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Arginase Deficiency Disorder

Arginase Deficiency Disorder is a rare, genetic disorder that is characterized by the lack of an enzyme, arginase, which is important for body metabolism.

What are other Names for this Condition? (Also known as/Synonyms)

  • ARG1 Deficiency Disorder
  • Arginase Deficiency Disease
  • Hyperargininemia

What is Arginase Deficiency Disorder? (Definition/Background Information)

  • Arginase Deficiency Disorder is a rare, genetic disorder that is characterized by the lack of an enzyme, arginase, which is important for body metabolism
  • The predisposing risk factor of Arginase Deficiency Disorder is inheriting two mutated copies of the gene that causes the disorder from the parents. Arginase Deficiency Disorder is caused by mutation in the ARG1 gene that is inherited in an autosomal recessive manner
  • Arginase Deficiency Disorder is a congenital disorder that is mostly diagnosed during the neonatal period, since infants are now screened at birth for this disorder. Certain populations in northern Mexico and northern Quebec are more affected by Arginase Deficiency Disorder than other regions in the world
  • The signs and symptoms associated with Arginase Deficiency Disorder typically do not appear during the first few months (or even up to a year) of the infant’s life. However, delayed growth during the ages of 1 to 3 years, and the lack of control of voluntary movements are strong indicators of this deficiency disorder. Complications include persistent liver dysfunction or central nervous system abnormalities
  • A diagnosis may be established during newborn screening by detecting a higher-than-normal concentration of arginine in blood, which may be the result of Arginase Deficiency Disorder
  • Treatment options include dialysis to lower blood ammonia (nitrogen) concentration, nitrogen scavenger drugs, and dietary restrictions. The prognosis of Arginase Deficiency Disorder is generally good, so long as the necessary dietary restrictions are adhered to and proper medication is taken before symptom onset
  • There are no preventive measures available for this disorder, as it is caused by genetic factors. Genetic counseling may help couples determine risks of having a child with Arginase Deficiency Disorder

Who gets Arginase Deficiency Disorder? (Age and Sex Distribution)

  • The age distribution of Arginase Deficiency Disorder is in the newborn population, since neonates are now screened after birth (in many regions of the world) for this disorder
  • The disorder affects males and females equally and no gender preference is seen
  • All racial and ethnic groups are at equal risk. Nevertheless, Arginase Deficiency Disorder presents itself most commonly in areas of northern Mexico and northern Quebec (in the French population)

What are the Risk Factors for Arginase Deficiency Disorder? (Predisposing Factors)

  • Arginase Deficiency Disorder is an inherited genetic disorder, and hence, a positive family history is an important predisposing factor that may increase one’s risk for this disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Arginase Deficiency Disorder? (Etiology)

  • The main cause behind Arginase Deficiency Disorder is the absence of a very crucial enzyme in the urea cycle. The urea cycle is a metabolic process in the body, which produces ammonia during breakdown. Urea cycle is very important in eliminating nitrogen waste from the body
  • Because this enzyme is responsible for breaking down the body’s nitrogen waste and removing it from the body, the lack of this enzyme results in the buildup of nitrogen and arginine in blood and cerebrospinal fluid
  • The mutation of both copies of the ARG1 gene results in the expression of Arginase Deficiency Disorder in the individual. One mutated copy must be inherited from each parent, termed autosomal recessive trait. The parents may both be carriers, may both have the disorder, or one parent may be a carrier while the other has the disorder

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Arginase Deficiency Disorder?

The signs and symptoms of Arginase Deficiency Disorder do not typically present themselves immediately following the child’s birth. It may be absent even up to a year after birth.

  • If a child between the ages of 1-3 years shows signs of developmental delay, growth delays, lack of control of voluntary movements (especially in the legs), and progressive stiffness, a healthcare provider may suspect Arginase Deficiency Disorder
  • Other signs include lack of appetite, vomiting, nausea, seizures, fatigue, and/or coma

How is Arginase Deficiency Disorder Diagnosed?

The main diagnosis of Arginase Deficiency Disorder occurs during neonatal screening, shortly after the child is born, in a majority of cases.

  • The infant is tested for arginase enzyme activity, which is unusually low if the child is affected
  • Other tests to diagnose Arginase Deficiency Disorder include a blood test to test for arginine concentration in the blood plasma. In the affected child, the concentration is abnormally high, which may raise a suspicion of this deficiency disorder

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Arginase Deficiency Disorder?

The complications of Arginase Deficiency Disorder may include the following (below). Complications are especially observed in children who are not diagnosed early enough or who do not receive adequate treatment.

  • Impaired cognitive development
  • Persistent muscle stiffness
  • Inability to walk
  • Loss of bowel/bladder control
  • Severe intellectual disability

Other complications may include impaired liver function due to high nitrogen levels in blood.

How is Arginase Deficiency Disorder Treated?

The main course of treatment for Arginase Deficiency Disorder is a reduction of ammonia (the form of nitrogen carried in blood) and arginine in the blood plasma. The treatment is also geared towards preventing excess ammonia from building up in blood.

