Argininemia

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Arginase deficiency
Hyperargininemia

ICD-10 Coding

E72.21, Argininemia

Disorder Category

Amino acidemia

Screening

Abnormal Finding

Elevated arginine

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=NA; specificity=NA

Description

Arginase deficiency is a distal urea cycle disorder caused by a near complete absence of arginase enzyme activity. Unlike other urea cycle defects, hyperammonia is relatively rare and typically mild in arginase deficiency. If not picked up on newborn screening, arginase deficiency usually presents after 1 year of age with progressive lower limb spasticity, developmental delays, cognitive impairment, seizures, microcephaly, and sometimes growth deficiency in early childhood.

Clinical Characteristics

With treatment of argininemia, the clinical progression of the disease may be halted, though symptoms that have already manifested are not likely to be reversible. Additionally, hyperammonemic crises may be averted and growth/developmental outcomes improvedTreatment varies by type of enzyme defect but may include diets that restrict phenylalanine and treatment with synthetic tetrahydropterin, folinic acid, and/or neurotransmitter precursors. Treatment is generally managed or led by the pediatric metabolic specialists.
Treatment strategies focus on reducing plasma arginine levels by restricting overall dietary protein intake and supplementing with arginine-free essential amino acid formula. Also, nitrogen scavenging medications (sodium benzoate, sodium phenylbutyrate) can be used to reduce ammonia levels as part of acute and chronic management. Patients should be monitored periodically by a metabolic geneticist and metabolic dietitian to verify adequacy of amino acid and ammonia levels, which may require adjustments as patients age. Symptom management may involve other specialties, including neurology for seizure control, physical medicine and rehabilitation for spasticity and mobility care, and developmental pediatrics for developmental monitoring and intervention. In rare cases, liver transplantation has successfully been used for more severely affected patients. [Kido: 2021]
Without treatment, clinical symptoms typically begin as early as 1 year of age or as late as adolescence. Mild hyperammonemia may be present, though it is extremely rare for it to be a life-threatening emergency as is in the other urea cycle disorders. Most often, infancy and early childhood growth and development may initially be normal, followed by slowly progressive lower limb spasticity, cognitive decline, microcephaly, seizures, and growth deficiency. [Keshavan: 2022] [Chandra: 2019] Acute symptoms may be triggered by prolonged fasting, increased energy demands (fever, stress, lack of sleep), and high-protein meals, though hyperammonemic crises are rare.
Initial signs and symptoms of arginase deficiency may include:
  • Developmental delay
  • Lower limb spasticity/toe walking
  • Microcephaly
  • Lab findings:
    • Elevated arginine
    • Elevated urine orotic acid
    • Hyperammonemia (though uncommon for it to be >150 µmol/L))
    • Elevated guanidinoacetate
    • Mild liver dysfunction
Subsequent signs and symptoms may include:
  • Poor growth
  • Loss of ambulation
  • Joint contractures
  • Seizures (generalized tonic-clonic)
  • Cognitive decline
  • Incontinence (urine and stool)
  • Cortical atrophy on brain imaging

Incidence

Arginase deficiency is one of the rarest urea cycle defects, with an estimated global incidence of 1:357,000 live births and a population prevalence of 1:726,000 people. [Catsburg: 2022] The incidence of all urea cycle disorders is 1:35,000. [Summar: 2013]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for poor feeding, vomiting, and lethargy.
  • Provide emergency treatment/referral for lethargy, hypotonia, seizures, signs of liver disease (see the ACT Sheet for Argininemia (ACMG) (PDF Document 348 KB) for additional information).

