Arginase deficiency

Title

Other Names:

ARG1 deficiency; Hyperargininemia; Argininemia

Categories:

Congenital and Genetic Diseases; Metabolic disorders; RDCRN

Summary Summary

Arginase deficiency is an inherited metabolic condition in which the body is unable to process arginine (a building block of protein). As a result, people affected by the condition have high levels of arginine in the blood and may also experience episodes of hyperammonemia (a buildup of ammonia in the blood).^[1]^[2] The features of arginase deficiency generally develop between ages one and three years. Signs and symptoms may include poor growth, spasticity (abnormal tensing of the muscles), developmental delay, loss of developmental milestones, intellectual disability, seizures, and microcephaly.^[3]^[2]^[1] Arginase deficiency is caused by changes (mutations) in the ARG1 gene and is inherited in an autosomal recessive manner.^[2]^[3] Treatment is focused on lowering arginine levels and preventing hyperammonemia. People with arginase deficiency must follow a very low protein diet under the supervision of a medical team with experience treating metabolic conditions. They may also need to take certain medications (called nitrogen-scavenging drugs).^[3]^[1]

Last updated: 4/17/2016

Symptoms Symptoms

The signs and symptoms of arginase deficiency and the age at which they develop can vary from person to person. Most affected people appear to be healthy with normal development at birth and during early childhood. The first features of the condition often become apparent between the ages of one and three years, although cases of earlier and later onset have been reported.^[1]^[3]

Signs and symptoms may include:^[1]^[3]^[2]

Poor growth
Spasticity (abnormal tensing of the muscles)
Developmental delay
Loss of previously acquired developmental milestones
Intellectual disability
Seizures
Microcephaly
Problems with balance and coordination

Occasionally, people with arginase deficiency may have episodes of severe hyperammonemia (a buildup of ammonia in the blood). Although rare, these episodes are more likely to occur following a high-protein meal or during periods of stress caused by illness or fasting. Hyperammonemia can be associated with irritability, lethargy, refusal to eat, and vomiting.^[2]

If arginase deficiency is undiagnosed or if an affected person is unable to follow the strict diet, the prognosis is poor and may include severe intellectual disability and muscle stiffness; loss of the ability to walk; and loss of bladder and bowel control. However, even with treatment, the outcome can vary.^[3]

Last updated: 5/9/2016

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Aminoaciduria	90%
Behavioral abnormality	90%
Cognitive impairment	90%
Neurological speech impairment	90%
EEG abnormality	50%
Hemiplegia/hemiparesis	50%
Hyperammonemia	50%
Seizures	50%
Anorexia	-
Autosomal recessive inheritance	-
Diaminoaciduria	-
Hyperactivity	-
Intellectual disability	-
Irritability	-
Oroticaciduria	-
Postnatal growth retardation	-
Progressive spastic quadriplegia	-
Vomiting	-

Last updated: 9/1/2016

Cause Cause

Arginase deficiency is caused by changes (mutations) in the ARG1 gene, which provides instructions for making an enzyme called arginase. This enzyme plays a key role in the urea cycle, a sequence of reactions that process the excess nitrogen released when the body uses protein. Arginase controls the final step of the urea cycle, which removes nitrogen from arginine and makes a compound called urea. Urea is released by the kidneys in urine.^[2]

Mutations in ARG1 cause absent or reduced levels of functional arginase. As a result, arginine is not broken down properly, urea cannot be produced, and excess nitrogen builds up in the blood (ammonia). Increased levels of ammonia and arginine are thought to cause the many signs and symptoms associated with arginase deficiency.^[2]

Last updated: 5/9/2016

Inheritance Inheritance

Arginase deficiency is inherited in an autosomal recessive manner.^[3]^[2] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Last updated: 5/9/2016

Diagnosis Diagnosis

A diagnosis of arginase deficiency is often suspected based on the presence of characteristic signs and symptoms. Special blood tests to measure plasma levels of arginine and ammonia may then be ordered to further investigate the concerning symptoms. A diagnosis of arginase deficiency is confirmed when genetic testing identifies a disease-causing change (mutation) in each copy of the ARG1 gene or a blood test demonstrates reduced arginase enzyme activity in the red blood cells.^[1]^[3]

In some cases, arginase deficiency in a newborn may be suspected if elevated levels of arginine are found through newborn screening.^[3] For more information on newborn screening, including which conditions are screened for in each state, please visit Baby's First Test.

