Arginase Deficiency

Arginase Deficiency

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Arginase Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • hyperargininemia

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.

Standard Therapies

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.



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 http://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: http://www.ncbi.nlm.nih.gov/omim/207800 . Accessed April 27, 2011.

Resources

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

Internet: http://www.CLIMB.org.uk



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

Internet: http://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

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison

Bldg 31, Rm 9A06

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Tel: (301)496-3583

Email: NDDIC@info.niddk.nih.gov

Internet: http://www2.niddk.nih.gov/



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

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.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

Internet: http://rarediseasesnetwork.epi.usf.edu/ucdc/index.htm



Medical Home Portal

Dept. of Pediatrics

University of Utah

P.O. Box 581289

Salt Lake City, UT 84158

Tel: (801)587-9978

Fax: (801)581-3899

Email: mindy.tueller@utah.edu

Internet: http://www.medicalhomeportal.org



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.

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