Clinical Diagnosis

Clinical findings are not specific, but the disorder may be suspected in instances of progressive loss of developmental milestones and spasticity.

Testing

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 >150 µmol/L) 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.

Testing Strategy

To confirm/establish 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 (sequence analysis followed by deletion/duplication analysis if two mutations are not identified) 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.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in ARG1.

Natural History

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, more commonly spastic diplegia, 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 intellectual disability.

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.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been described.

Prevalence

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; the true incidence in non-related populations is unknown.

Arginase deficiency may be more common in parts of Japan and among French Canadians.

Evaluations Following Initial Diagnosis

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
• Genetics consultation

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.

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.

Prevention of Primary Manifestations

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/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].
• Liver transplantation eliminates the hyperargininemia and presumably the risk for hyperammonemia.

Prevention of Secondary Complications

Most individuals with arginase deficiency have persistent hepatic synthetic function abnormalities, particularly, elevated prothrombin time. In some circumstances hepatic fibrosis and cirrhosis have developed and have either been fatal or required a liver transplant.

Arginine is the substrate for nitric oxide synthase; however, abnormalities in this pathway have not been described. The spasticity may be reactive and instances of marked improvement with Botox^® have been described.

Surveillance

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. If treatment fails to arrest the neurologic deterioration or if spasticity is symptomatic, appropriate orthopedic and physical therapy interventions are indicated.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

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.

Pregnancy Management

The authors are not aware of any instance in which pregnancy has been reported in a woman with arginase deficiency; therefore, no inference can be drawn about the safety of pregnancy to the mother or the fetus.

Therapies Under Investigation

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.

Other

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.

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 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 Detection

Carrier testing for at-risk family members by measurement of red blood cell arginase enzyme activity detects most carriers.

Carrier testing for at-risk family members with mutation analysis is possible if the disease-causing mutations in the family are known.

Related Genetic Counseling Issues

See 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. 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 of affected individuals.

Prenatal Testing

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].

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 an option for some families in which the disease-causing mutations have been identified.

Literature Cited

1. De Deyn PP, Marescau B, Qureshi IE, Cederbaum SD, Lambert M, Cerone R, Chamoles N, Specola N, Leonard JV, Gatti R, Kang SS, Mizutani N, Rezvani I, Snyderman SE, Terheggen HG, Yoshino M, Appel B, Martin JJ, Beaudet AL, Vilarinho L, Hirsch E, Jakobs K, van der Knaap MS, Naito H, Pickut BA, Shapira SK, Fuchshuber A, Roth B, Hylan K. Hyperargininemia: a treatable inborn error of metabolism? In: De Deyn PP, Marescau B, Qureshi IA, Mori A, eds. Guanidino Compounds in Biology and Medicine II. London, UK: John Libbey; 1997:53-69.
2. Hewson S, Clarke JT, Cederbaum S. Prenatal diagnosis for arginase deficiency: a case study. J Inherit Metab Dis. 2003;26:607–10. [PubMed: 14605507]
3. Iyer R, Jenkinson CP, Vockley JG, Kern RM, Grody WW, Cederbaum S. The human arginases and arginase deficiency. J Inherit Metab Dis. 1998;21 Suppl 1:86–100. [PubMed: 9686347]
4. Korman SH, Gutman A, Stemmer E, Kay BS, Ben-Neriah Z, Zeigler M. Prenatal diagnosis for arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis. Prenat Diagn. 2004;24:857–60. [PubMed: 15565656]
5. Morris SM Jr, Bhamidipati D, Kepka-Lenhart D. Human type II arginase: sequence analysis and tissue-specific expression. Gene. 1997;193:157–61. [PubMed: 9256072]
6. Prasad AN, Breen JC, Ampola MG, Rosman NP. Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. J Child Neurol. 1997;12:301–9. [PubMed: 9378897]
7. Scaglia F, Lee B. Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C Semin Med Genet. 2006;142C:113–20. [PubMed: 16602094]
8. Vockley JG, Goodman BK, Tabor DE, Kern RM, Jenkinson CP, Grody WW, Cederbaum SD. Loss of function mutations in conserved regions of the human arginase I gene. Biochem Mol Med. 1996;59:44–51. [PubMed: 8902193]

Suggested Reading

1. Boles RG, Stone ML. A patient with arginase deficiency and episodic hyperammonemia successfully treated with menses cessation. Mol Genet Metab. 2006;89:390–1. [PubMed: 16963300]
2. Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005;84:243–51. [PubMed: 15694174]

Author Notes

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.

Revision History

• 9 February 2012(me) Comprehensive update posted live
• 5 October 2010 (cd) Revision: deletion/duplication analysis available clinically
• 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