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Last updated: 04/11/2023
Years published: 1986, 1987, 1990, 1992, 1993, 1996, 1997, 2001, 2011, 2016, 2019, 2023
NORD gratefully acknowledges Stephen Cederbaum, MD, University of California Los Angeles Medical Center, for assistance in the preparation of this report.
Summary
Arginase-1 deficiency is a rare inherited disorder characterized by complete or partial lack of the enzyme arginase in the liver and red blood cells. 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, progressive spasticity, short stature and intellectual disability. Most affected infants can now be identified at birth through newborn screening. Arginase-1 deficiency is inherited as an autosomal recessive genetic disorder.
Introduction
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. In arginase-1 deficiency the accumulation of arginine in the body and not excess ammonia is the predominant biochemical and pathological abnormality.
Symptoms associated with arginase-1 deficiency differ from those associated with other disorders of the urea cycle. Most infants with arginase-1 deficiency do not exhibit any symptoms during the first few months to a year of life. Infants with arginase-1 deficiency infrequently experience severe hyperammonemia or hyperammonemic coma, which are characteristic of the other urea cycle disorders.
Affected children may 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.
Almost all affected children have growth deficiency and many also experience seizures.
Arginase-1 deficiency is inherited as an autosomal recessive genetic disorder and is caused by changes (mutations or pathogenic variants) 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 altered gene for the same trait, one from each parent. If an individual inherits 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 altered 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 is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered gene, which increases the risk to have children with a recessive genetic disorder.
Arginase-1 deficiency has been estimated to occur in approximately 1 in 300,000-1,000,000 births.
Arginase-1 deficiency is among 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-1 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. This is likely to change now that arginase-1 deficiency can be diagnosed by newborn screening.
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 pathogenic variants the ARG1 gene 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. This should be used only when the high levels are producing severe symptoms.
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). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only. Ravicti is a form of phenylbutyrate that is less irritating to the gastrointestinal track and easier to take.
Dietary restrictions in individuals with arginase-1 deficiency are aimed at limiting the amount of arginine and protein intake. Children with arginase-1 deficiency are placed on a low-protein, arginine-restricted diet supplemented by essential amino acids.
Seizures are treated with phenobarbital or carbamazepine. Valproic 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 and to be sure that liver function is not impaired. 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
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about arginase deficiency:
Stephen Cederbaum, MD
IDDRC/NPI
635 Charles E. Young Dr. South, Rm 347
Los Angeles, CA 90095-7332
Phone: 310 825-0402
Fax: 310 206-5061
Email: [email protected]
TEXTBOOKS
Disorders of the Urea Cycle and Related Enzymes. In Saudubray J-M, Baumgartner MR, Garcia-Cazorla A, Walter J. Eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Springer, 2022.
Urea Cycle Enzymes. Brusilow SW, Horwich Al. The Online Metabolic and Molecular Bases of Inherited Disease Eds. David Valle, et al. New York, NY: McGraw-Hill, 2014, https://ommbid.mhmedical.com/content.aspx?sectionid=225084071&bookid=2709 Accessed Feb 6, 2023.
INTERNET
Sun A, Crombez EA, Wong D. Arginase Deficiency. 2004 Oct 21 [Updated 2020 May 28]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1159/ Accessed Feb 6, 2023.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Argininemia; Entry No: 207800. Last Updated 12/13/2022. Available at: https://www.ncbi.nlm.nih.gov/omim/207800 Accessed Feb 6, 2023.
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