential amino acids may result in endogenous protein catabolism and nitrogen release. High parenteral glucose plus insulin can be used acutely to diminish endogenous protein catabolism. Individuals should be transitioned from parenteral to enteral feeds as soon as possible. In early treatment, feeding 1.0 to 1.5 g of protein/kg body weight with 50% as essential amino acids is advised, particularly for infants. Older children require and tolerate lower protein intake.
Reducing the risk of neurologic damage. Cautionary measures are physiologic stabilization with intravenous fluids (10% dextrose with one-quarter normal saline) and cardiac pressors as necessary while avoiding overhydration and resulting cerebral edema, the duration of which correlates with poor neurologic outcome.
Older individuals are at risk for episodes of hyperammonemia and should continue to be managed by a specialist in metabolic disorders.
Seizures are easily treated by phenobarbital or carbamazepine.
Acute intercurrent illnesses should be treated promptly with special dietary intervention or hospitalization to minimize the effect of catabolism.
The goal should be maintenance of plasma arginine concentration as near normal as possible, consistent with the individual's tolerance for the following interventions:
Restriction of dietary protein through use of specialized formulas. In the best of circumstances, the affected individual should be on the minimal protein intake needed to maintain protein biosynthetic function, growth, and normal or near-normal plasma amino acid concentrations. Half or more of dietary protein should be an arginine-free essential amino acid mixture.
Administration of oral nitrogen scavenging drugs. Sodium benzoate or sodium phenylbutyrate at a dose of 250 mg/kg/day up to 10 g per day (typically described as per meter sq body surface area) in three divided doses may be used as well [De Deyn et al 1997, Iyer et al 1998].
Patients are seen at regular intervals determined by their age and degree of metabolic stability.
Infants should be seen monthly or more frequently, with monitoring of plasma concentration of ammonia and amino acids; growth; and neurologic function.
Valproic acid is to be avoided as it exacerbates hyperammonemia in urea cycle and other inborn errors of metabolism [Scaglia & Lee 2006].
Because the age of onset is delayed and the manifestations can vary, all sibs, but especially younger ones, should be tested by plasma quantitative amino acid analysis or by enzymatic and/or molecular genetic testing if the family-specific mutations are known to see if they are affected so that morbidity can be reduced by early diagnosis and treatment.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Immunizations can be provided on the usual schedule.
Multivitamin and fluoride supplementation are indicated for all affected individuals.
Appropriate use of antipyretics is indicated. Ibuprofen is preferred over acetaminophen.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Arginase deficiency is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
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.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband
Although most severely affected individuals have not reproduced, those who are successfully treated are likely to be fertile.
The offspring of an individual with arginase deficiency are obligate heterozygotes (carriers).
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 of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members using red blood cell arginase activity detects most carriers. Note: Although no laboratories listed in the GeneTests Laboratory Directory are offering this testing, it may be available.
Carrier testing for at-risk family members with mutation analysis is possible if the disease-causing mutations in the family are known.
See Testing of Relatives at Risk for information on testing 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 testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See DNA banking for a list of laboratories offering this service. See
for a list of laboratories offering DNA banking.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified in the family before prenatal testing can be performed.
Biochemical genetic testing. If molecular genetic testing is not possible, prenatal diagnosis 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]. Note: Although no laboratories listed in the GeneTests Laboratory Directory are offering this testing, it may be available.
Neither amniocytes nor chorionic villous cells normally 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.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| ARG1 | 6q23 | Arginase-1 | ARG1 @ LOVD | ARG1 |
Normal allelic variants. ARG1 is approximately 10-15 kb in length and has eight exons and seven introns (see Ensembl Gene Report).
Pathologic allelic variants. Mutations are located throughout the coding region of the gene. Missense mutations are generally found in amino acids that have been highly conserved during evolution and especially in sequences involved in the active site of the enzyme. Chain-terminating mutations and deletions and insertions may be found anywhere in the gene [Vockley et al 1996].
Normal gene product. Arginase-1 is 322 amino acids long and is manganese dependent; it exists in nature as a trimer, and, unlike arginase-2, which is located in mitochondrial matrix, is located in the cytosol. The enzyme is highly stable and can be completely reactivated, if not denatured, by treating with manganese at 65° C. Expression is highest in the liver and RBCs. (Reference sequence NP_000036.200)
Abnormal gene product. The mutated arginase-1 protein is rarely stable enough to be detected in the mature red blood cells of affected individuals by immunologic means. A second, ancestral arginase gene (ARG2) located on 14q, is expressed in different tissue and cell types and may partially compensate for deficiency of arginase-1. It is thought that, from an evolutionary perspective, the ARG2 gene existed first and that ARG1 arose from it following a gene duplication event. The two gene products are more than 50% homologous at the amino acid level [Morris et al 1997, Iyer et al 1998].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Stephen Cederbaum is Professor of Psychiatry, Pediatrics and Human Genetics at UCLA. He is Chief Emeritus of the Division of Genetics in the Department of Pediatrics and is in charge of the clinical genetics service. His area of special interest is biochemical genetics.
Eric Crombez is a specialist in biochemical genetics. He was formerly co-director, with Dr. Cederbaum, of the Urea Cycle Disorders Consortium site at UCLA and is now at Shire HGT in Cambridge, MA.
1 September 2009 (me) Comprehensive update posted live
30 June 2008 (cd) Revision: sequence analysis and prenatal testing available for ARG1 mutations
13 February 2007 (me) Comprehensive update posted to live Web site
21 October 2004 (me) Review posted to live Web site
2 March 2004 (sc) Original submission
