Arginase Deficiency

Overview

Arginase deficiency is the least common of the urea cycle disorders. It results from the absence of the enzyme arginase 1, which breaks down arginine to ornithine and urea, leading to episodic hyperammonemia. Although the hyperammonemia is usually mild, it could be life-threatening. Infants and young children with this disorder usually appear normal until they reach ages 1 to 4 years old and begin showing spasticity and developmental delay. Many children also develop microcephaly. If untreated, developmental regression and seizures often occur. Early diagnosis and nutritional management can control many of the deleterious neurological effects observed in this condition.

Other Names & Coding

Argininemia ARG1 deficiency Hyperargininemia

ICD-10 coding

E72.21, Argininemia

ICD-10 for Argininemia (icd10data.com) provides further coding details.

Prevalence

The prevalence of arginase deficiency is unknown. The incidence of Arginase deficiency is 1:950,000. The incidence of all urea cycle disorders is 1:35,000. In the United States, that equates to about 113 new patients per year. [Summar: 2013]

Genetics

Arginase deficiency is an autosomal recessive disorder. It appears to be more common and/or more severe in northern Mexico and in the French Canadian population in northern Quebec. [Ibarra-González: 2010] [Qureshi: 1983] A family history may reveal consanguinity. Activity of the enzyme can be tested in red blood cells. The identification of 1 mutation in each allele of the ARG1 gene, encoding for arginase by DNA sequencing, can definitively confirm the diagnosis.

Prognosis

The prognosis improves with treatment when a restricted-protein diet and nitrogen-scavenging medications are started before the onset of symptoms. Once children show symptoms, treatment may help stabilize the process, but it does not usually reverse the symptoms. Even with treatment, most affected children show some degree of intellectual disability, which is likely related to the accumulation of arginine and related compounds in the brain.

Practice Guidelines

There are no published guidelines for care of children with arginase deficiency.

Roles of the Medical Home

Children with arginase deficiency, whether diagnosed presymptomatically or after disabilities are present, should be considered to have a chronic condition. They should be managed with chronic care visits by their medical home and followed concurrently with metabolic genetics.

Clinical Assessment

Pearls & Alerts for Assessment

Spastic diplegia may occur with cerebral palsy or arginase deficiency

Children with a clinical presentation of cerebral palsy, particularly the spastic diplegic type, may have arginase deficiency.

Screening

For the Condition

Arginase deficiency can be diagnosed through the newborn screening program with elevated arginine levels. Some patients may not be identified by newborn screening. See the Portal's Argininemia for protocol to follow upon notification of a positive newborn screen.

Of Family Members

Because individuals with arginase deficiency may be asymptomatic unless they become sufficiently ill or physically stressed, siblings of children with arginase deficiency should be tested. Testing usually involves plasma quantitative amino acid analysis, plasma ammonia, urine orotic acid, enzyme activity determination in red blood cells, or genetic testing if the mutation in the family is known.

For Complications

Children who are diagnosed with arginase deficiency after the newborn period should have developmental and neurologic assessments and may need therapy for spasticity and intellectual disability. See the Cerebral Palsy and the Intellectual Disability & Global Developmental Delay for assessment information and details of therapy.

Presentations

Without early biochemical diagnosis, children can present with spastic diplegia, developmental delays, microcephaly, or episodic hyperammonemia with lethargy. Although most children with arginase deficiency will have an indolent course, there have been case reports of severe presentations in infancy with acute hyperammonemia as in other urea cycle disorders. [Jain-Ghai: 2011]
Although urea cycle disorders are included in newborn screening panels in the U.S. and many other countries, it is not yet clear how easily patients with arginase deficiency can be diagnosed with this methodology. The most frequent urea cycle disorders (ornithine transcarbamylase deficiency) is not yet detected by newborn screening programs and, in most cases, severe forms of these conditions will present before the results of the screening are back. For these reasons, physicians should maintain a high index of suspicion in children who present with lethargy in the first few days of life and obtain a plasma ammonia if other causes for the clinical presentation are not identified.