Last updated: 5/10/2016

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Newborn Screening

An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.
Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

Treatment Treatment

The main goals in the treatment of arginase deficiency are lowering arginine levels and preventing hyperammonemia (a buildup of ammonia in the blood). People with arginase deficiency must be closely supervised by a medical team with experience treating metabolic conditions and often require frequent blood tests to check their arginine levels. Because arginine is a building block of protein, affected people must follow a diet that is very low in protein. In fact, it is often recommended that people with arginase deficiency eat the minimal amount of protein needed to maintain good health, which varies based on many factors including age and weight. Protein is found in high amounts in meat, fish, beans, dairy products, eggs and nuts; however, it also occurs in foods like pasta, fruit and vegetables. Under the guidance of a metabolic dietician, people with arginase deficiency must closely monitor all the protein they eat. They are often advised to drink special formulas and/or buy medical foods in which the protein levels are tailored to fit their needs. Affected people may also need to take certain medications (called nitrogen-scavenging drugs) to reduce levels of arginine.^[3]^[1]

During an episode of severe hyperammonemia, people with arginase deficiency are generally treated in the hospital. They may require dialysis, nitrogen-scavenging medications, intravenous (IV) fluids/feeds or other treatments. These treatments are given to quickly reduce blood ammonia levels and prevent brain damage.^[3]

GeneReviews offers more specific information on the treatment of arginase deficiency and urea cycle disorders, in general. Please click on the links to access these resources.

Last updated: 4/17/2016

Management Guidelines

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
Arginase Deficiency
Urea Cycle Disorders Overview
The NORD Physician Guide for Arginase deficiency was developed as a free service of the National Organization for Rare Disorders (NORD) and it's medical advisors. The guides provide a resource for clinicians about specific rare disorders to facilitate diagnosis and treatment of their patients with this condition.

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Glycerol phenylbutyrate (Brand name: Ravicti) - Manufactured by Hyperion Therapeutics, Inc.
FDA-approved indication: Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients > or = to 2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).
National Library of Medicine Drug Information Portal

Prognosis Prognosis

The long-term outlook (prognosis) for people with arginase deficiency varies from person to person and depends on many factors, including the severity of the condition, the affected person's ability to follow the strict diet recommendations and the response to treatment. For example, some children appear to have more severe intellectual disability while others are more physically affected (i.e. severe spasticity with joint contractures). It is thought that approximately 75% of affected people survive the condition and live long lives.^[3]

If the condition is undiagnosed or if an affected person is unable to follow the strict diet, the prognosis is poor and may include severe intellectual disability and muscle stiffness; loss of the ability to walk; and loss of bladder and bowel control.^[3] However, even with treatment, the outcome can vary. In some cases, treatment has been shown to lower arginine levels in both the blood and the cerebrospinal fluid significantly, with some affected people even having near normal levels. With this response, continued treatment would be expected to improve long-term outlook and prevent progression of neurological symptoms. However, some affected people who follow the recommended treatment regimen may continue to have high levels of arginine in their blood, which can be associated with symptoms that worsen overtime.^[1] In fact, one study found that 50% of people with arginase deficiency who are compliant with treatment see an improvement in symptoms, 25% have symptoms that remain the same, and 25% experience a progression of the condition.^[4]

Last updated: 4/13/2016

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

The U.S. National Institutes of Health, through the National Library of Medicine, developed ClinicalTrials.gov to provide patients, family members, and members of the public with current information on clinical research studies. There is a study titled Study of Treatment and Metabolism in Patients With Urea Cycle Disorders which may be of interest to you. To find this trial, click on the link above.

