Arginase deficiency

Información en español Title

Other Names:

ARG1 deficiency; Hyperargininemia; Argininemia

Categories:

Congenital and Genetic Diseases; Metabolic disorders; RDCRN

Summary Summary

Arginase deficiency is an inherited metabolic disease in which the body is unable to process arginine (a building block of protein).^[1]^[2] It belongs to a group of disorders known as urea cycle disorders. These occur when the body's process for removing ammonia is disrupted, which can cause ammonia levels in the blood to rise (hyperammonemia). In most cases, symptoms appear between the ages of one and three years. Symptoms may include feeding problems, vomiting, poor growth, seizures, and stiff muscles with increased reflexes (spasticity). People with arginase deficiency may also have developmental delay, loss of developmental milestones, and intellectual disability.^[3]^[2]^[1] Arginase deficiency is caused by 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 are generally placed on a very low-protein diet with the help of a registered metabolic dietitian. They may be prescribed certain medications called nitrogen-scavenging drugs.^[3]^[1]

Last updated: 4/25/2017

Symptoms Symptoms

Most people with arginase deficiency appear to be healthy at birth and have normal development during early childhood. The first features of arginase deficiency often appear between the ages of one and three years. In some cases, symptoms may begin earlier or later.

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

Poor growth (present in all the people who have arginase deficiency)
Stiff muscles and increased reflexes (spasticity)
Developmental delay
Loss of previously acquired developmental milestones
Intellectual disability
Seizures
Small head size (microcephaly)
Problems with balance and coordination

Occasionally, people with arginase deficiency have episodes of severe buildup of ammonia in the blood (hyperammonemia). 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 cause irritability, lethargy, refusal to eat, breathing difficulty, movement disorders, vomiting and, in severe cases, coma.^[2]

If arginase deficiency is undiagnosed or if the person with the disorder is unable to follow the strict low-protein diet, severe intellectual disability and muscle stiffness may develop, as well as loss of the ability to walk and loss of bladder and bowel control.^[3]

Last updated: 4/25/2017

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)
Behavioral abnormality	Very frequent (present in 80%-99% of cases)
Diaminoaciduria	Very frequent (present in 80%-99% of cases)
Intellectual disability, severe	Very frequent (present in 80%-99% of cases)
Neurological speech impairment	Very frequent (present in 80%-99% of cases)
EEG abnormality	Frequent (present in 30%-79% of cases)
Hemiplegia/hemiparesis	Frequent (present in 30%-79% of cases)
Hyperammonemia	Frequent (present in 30%-79% of cases)
Progressive spastic quadriplegia	Frequent (present in 30%-79% of cases)
Seizures	Frequent (present in 30%-79% of cases)
Anorexia	-
Autosomal recessive inheritance	-
Hyperactivity	-
Intellectual disability	-
Irritability	-
Oroticaciduria	-
Postnatal growth retardation	-
Vomiting	-

Last updated: 6/1/2017

Cause Cause

Arginase deficiency is caused by 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 as ammonia. Increased levels of ammonia and arginine are thought to cause the many signs and symptoms associated with arginase deficiency.^[2]

Compared to other urea cycle disorders, ammonia levels are not as high in arginase deficiency. Typically, ammonia levels are only mildly elevated or even normal in arginase deficiency. Some researchers believe that there may be other factors besides ammonia level involved in the cause of the neurological symptoms of arginase deficiency.^[4]

Last updated: 4/25/2017

Inheritance Inheritance

Arginase deficiency is inherited in an autosomal recessive manner.^[3]^[2] This means that to be affected, a person must have a disease-causing mutation in both copies of the gene associated with arginase deficiency. The parents of a person with arginase deficiency 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 metabolic disorder. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the genetic disorder, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the genetic disorder AND not be a carrier.

Last updated: 4/25/2017

Diagnosis Diagnosis

A diagnosis of arginase deficiency is often suspected based on the person's signs and symptoms. Special blood tests to measure levels of arginine and ammonia may then be ordered. A diagnosis of arginase deficiency is confirmed when genetic testing identifies a disease-causing 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, visit Baby's First Test.

Last updated: 4/25/2017

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 to lower arginine levels and to prevent buildup of ammonia in the blood (hyperammonemia). People with arginase deficiency must be closely supervised by a medical team with experience treating metabolic disorders. They may need frequent blood tests to check arginine levels.

Because arginine is a building block of protein, people with arginase deficiency must follow a diet that is very low in protein. It is often recommended they 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 dietitian, 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. People with arginase deficiency may also need to take certain medications (called nitrogen-scavenging drugs) to reduce their levels of arginine.^[3]^[1]

If people with arginase deficiency have episodes of hyperammonemia, they may be given intravenous (IV) fluids. 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, or other treatments. These treatments are given to quickly reduce blood ammonia levels and prevent brain damage.^[3]

Last updated: 4/25/2017

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 Horizon Pharma, Inc.
FDA-approved indication: Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients at least 2 months 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. It depends on many factors, including the severity of the disorder, the 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 (e.g. severe spasticity with joint contractures). It is thought that approximately 75% of people with arginase deficiency live long lives.^[3]

If the disorder is not diagnosed or if a person with arginase deficiency 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 significantly lower arginine levels in both the blood and the cerebrospinal fluid, with some 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 people with arginase deficiency 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 over time.^[1] In fact, one older 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 metabolic disorder.^[5]

Nonetheless, early diagnosis in the clinical course allows for improved outcome in most cases. Following a low-protein diet is essential for a better prognosis. Patients and caregivers need to be instructed to seek early medical attention for illnesses, such as fever, because hyperammonemia, although uncommon in this disease, can occur.^[6]

Last updated: 4/25/2017

Do you have updated information on this condition? Let us know.

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

ClinicalTrials.gov lists trials that are studying or have studied Arginase deficiency. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

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.

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

Do you know of an organization? Send us your suggestions.

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

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

How is arginase deficiency different from the other urea cycle disorders? See answer
What is the best treatment for a 3 year old who has arginase deficiency? And what is the prognosis? See answer

Have a question? Contact a GARD Information Specialist.

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. https://www.ncbi.nlm.nih.gov/pubmed/?term=26123990.
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/.
Amayreh W, Meyer U & Das A M. Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring. Dev Med Child Neurol. 2014; 56:1021–1024. https://www.ncbi.nlm.nih.gov/pubmed/?term=24814679.
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. https://www.ncbi.nlm.nih.gov/pubmed/?term=9378897.
Roth KS. Arginase Deficiency. Medscape Reference. September 8, 2015; http://emedicine.medscape.com/article/941838-overview#a5.
Hereditary urea cycle abnormality. MedlinePlus. 2015; https://medlineplus.gov/ency/article/000372.htm.