  • To reduce very high plasma (blood) ammonia concentrations, a dialysis may be performed. This is only recommended if severe symptoms are noted due to very high ammonia levels in blood
  • Medications, known as nitrogen scavenger drugs (sodium phenylacetate and sodium benzoate), are also offered as treatment. These drugs provide the body with an alternative pathway to excrete nitrogen (instead of the normal urea cycle)
  • Another important aspect of Arginase Deficiency Disorder treatment is appropriate dietary restriction. This is aimed at limiting arginine intake through proteins in the diet. Essential amino acids are offered as dietary supplements, since these amino acids may be not taken in adequate quantities when one is placed on a low-protein diet
  • If the individual has seizures associated with Arginase Deficiency Disorder, anti-seizure medications, such as carbamazepine or phenobarbital, may be administered

Blood tests are periodically undertaken to monitor plasma ammonia and arginine levels, as well as to ensure that the liver is functioning well.

How can Arginase Deficiency Disorder be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Arginase Deficiency Disorder, since it is a genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Arginase Deficiency Disorder
  • Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Arginase Deficiency Disorder? (Outcomes/Resolutions)

  • The prognosis of Arginase Deficiency Disorder is typically good, as long as appropriate measures are taken to prevent excess build-up of nitrogen in blood. Such measures include a restricted protein diet and use of medications known as nitrogen scavenger drugs. These drugs are responsible for allowing the body a different method of eliminating nitrogen waste from the body, thereby preventing its harmful buildup
  • These treatment measures lead to a very optimal outcome if begun before onset of significant symptoms. However, if the child shows symptoms, the treatment usually helps in preventing further deterioration of the signs and symptoms; the signs and symptoms that are already present, may not get better though
  • If, however, the child shows symptoms, the treatment is targeted at stabilizing nitrogen excretion, even though a reversal of symptoms cannot be achieved
  • Arginase Deficiency Disorder can be a fatal condition, if it is not detected, or if a suitable treatment regimen is not established early enough

Additional and Useful Relevant Information for Arginase Deficiency Disorder:

  • The genetic carrier testing blood test is performed when parents-to-be wish to assess their risk of passing on a genetic disorder to their children

The following link can help you understand the genetic carrier testing blood test:


What are some Useful Resources for Additional Information?

National Urea Cycle Disorders Foundation
75 S. Grand Ave., Pasadena, CA 91105
Phone: (626) 578-0833
Email: ucdsupport@nucdf.org
Website: http://www.nucdf.org

Genetic and Rare Diseases (GARD) Information Center
PO Box 8126 Gaithersburg, MD 20898-8126
Toll-Free: (888) 205-2311
TTY: (888) 205-3223
International Telephone Access Number: (301) 251-4925
Fax: (301) 251-4911
Website: http://rarediseases.info.nih.gov

References and Information Sources used for the Article:

Cederbaum, MD, S. (2016). Arginase Deficiency. In National Organization for Rare Disorders.

Wong, MD, D., Cederbaum, MD, S., & Crombez, MD, E. A. (2014, August 28). Arginase Deficiency. In GeneReviews.

Arginase Deficiency (2016, August 23). In Genetics Home Reference: Your Guide to Understanding Genetic Conditions.

Longo, MD PhD, N., & Kerr, MD PhD, L. M. (2015, December). Arginase Deficiency. In Medical Home Portal.

Helpful Peer-Reviewed Medical Articles:

Iyer, R. K., Yoo, P. K., Kern, R. M., Rozengurt, N., Tsoa, R., O'Brien, W. E., ... & Cederbaum, S. D. (2002). Mouse model for human arginase deficiency.Molecular and cellular biology, 22(13), 4491-4498.

Iyer, R., Jenkinson, C. P., Vockley, J. G., Kern, R. M., Grody, W. W., & Cederbaum, S. (1998). The human arginases and arginase deficiency.Journal of inherited metabolic disease, 21(1), 86-100.

Crombez, E. A., & Cederbaum, S. D. (2005). Hyperargininemia due to liver arginase deficiency. Molecular genetics and metabolism, 84(3), 243-251.

Michels, V. V., & Beaudet, A. L. (1978). Arginase deficiency in multiple tissues in argininemia. Clinical genetics, 13(1), 61-67.

Terheggen, H. G., Lowenthal, A., Lavinha, F., Colombo, J. P., & Rogers, S. (1975). Unsuccessful trial of gene replacement in arginase deficiency.Zeitschrift für Kinderheilkunde, 119(1), 1-3.

Adriaenssens, K., Karcher, D., Lowenthal, A., & Terheggen, H. G. (1976). Use of enzyme-loaded erythrocytes in in-vitro correction of arginase-deficient erythrocytes in familial hyperargininemia. Clinical chemistry, 22(3), 323-326.

Spector, E. B., Kiernan, M., Bernard, B., & Cederbaum, S. D. (1980). Properties of fetal and adult red blood cell arginase: a possible prenatal diagnostic test for arginase deficiency. American journal of human genetics,32(1), 79.

Grody, W. W., Kern, R. M., Klein, D., Dodson, A. E., Wissman, P. B., Barsky, S. H., & Cederbaum, S. D. (1993). Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme. Human genetics, 91(1), 1-5.