Diagnostic Criteria

Diagnosis is based on hyperammonemia, elevated arginine on plasma amino acids, reduced arginase activity in red blood cells, and the presence of mutations in the ARG1 gene.

Differential Diagnosis

The most important differential diagnosis for arginase deficiency is cerebral palsy. [Asnis: 1979] Spastic diplegia is the most common pattern of motor abnormalities in arginase deficiency. [Lee: 2011] Arginase deficiency, leukodystrophy, and other uncommon conditions should be considered in children without a clear historical reason for or typical MRI findings of cerebral palsy.
Assessment information for these differential diagnoses can be found in the Portal's Cerebral Palsy and Leukodystrophies.

Comorbid & Secondary Conditions

Intellectual disability occurs frequently in children with arginase deficiency for the repeat bouts of hyperammonemia and for the elevated arginine. Elevated arginine levels increase the synthesis and the accumulation of guanidinoacetic acid that is neurotoxic. Spastic diplegia is usually noted after 2 years of age. Many older children have an ataxic gait.

History & Examination

Current & Past Medical History

Delays in development can be noted early in life. Some patients develop microcephaly after birth. Spastic diplegia usually appears after 2 years of age. Affected patients may spontaneously avoid protein in their diet. Ataxia and seizures are frequent complications in the teenage years.

Family History

Because arginase deficiency is an autosomal recessive condition, family history is not usually helpful (though consanguinity might be considered).

Pregnancy/Perinatal History

No abnormalities are expected.

Developmental & Educational Progress

Delays in development may occur if the diet and other therapies are not strictly adhered to. Delays can be seen even in optimally treated children due to the accumulation of arginine and guanidino compounds that are neurotoxic. Children should be monitored carefully and receive developmental/educational therapies as needed.

Social & Family Functioning

The child should be followed by developmental services starting early in life.

Physical Exam

The exam is completely normal in young infants. Adherence to the diet reduces the risk for complications. Growth failure, lethargy, spasticity, acquired microcephaly, developmental delays, ataxia, and seizures can be seen in untreated or poorly treated older patients.

Neurologic Exam

Deep tendon reflexes can be increased. Toe walking can be observed in untreated patients.

Testing

Sensory Testing

Sensory testing is usually normal.

Laboratory Testing

The first line of testing consists of the measurement of plasma ammonia and plasma amino acids. The excretion of orotic acid in urine is usually markedly increased in these patients. These tests can be ordered in a patient presenting symptomatically or in patients identified by newborn screening with elevated arginine levels.
Levels of guanidinoacetic acid (part of laboratory testing for inborn errors of creatine metabolism) are usually increased in patients with arginase deficiency despite normal creatine levels.

Imaging

Brain MRI can show brain atrophy in the absence of therapy. EEG as clinically necessary for suspicion of seizures.

Genetic Testing

Enzyme assay in red blood cells and sequencing of the ARG1 gene can confirm the diagnosis.

Other Testing

All children with arginase deficiency should have developmental and neurologic evaluations.

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see ID providers [2])

Evaluation is important for confirmation of the diagnosis and initiation of management. Ongoing management includes periodic visits.

Treatment & Management

Pearls & Alerts for Treatment & Management

Avoid valproic acid

Valproic acid should be avoided because it may contribute to hyperammonemia.

Extreme physical stress and individuals with acute illnesses

Extreme physical stress, such as dehydration and starvation, should be avoided and individuals with acute illness should be followed closely so their diet can be modified or they can be managed as inpatients if necessary. Arginase Deficiency (NECMP).

Avoid systemic steroids

They may cause catabolism and aggravate hyperammonemia.

Older individuals still at risk for hyperammonemia

Older individuals are still prone to episodes of hyperammonemia and should continue to be followed by metabolic genetics. They usually spontaneously adopt a low-protein diet to prevent hyperammonemia.

