NORD gratefully acknowledges Stephen Cederbaum, MD, University of California Los Angeles Medical Center, for assistance in the preparation of this report.
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 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.
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.
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.
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 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.
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
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about arginase deficiency:
Stephen Cederbaum, M.D.
635 Charles E. Young Dr. South, Rm 347
Los Angeles, CA 90095-7332
Phone: 310 825-0402
Fax: 310 206-5061
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.
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.
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.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100