Arginase Deficiency
Overview
One of the known urea cycle disorders, all characterized by hyperammonemia and encephalopathy. A deficiency, usually near complete absence, of activity of arginase, blocks the final step of the cycle. Unlike other urea cycle defects, argininemia usually presents after 1 year of age with progressive spastic paraparesis, developmental delays, seizures that become progressively harder to control, and sometimes acquired microcephaly and short stature. On rare occasions, it presents early in life, as with other urea cycle defects.Incidence
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]Prenatal Testing
Genetic testing possible by amniocentesis or chorionic villus sampling (CVS) if both disease causing mutations of an affected family member have been identified. Enzyme testing by fetal blood sampling (arginase is expressed in red cells).Other Testing
Genetic testing is possible for at-risk family members if both disease causing mutations of an affected family member have been identified.Clinical Characteristics
With treatment before a serious hyperammonemic episode, clinical and developmental outcome may be improved. Without treatment, symptoms may begin shortly after birth or as late as a few years of age, but most affected children will show developmental delays at about 1 year of age followed by progressive spasticity even in the absence of acute episodes of hyperammonemia. Acute symptoms may occur during prolonged fasting, periods of increased energy demands (fever, stress, lack of sleep), and after meals high in protein.Initial signs and symptoms may include:
- Poor appetite
- Illness or fussiness following high-protein feedings
- Vomiting
- Irritability
- Lethargy
- Lab findings:
- Elevated arginine
- Elevated urine orotic acid
- Hyperammonemia (though usually not as high as in other urea cycle defects)
- Elevated guanidinoacetate
- Poor growth
- Muscle weakness
- Spasticity
- Microcephaly
- Seizures
- Intellectual disability
- Death (up to 75% live long, though handicapped, lives)
Follow-up Testing after Positive Screen
Plasma amino acid analysis and urine orotic acid. Enzyme assay on red blood cells can be used to confirm the diagnosis. DNA testing is used for final diagnostic confirmation.Primary Care Management
Upon Notification of the + Screen
- Contact the family and evaluate the infant for poor feeding, vomiting, lethargy;
- Provide emergency treatment/referral for lethargy, hypotonia, seizures, signs of liver disease (see the ACT Sheet for Argininemia (ACMG) (
348 KB) for additional information);
- To confirm the diagnosis, work with the following service(s): Newborn Screening Services (see RI providers [2]);
- For evaluation and ongoing collaborative management, consult the following service(s): Pediatric Genetics (see RI providers [5]);
If the Diagnosis is Confirmed
- Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Argininemia - Information for Parents (STAR-G));
- Assist in implementation and support of a low protein diet;
- Sodium benzoate or phenylbutyrate therapy help reduce arginine and ammonia levels;
- Periodic monitoring of amino acid and ammonia levels is indicated;
- For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.
- Periodic Botox injections and heel cord lengthening can improve spasticity in these patients.
Specialty Care Collaboration
Initial consultation and ongoing collaboration with the following service(s): Pediatric Genetics (see RI providers [5]). A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.Resources
Information & Support
For Professionals
Argininemia Acute Illness Protocol (NECMP)
Guideline for clinicians treating the sick infant or child with argininemia; developed under the direction of Dr. Harvey Levy,
Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School,
for the New England Consortium of Metabolic Programs.
Argininemia (OMIM)
An extensive review of literature providing technical information for genetic disorders; Online Mendelian Inheritance in Man
site, hosted by Johns Hopkins University.
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.
Resources for Argininemia (Disease InfoSearch)
Compilation of information, articles, and links to support; from Genetic Alliance.
National Newborn Screening & Global Resource Center (NNSGRC)
Fact sheets, data reports, publications, and information for clinicians about genetic screening that includes links to state
genetic contacts.
Genetics in Primary Care Institute (AAP)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; American
Academy of Pediatrics.
For Parents and Patients
Argininemia (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the 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 a diagnosis
of arginase deficiency; Screening, Technology, and Research in Genetics.
National Urea Cycle Disorders Foundation
This non-profit organization gives support and information that includes medical lectures on urea cycle disorders, nutrition
and medication resources, and information about events and conferences.
Baby's First Test (Genetic Alliance)
Clearinghouse for local, state, and national newborn screening education, programs, policies, and resources. Also, provides
many ways for people to connect and share their viewpoints and questions about newborn screening; supported by the U.S. Department
of Health and Human Services.
Newborn Screening Information for Families (NNSGRC)
Information for families about genetic screening. Links to support groups, advocacy groups, and state genetic contacts; National
Newborn Screening and Global Resource Center.
Center for Parent Information and Resources (DOE)
Parent centers in every state provide training to parents of children with disabilities and provide information about special
education, transition to adulthood, health care, support groups, local conferences and other federal, state, and local services.
This link has a search tool to help you find the parent center in your state; Department of Education, Office of Special Education.
Tools
ACT Sheet for Argininemia (ACMG) ( 348 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical
Genetics.
Confirmatory Algorithms for Argininemia (ACMG) ()
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.
Services in Rhode Island
Newborn Screening Services
See all Newborn Screening Services services providers (2) in our database.
For other services related to this condition, browse our Services categories or search our database.
Studies
Arginase Deficiency (ClinicalTrials.gov)
Comprehensive list of research studies related to congenital heart disease; National Institutes of Health.
Helpful Articles
PubMed search for argininemia in children, last 5 years.
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
Therrell BL, Currier R, Lapidus D, Grimm M, Cederbaum SD.
Newborn screening for hyperargininemia due to arginase 1 deficiency.
Mol Genet Metab.
2017;121(4):308-313.
PubMed abstract
Huemer M, Carvalho DR, Brum JM, Ünal Ö, Coskun T, Weisfeld-Adams JD, Schrager NL, Scholl-Bürgi S, Schlune A, Donner MG, Hersberger
M, Gemperle C, Riesner B, Ulmer H, Häberle J, Karall D.
Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.
J Inherit Metab Dis.
2016;39(3):331-340.
PubMed abstract
Page Bibliography
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