Argininosuccinic Aciduria

Other Names

Argininosuccinic acid lyase deficiency (ASAL)

Argininosuccinase deficiency

ASL deficiency

Diagnosis Coding

E72.22, Arginosuccinic aciduria

Disorder Category

An amino acidemia

Screening

Finding

Elevated citrulline and argininosuccinic acid

Tested By

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

Overview

Argininosuccinic aciduria is an amino acid disorder resulting from deficiency of argininosuccinate lyase, disrupting the 4th step of the urea cycle. It is characterized by hyperammonemia and encephalopathy. The enzyme argininosuccinic acid lyase is deficient, blocking conversion of argininosuccinate to fumarate and arginine. This disease differs from other urea cycle defects because it can lead to chronic liver disease, neurocognitive deficiencies, trichorrhexis nodosa, and systemic hypertension despite optimal metabolic control.

Incidence

Approximately 1:300,000 live births [Therrell: 2014]

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing is possible by amniocentesis or chorionic villus sampling (CVS) if both disease-causing mutations of an affected family member have been identified. Enzyme testing possible by amniocentesis or CVS.

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 hyperammonemic crises, normal mental and physical development is possible; however, individuals with argininosuccinic aciduria deficiency are at risk for complications including chronic liver failure, neurocognitive deficiencies, trichorrhexis nodosa (caused by arginine deficiency), and systemic hypertension.

Without treatment, symptoms usually begin a few days after birth. The results of newborn screening can return after the infant is already symptomatic. Less severe variants may present in childhood. Acute symptoms may occur during prolonged fasting, periods of increased energy demands (fever, stress, rapid growth), and after meals high in protein. Initial symptoms may include:
  • Poor appetite
  • Vomiting
  • Irritability
  • Seizures
  • Lethargy
  • Lab findings:
    • Hyperammonemia
    • Elevated transaminases
    • Prolonged PT/PTT
    • Elevated citrulline
    • Elevated glutamine
    • Elevated argininosuccinic acid
    • Elevated urine orotic acid
(NOTE: Some laboratories have difficulties in identifying argininosuccinic acid in plasma, and urine amino acids might prove valuable in such cases.)


Subsequent symptoms may include:
  • Poor growth/failure to thrive
  • Liver enlargement
  • Muscle weakness
  • Short, dry, brittle hair (trichorrhexis nodosa)
  • Cerebral edema
  • Seizures
  • Intellectual disability
  • Death

Treatment includes a low-protein diet, arginine supplementation, and the use of a nitrogen scavenger (sodium benzoate or sodium/glycerol phenylbutyrate) to remove the nitrogen load using an alternative mechanism. Patients should be monitored periodically with laboratory tests to verify adequate amino acid concentrations and for maintenance of normal ammonia levels.

Follow-up Testing after Positive Screen

Quantitative plasma ammonia and amino acid analysis, urine orotic acid

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill. See Argininosuccinic Aciduria - Information for Parents (STAR-G).
  • Assist in the implementation and support of a low-protein diet and arginine and essential amino acid supplements.
  • Ammonia scavenging medications (e.g., sodium benzoate or sodium phenylbutyrate) are usually indicated and prescribed by pediatric genetics.
  • Regular blood tests to monitor amino acid and ammonia levels may be indicated.
  • Immediate hospital admission may be required to help reduce ammonia levels during episodes of hyperammonemia or illness.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Collaboration

If the child is affected, refer for initial consultation, ongoing collaboration, and genetic counseling for the family. A dietician may work with the family to devise an optimal approach to dietary management.

Resources

Information & Support

For Professionals

Argininosuccinic Aciduria (OMIM)
Extensive review of literature providing technical information for providers on genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

Argininosuccinate Lyase Deficiency (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 Argininosuccinic Aciduria (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links 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

Argininosuccinic Aciduria (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

Argininosuccinic Aciduria - 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.

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.

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. See the link for Download a List of Parent Centers across the USA to find the parent center in your state; Department of Education, Office of Special Education.

Tools

ACT Sheet for Elevated Citrulline (ACMG) (PDF Document 346 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Argininosuccinic Aciduria Acute Illness Protocol (NECMP)
Guideline for clinicians treating the sick infant/child who has previously been diagnosed with argininosuccinic acidemia (ASA); 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.

Confirmatory Algorithms for Elevated Citrulline (ACMG) (PDF Document)
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 for Patients & Families in Idaho (ID)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).
Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

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

Argininosuccinic Aciduria (ClinicalTrials.gov)
Comprehensive list of research studies related to argininosuccinic aciduria; National Institutes of Health.

Helpful Articles

PubMed search for argininosuccinic aciduria, last 5 years.

Baruteau J, Diez-Fernandez C, Lerner S, Ranucci G, Gissen P, Dionisi-Vici C, Nagamani S, Erez A, Häberle J.
Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects.
J Inherit Metab Dis. 2019;42(6):1147-1161. PubMed abstract

Authors & Reviewers

Initial publication: September 2007; last update/revision: December 2019
Current Authors and Reviewers:
Author: Chelsea Norman, BS, RDN, CD
Reviewer: Nicola Longo, MD, Ph.D.
Authoring history
2012: revision: Kimberly Hart, MS, LCGCA
2007: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text