In the event of lethargy or coma

Individuals who present symptomatically with lethargy or coma usually have high ammonia levels and are prone to brain damage if the situation is not quickly corrected. Metabolic genetics should be consulted immediately. Ammonia is decreased by the administration of intravenous fluid calories in the form of glucose and intralipids. Fluid administration can lead to brain edema. For this reason, adequate sodium salts should be included in all intravenous preparations. Intravenous mannitol followed by hypertonic saline might also be considered. In some cases, dialysis and the administration of the nitrogen scavenging medications sodium phenylacetate and sodium benzoate are necessary. If the patient is not in shock, oral scavengers (sodium phenylbutyrate or glycerol triphenylbutyrate) can be used instead of the IV preparation. These medications are always used once adequate calories are provided to prevent further catabolism.

How should common problems be managed differently in children with Arginase Deficiency?

Growth or Weight Gain

Most patients have normal weight and height early on. Some can develop high-weight gain later in life due to increased intake of carbohydrates. All patients need to be followed by a dietitian specialized in metabolic disorders.

Development (Cognitive, Motor, Language, Social-Emotional)

Most patients with arginase deficiency are only mildly delayed early in life, with the delays becoming more evident as the child becomes older.

Viral Infections

Infections should be treated as in other children. Avoid excessive rises in body temperature to prevent catabolism, ibuprofen is preferred to acetaminophen to lower body temperature.

Over the Counter Medications

Avoid the use of medications capable of narcotics in patients with depressed sensorium.

Prescription Medications

Valproic acid may contribute to hyperammonemia. Oral or parenteral steroids should be used with cautions given their potential of triggering acute hyperammonemia.

Common Complaints

Headaches can be caused by hyperammonemia. Mood disturbances have been associated with fluctuations of ammonia levels.

Systems

Nutrition/Growth/Bone

Treatment of hyperargininemia focuses on dietary protein restriction, supplementation of essential amino acids, and the use of alternative pathways (sodium phenylbutyrate and/or benzoate) to remove the nitrogen waste. [Iyer: 1998] Treated patients have fewer and more easily controlled hyperammonemic crises and less progressive neurological deterioration.
Children with arginase deficiency are placed on protein-restricted diets and given special formulas to maintain normal plasma amino acid concentrations. Ammonia and amino acid concentrations, growth, developmental progress, and neurologic function are monitored closely. Nitrogen scavenging medications (sodium benzoate or sodium phenylbutyrate) are necessary for all patients with arginase deficiency. High-protein foods such as meat, fish, and dairy products are avoided. The minimum amount of protein necessary for growth is given to children and personalized based on individual tolerance. Fifty percent or more of these proteins should be derived from high-quality foods or special formulas enriched in essential amino acids. Special formulas without protein are necessary to provide calories from fat and sugar and to provide adequate minerals and vitamins.
Sodium phenylbutyrate and benzoate can be used to reduce the concentration of glutamine and glycine and to dispose of excess nitrogen. It is important to remember that the condition is aggravated by fasting. One common complication in older children is post-operative encephalopathy in which the catabolic state induced by the necessary fasting before anesthesia and surgery. This can be prevented by the administration of proper IV fluids until the patient receives adequate calories by mouth. Even with optimal intervention, it is unclear whether all consequences of the disease can be successfully prevented.

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see ID providers [2])

The frequency of visits should be determined by age and stability. Infants will need relatively frequent visits; older individuals who are not prone to episodes of hyperammonemia are generally seen annually.

Medical Genetics (see ID providers [3])

Ongoing management should involve periodic collaboration with a metabolic geneticist who can offer new research findings and experience, as well as genetic counseling for the family and the patient.

Nutrition, Metabolic (see ID providers [13])

Refer for assessment and modification of the diet to changing needs.

Development (general)

Infants with arginase deficiency, whether symptomatic or not, should be followed by an Early Intervention Program. Developmental milestone achievement and school progress should be monitored closely by the medical home.

Specialty Collaborations & Other Services

Early Intervention for Children with Disabilities/Delays (see ID providers [149])

Involve early on since children with arginase deficiency are at risk for developmental delays.

Transitions

Individuals will need to remain on the protein-restricted diet for life. Care should be transitioned to a provider of internal medicine or family practice by adulthood, with the process beginning around age 14. See Transition Issues for more information about the clinician's role in transitioning adolescents with special health care needs to adult care.