Patient Registry

The Urea Cycle Disorders Consortium is a team of doctors, nurses, research coordinators, and research labs throughout the US, working together to improve the lives of people with Urea Cycle Disorders. The Urea Cycle Disorders Consortium maintains a registry for patients who wish to be contacted about clinical research opportunities.
For more information on the registry see: http://rarediseasesnetwork.epi.usf.edu/ucdc/takeaction/index.htm

Organizations Organizations

Nonprofit support and advocacy groups bring together patients, families, medical professionals, and researchers. These groups often raise awareness, provide support, and develop patient-centered information. Many are the driving force behind research for better treatments and possible cures. They can direct people to research, resources, and services. Many groups also have experts who serve as medical advisors. Visit their website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD. Suggest an organization to add.

Organizations Supporting this Disease

Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Toll-free: 0800 652 3181
Telephone: 0845 241 2173
E-mail: contact@climb.org.uk
Website: http://www.climb.org.uk
National Urea Cycle Disorders Foundation
75 South Grand Avenue
Pasadena, CA 91105
Telephone: 800-38-NUCDF (800-386-8233)
Fax: 818-790-2460
E-mail: info@nucdf.org
Website: http://www.nucdf.org

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Financial Resources

Good Days provides help to patients with life-altering conditions. Assistance includes help with the cost of medications and travel.
The HealthWell Foundation provides financial assistance for underinsured patients living with chronic and life-altering conditions. They offer help with drug copayments, deductibles, and health insurance premiums for patients with specific diseases. The disease fund status can change over time, so you may need to check back if funds are not currently available.

Education Resources

The Genetics Education Materials for School Success (GEMSS) aims to assure that all children with genetic health conditions succeed in school-life. Their Web site offers general and condition-specific education resources to help teachers and parents better understand the needs of students who have genetic conditions.

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

Genetics Home Reference (GHR) contains information on Arginase deficiency. This website is maintained by the National Library of Medicine.
MedlinePlus.gov provides more information on urea cycle disorders in general. MedlinePlus is a Web site designed by the National Library of Medicine to help you research your health questions.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Arginase deficiency. Click on the link to view a sample search on this topic.

News & Events News & Events

Other Conferences

Reaching for a Cure: 2011 NUCDF Annual Conference, July 8 2011 - July 10, 2011
Location: Sheraton Denver Downtown, Denver, Colorado
Description: This conference offers the unique opportunity to meet other UCD families, stay informed, and learn about new advances in research, treatment and management to improve the lives of children and adults with UCD. Working together, our NUCDF families and community of committed researchers and medical professionals are making a major impact with advances in the understanding of UCDs, accelerating research, and improved outcomes in children and adults with UCD. In the past four years, research for UCDs has increased by 400%! Let's continue the momentum and end the devastating effects of UCD.

Related Diseases Related Diseases

The following diseases are related to Arginase deficiency. If you have a question about any of these diseases, you can contact GARD.

Urea cycle disorders

GARD Answers GARD Answers

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What is the best treatment for a 3 year old who has arginase deficiency? And what is the prognosis? See answer

References References

Schlune A, Vom Dahl S, Häussinger D, Ensenauer R, Mayatepek E. Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. September 2015; 47(9):1751-1762.
Arginase deficiency. Genetics Home Reference. August 2013; http://ghr.nlm.nih.gov/condition/arginase-deficiency.
Derek Wong, MD, Stephen Cederbaum, MD, and Eric A Crombez, MD. Arginase Deficiency. GeneReviews. August 2014; http://www.ncbi.nlm.nih.gov/books/NBK1159/.
Prasad AN, Breen JC, Ampola MG, Rosman NP. Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. J Child Neurol. August 1997; 12(5):301-309.