Arginase Deficiency

Description

Other Names

Argininemia
ARG1 deficiency
Hyperargininemia

Diagnosis Coding

ICD-10

E72.21, Argininemia

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

Description

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 occur in the majority of individuals. Early diagnosis and nutritional management can control many of the deleterious neurological effects observed in this condition.

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. There are certain geographical areas, such as northern Mexico [Ibarra-González: 2010] or the French Canadian population in northern Quebec [Qureshi: 1983] where it appears to be more common and/or more severe. The family history may reveal consanguinity. The only gene known to be involved in clinical arginase deficiency is ARG1, which can be tested for clinically.

Prognosis

The prognosis is excellent if treatment with a restricted-protein diet and nitrogen-scavenging medications begins before the onset of symptoms. Once children show symptoms, treatment may help stabilize the process, but does not usually reverse the symptoms.

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.

Practice Guidelines

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

Helpful Articles

PubMed search for arginase deficiency in children and adolescents

Scaglia F, Lee B.
Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency.
Am J Med Genet C Semin Med Genet. 2006;142C(2):113-20. PubMed abstract / Full Text

Clinical Assessment

Screening

For The Condition

Arginase deficiency can be diagnosed through newborn screening with elevated arginine levels. See the Portal's Arginase Deficiency page 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. This 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 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. [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, Initial Diagnosis and Leukodystrophies, Initial Diagnosis.

Pearls & Alerts

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.

History & Examination

Family History

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

Pregnancy Or Perinatal History

No abnormalities are expected.

Current & Past Medical History

Delays in development may occur if the child/youth/family has not strictly adhered to the diet and other therapy. Children should be monitored carefully and receive developmental/educational therapies as needed.

Physical Exam

The exam should remain completely normal with adherence to the diet. Growth failure, lethargy, spasticity, acquired microcephaly, developmental delays, and seizures can be seen in untreated or poorly treated older patients.

Testing

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 also 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.

Imaging

EEG as clinically necessary for suspicion of seizures.

Genetic Testing

Enzyme assay in rat cells or sequencing of the ARG1 gene confirms the diagnosis.

Other Testing

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

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

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

Nutrition, Metabolic (see Services below for relevant providers)

Nutritional guidance is needed to initiate and maintain a restricted-protein diet. Ongoing guidance on maintaining the protein-restricted diet is helpful as the child grows and develops.

Treatment & Management

Pearls & Alerts

Avoid valproic acid

Valproic acid should be avoided as 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. See Argininemia Acute Illness Protocol (NECMP).

Adolescents still need involvement from metabolic genetics

Older individuals are still prone to episodes of hyperammonemia and should continue to be followed by metabolic genetics.

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. These are always used in addition to the provision of adequate calories to prevent catabolism.

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. 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 at time of 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 can complicate this condition. Even with optimal intervention, it is unclear whether all consequences of the disease can be successfully prevented.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

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 yearly.

Pediatric Genetics (see Services below for relevant providers)

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 Services below for relevant providers)

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.

Subspecialist Collaborations & Other Resources

Early Intervention for Children with Disabilities/Delays (see Services below for relevant providers)

Early Intervention should be involved early on as 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 by 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.

Frequently Asked Questions

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.

Issues Related to Arginase Deficiency

Funding & Access to Care

Formula Funding

Resources

Information for Clinicians

Argininemia (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information for the condition; National Center for Biotechnology Information, U.S. National Library of Medicine.

Argininemia (OMIM)
An extensive review of literature providing technical information for genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

Resources for Argininemia (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Urea Cycle Disorders Overview (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; U.S. National Library of Medicine.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Helpful Articles

PubMed search for arginase deficiency in children and adolescents

Scaglia F, Lee B.
Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency.
Am J Med Genet C Semin Med Genet. 2006;142C(2):113-20. PubMed abstract / Full Text

Clinical Tools

Patient Education & Instructions

Learn the Signs. Act Early (CDC)
Tools, videos, lists, and learning materials to track a child’s development (ages 2 months to 5 years) and act if concerned about progress; Centers for Disease Control and Prevention.

Information & Support for Families

Family Diagnosis Page

Information on the Web

Arginase Deficiency (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; U.S. 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 an initial diagnosis of a newborn disorder; Screening, Technology, and Research in Genetics.

Support National & Local

National Urea Cycle Disorders Foundation
This non-profit organization provides support services and information for families; medical lectures on urea cycle disorders; nutrition and medication resources; and information about events and conferences.

Studies/Registries

Arginase Deficiency (ClinicalTrials.gov)
Comprehensive list of research studies related to congenital heart disease; National Institutes of Health.

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

Services for Patients & Families

Early Intervention for Children with Disabilities/Delays

See all Early Intervention for Children with Disabilities/Delays services providers (13) in our database.

Nutrition, Metabolic

See all Nutrition, Metabolic services providers (2) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (4) in our database.

Pediatric Metabolic Genetics

See all Pediatric Metabolic Genetics services providers (2) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors

Authors: Lynne M. Kerr, MD, PhD - 10/2011
Chuck Norlin, MD - 10/2011
Reviewing Author: Nicola Longo, MD, Ph.D. - 10/2011

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

Scaglia F, Lee B.
Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency.
Am J Med Genet C Semin Med Genet. 2006;142C(2):113-20. PubMed abstract / Full Text

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