No Related Issues were found for this diagnosis.

Ask the Specialist

What treatments for arginase deficiency are recommended?

Treatment is by dietary protein restriction, supplementation of essential amino acids, and the use of alternative pathways (sodium phenylbutyrate and/or benzoate) to remove the nitrogen waste.

Resources for Clinicians

On the Web

Arginase Deficiency (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Argininemia (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Resources for Argininemia (Disease InfoSearch)
Compilation of information, articles, and links to support; from Genetic Alliance.

Urea Cycle Disorders Overview (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Helpful Articles

PubMed search for arginase deficiency in children and adolescents

Carvalho DR, Brum JM, Speck-Martins CE, Ventura FD, Navarro MM, Coelho KE, Portugal D, Pratesi R.
Clinical features and neurologic progression of hyperargininemia.
Pediatr Neurol. 2012;46(6):369-74. PubMed abstract

Sin YY, Baron G, Schulze A, Funk CD.
Arginase-1 deficiency.
J Mol Med (Berl). 2015;93(12):1287-96. PubMed abstract

Clinical Tools

Care Processes & Protocols

Confirmatory Algorithms for Arginine Elevated (ACMG) ( PDF Document 155 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Patient Education & Instructions

Learn the Signs Act Early (CDC)
Offers many tools, videos, lists, learning materials, and a developmental Milestone Tracker app (ages 2 months to 5 years); Centers for Disease Control and Prevention.

Resources for Patients & Families

Arginase Deficiency (FAQ)

Information on the Web

Arginase Deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Argininemia - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by genetic specialists, for families who have received a diagnosis of arginase deficiency; Screening, Technology, and Research in Genetics.

National & Local Support

National Urea Cycle Disorders Foundation
Support and information that includes medical lectures on urea cycle disorders, nutrition and medication resources, and information about events and conferences.

Studies/Registries

Arginase Deficiency (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Urea Cycle Disorders Consortium (Rare Diseases Network)
A consortium bringing together researchers and patients for clinical trials.

Services for Patients & Families in Idaho (ID)

Service Categories	NW		NM	NV	OH	RI
Biochemical Genetics (Metabolics)	1	1	2	1	3	3
Early Intervention for Children with Disabilities/Delays	3	35	32	3	14	55
Medical Genetics	1	2	5	1	4	8
Nutrition, Metabolic	13	13	15	14	15	14

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: November 2011; last update/revision: July 2018

Current Authors and Reviewers:

Author:

Nicola Longo, MD, Ph.D.

Authoring history

2011: first version: Lynne M. Kerr, MD, PhD^A; Nicola Longo, MD, Ph.D.^R

^AAuthor; ^CAContributing Author; ^SASenior Author; ^RReviewer

Bibliography

Asnis GM, Asnis D, Dunner DL, Fieve RR.
Cogwheel rigidity during chronic lithium therapy.
Am J Psychiatry. 1979;136(9):1225-6. PubMed abstract

Ibarra-González I, Fernández-Lainez C, Vela-Amieva M.
Clinical and biochemical characteristics of patients with urea cycle disorders in a developing country.
Clin Biochem. 2010;43(4-5):461-6. PubMed abstract

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. PubMed abstract

Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A.
Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported?.
Mol Genet Metab. 2011;104(1-2):107-11. PubMed abstract / Full Text

Lee BH, Jin HY, Kim GH, Choi JH, Yoo HW.
Argininemia presenting with progressive spastic diplegia.
Pediatr Neurol. 2011;44(3):218-20. PubMed abstract

Qureshi IA, Letarte J, Ouellet R, Larochelle J, Lemieux B.
A new French-Canadian family affected by hyperargininaemia.
J Inherit Metab Dis. 1983;6(4):179-82. PubMed abstract

Sin YY, Baron G, Schulze A, Funk CD.
Arginase-1 deficiency.
J Mol Med (Berl). 2015;93(12):1287-96. PubMed abstract

Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B.
The incidence of urea cycle disorders.
Mol Genet Metab. 2013;110(1-2):179-80. PubMed abstract / Full Text