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Disease Profile

Arginase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

E72.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

ARG1 deficiency; Hyperargininemia; Argininemia

Categories

Congenital and Genetic Diseases; Metabolic disorders; RDCRN

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]

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 highprotein 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]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances

[ more ]

0000708
Diaminoaciduria
0008339
Global developmental delay
0001263
Intellectual disability, severe
Early and severe mental retardation
Mental retardation, severe
Severe mental retardation

[ more ]

0010864
Neurological speech impairment
Speech disorder
Speech impairment
Speech impediment

[ more ]

0002167
30%-79% of people have these symptoms
EEG abnormality
0002353
Hemiplegia/hemiparesis
Paralysis or weakness of one side of body
0004374
Hyperammonemia
High blood ammonia levels
0001987
Progressive spastic quadriplegia
0002478
Seizure
0001250
1%-4% of people have these symptoms
Cerebellar atrophy
Degeneration of cerebellum
0001272
Childhood onset
Symptoms begin in childhood
0011463
Cholestasis
Slowed or blocked flow of bile from liver
0001396
Episodic vomiting
0002572
Frequent falls
0002359
Hepatomegaly
Enlarged liver
0002240
Hyperargininemia
High blood arginine levels
Increased blood arginine concentration

[ more ]

0500153
Micronodular cirrhosis
0001413
Neonatal onset
0003623
Portal fibrosis
0006580
Spastic gait
Spastic walk
0002064
Percent of people who have these symptoms is not available through HPO
Anorexia
0002039
Autosomal recessive inheritance
0000007
Hyperactivity
More active than typical
0000752
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Irritability
Irritable
0000737
Oroticaciduria
High urine orotic acid levels
0003218
Postnatal growth retardation
Growth delay as children
0008897
Spastic paraparesis
0002313
Vomiting
Throwing up
0002013

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]

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.

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.
    • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are 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

      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]

      Management Guidelines

      • 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

        Organizations

        Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s 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

          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

          • 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.
          • Genetics Home Reference (GHR) contains information on Arginase deficiency. This website is maintained by the National Library of Medicine.
          • 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

            • 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
            • 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.

              References

              1. 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.
              2. Arginase deficiency. Genetics Home Reference. August 2013; https://ghr.nlm.nih.gov/condition/arginase-deficiency.
              3. Derek Wong, MD, Stephen Cederbaum, MD, and Eric A Crombez, MD. Arginase Deficiency. GeneReviews. August 2014; https://www.ncbi.nlm.nih.gov/books/NBK1159/.
              4. 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.
              5. 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.
              6. Roth KS. Arginase Deficiency. Medscape Reference. September 8, 2015; https://emedicine.medscape.com/article/941838-overview#a5.
              7. Hereditary urea cycle abnormality. MedlinePlus. 2015; https://medlineplus.gov/ency/article/000372.htm.

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