Arginase Deficiency

National Organization for Rare Disorders, Inc.

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Important

It is possible that the main title of the report Arginase Deficiency is not the name you expected.

Disorder Subdivisions

  • None

General Discussion

Arginase deficiency is a rare inherited disorder characterized by complete or partial lack of the enzyme arginase. Arginase is one of six enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the arginase enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood and arginine (hyperarginemia) in the blood and cerebrospinal fluid. Untreated children may exhibit seizures, spasticity, short stature and intellectual disability. Arginase deficiency is inherited as an autosomal recessive genetic disorder.



The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.

Symptoms

Symptoms associated with arginase deficiency differ from those associated with other disorders of the urea cycle. In most cases, infants with arginase deficiency do not exhibit any symptoms during the first few months to a year of life. Infants with arginase deficiency rarely experience severe hyperammonemia or hyperammonemic coma, which are characteristic of the other urea cycle disorders.



Affected children experience a lag in growth between one and three years and may walk on their toes and develop progressive stiffness and lack of control of voluntary movements of the legs (spastic diplegia). Cognitive development slows or stops and if untreated, children develop severe spasticity, an inability to walk, loss of bowel and bladder control and severe intellectual disability.



All affected children have growth deficiency and many also experience seizures.

Causes

Arginase deficiency is inherited as an autosomal recessive genetic disorder and is caused by mutations in the ARG1 gene. Mutations in the ARG1 gene result in production of an abnormal arginase enzyme.







Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.







All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Arginase deficiency has been estimated to occur in approximately 1 in 300,000-1,000,000 births.



Arginase deficiency is the least common of all the disorders of the urea cycle. The estimated frequency of urea cycle disorders collectively is one in 30,000. However, because urea cycle disorders like arginase deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.

Diagnosis

Most affected infants are now identified at birth through newborn screening. Arginase enzyme activity is usually not detectable in red blood cells from affected individuals. Molecular genetic testing is available to confirm the diagnosis. If two mutations are not found, red blood cell enzyme testing is used to confirm the diagnosis.

Standard Therapies

Treatment



Treatment should be coordinated by a metabolic specialist and is based on reducing plasma ammonia and arginine concentration, preventing excess ammonia from being formed, and reducing the amount of nitrogen in the diet.



Reduction of plasma ammonia concentration is accomplished by dialysis and several different methods are available.



The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous and oral forms of these medications are available (Ammonul and Ucephan). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only.



Dietary restrictions in individuals with arginase deficiency are aimed at limiting the amount of arginine and protein intake. Children with arginase deficiency are placed on a low-protein, arginine-restricted diet supplemented by essential amino acids.



Seizures are treated with phenobarbital or carbamazepine. Valporic acid should be avoided, as it can increase blood ammonia levels.



Affected individuals should receive periodic blood tests to determine the levels of ammonia and arginine in the blood. Excessive levels of ammonia or arginine should be promptly treated.



Genetic counseling is recommended for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222



TTY: (866) 411-1010



Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:



www.centerwatch.com.



Contact for additional information about arginase deficiency:



Stephen Cederbaum, M.D.



IDDRC/NPI



635 Charles E. Young Dr. South, Rm 347



Los Angeles, CA 90095-7332



Phone: 310 825-0402



Fax: 310 206-5061



Email: scederbaum@mednet.ucla.edu

References

TEXTBOOKS



Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:935-37.



Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:350-55.



Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:12-14.



Menkes JH, au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:46-52.



Urea Cycle Disorders. In: Gellis and Kagan (Eds.), Current Pediatric Therapy, 17th Ed., WB Saunders and Co.



JOURNAL ARTICLES



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(2):113-20.



Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005;84:243-51.



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.



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.



INTERNET



Cederbaum S and Crombez E. (Updated 10/5/10). Arginase Deficiency. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2011. Available at //www.genetests.org. Accessed April 27, 2011.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Argininemia; Entry No: 207800. Last Edited October 29, 2010. Available at: //www.ncbi.nlm.nih.gov/omim/207800 . Accessed April 27, 2011.

Supporting Organizations

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building
176 Nantwich Road
Crewe, CW2 6BG
United Kingdom
Tel: 4408452412173
Fax: 4408452412174
Email: enquiries@climb.org.uk
Website: //www.CLIMB.org.uk

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
Website: //rarediseases.info.nih.gov/GARD/

Medical Home Portal

Dept. of Pediatrics
University of Utah
Salt Lake City, UT 84158
Tel: (801)587-9978
Fax: (801)581-3899
Email: mindy.tueller@utah.edu
Website: //www.medicalhomeportal.org

NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison
Bldg 31, Rm 9A06
Bethesda, MD 20892-2560
Tel: (301)496-3583
Email: NDDIC@info.niddk.nih.gov
Website: //www2.niddk.nih.gov/

National Urea Cycle Disorders Foundation

75 South Grand Avenue
Pasadena, CA 91105-1602
Tel: (626)578-0833
Fax: (626)578-0823
Tel: (800)386-8233
Email: info@nucdf.org
Website: //www.nucdf.org

The Arc

1825 K Street NW, Suite 1200
Washington, DC 20006
Tel: (202)534-3700
Fax: (202)534-3731
Tel: (800)433-5255
Email: info@thearc.org
Website: //www.thearc.org

Urea Cycle Disorders Consortium

Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010
Tel: (815)333-4014
Email: jseminar@cnmc.org
Website: //rarediseasesnetwork.epi.usf.edu/ucdc/index.htm

For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.