Confirming the Diagnosis

  • To confirm the diagnosis of argininemia, work with Newborn Screening Services (see MT providers [4]).
  • Follow-up testing may include plasma amino acid analysis, urine orotic acid, and enzyme assay on red blood cells can be used to confirm the diagnosis. DNA testing is used for final diagnostic confirmation. Genetic testing is possible for at-risk family members if both disease-causing mutations of an affected family member have been identified.
  • Arginase deficiency is often misdiagnosed as cerebral palsy. Importantly, arginase deficiency is typically asymptomatic during early infancy, followed by progressive spasticity and cognitive decline; cerebral palsy is associated with acute intrapartum hypoxia, and neurological complications are present neonatally and non-progressive in nature. [Pearson: 2019]
  • All of the other urea cycle disorders (CPS1 deficiency, OTC deficiency, citrullinemia, and ASL deficiency) also have the potential to cause hyperammonemia, though often to a more severe degree than arginase deficiency. However, plasma amino acid levels can easily distinguish arginase deficiency with a significant elevation of arginine compared to the other urea cycle defects. Additionally, the neurological symptoms, including spasticity, are much more specific to arginase deficiency.

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Medical Genetics (see MT providers [8]).
  • 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 the implementation and support of a low protein diet.
  • Sodium benzoate or phenylbutyrate therapy helps reduce arginine and ammonia levels.
  • Periodic monitoring of amino acid and ammonia levels is indicated.
  • Assist in providing developmental and educational resources when needed.

Resources

Information & Support

Related Portal Content
Arginase Deficiency
Assessment and management information for the primary care clinician caring for the child with argininemia.

Arginase Deficiency (FAQ)
Answers to questions frequently asked by families with a child diagnosed with argininemia.

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

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

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.

For Parents and Patients

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.

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.

Arginase-1 Deficiency (NORD)
Clinical characteristics, signs, and symptoms, causes, affected population, related disorders, diagnosis, and therapies; National Organization of Rare Disease.

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.

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. See the "Find Your Parent Center Link" to find the parent center in your state; Department of Education, Office of Special Education.

Tools

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.

MT ACT Sheet for Argininemia (ACMG) (PDF Document 138 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Services for Patients & Families in Montana (MT)

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.

Studies

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

Helpful Articles

PubMed search for argininemia in children, last 5 years.

Asrani KH, Cheng L, Cheng CJ, Subramanian RR.
Arginase I mRNA therapy - a novel approach to rescue arginase 1 enzyme deficiency.
RNA Biol. 2018;15(7):914-922. PubMed abstract / Full Text

Morales JA, Sticco KL.
Arginase Deficiency.
StatPearls Treasure Island (FL): StatPearls Publishing. 2022(Aug. 13). 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

Authors & Reviewers

Initial publication: March 2007; last update/revision: April 2022
Current Authors and Reviewers:
Authors: Kimberly Stowers, MD
Hannah Holik
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2012: revision: Kimberly Hart, MS, LCGCR
2007: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Catsburg C, Anderson S, Upadhyaya N, Bechter M.
Arginase 1 Deficiency: using genetic databases as a tool to establish global prevalence.
Orphanet J Rare Dis. 2022;17(1):94. PubMed abstract / Full Text

Chandra SR, Christopher R, Ramanujam CN, Harikrishna GV.
Hyperargininemia Experiences over Last 7 Years from a Tertiary Care Center.
J Pediatr Neurosci. 2019;14(1):2-6. PubMed abstract / Full Text

Keshavan N, Wood M, Alderson LM, Cortina-Borja M, Skeath R, McSweeney M, Dixon M, Cleary MA, Footitt E, Batzios S.
Clinical status, biochemical profile and management of a single cohort of patients with arginase deficiency.
JIMD Rep. 2022;63(2):123-130. PubMed abstract / Full Text

Kido J, Matsumoto S, Takeshita E, Hayasaka C, Yamada K, Kagawa J, Nakajima Y, Ito T, Iijima H, Endo F, Nakamura K.
Current status of surviving patients with arginase 1 deficiency in Japan.
Mol Genet Metab Rep. 2021;29:100805. PubMed abstract / Full Text

Pearson TS, Pons R, Ghaoui R, Sue CM.
Genetic mimics of cerebral palsy.
Mov Disord. 2019;34(5):625-636. 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