Argininosuccinic Aciduria

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Argininosuccinic acid lyase (ASAL) deficiency
Argininosuccinate lyase (ASL) deficiency

ICD-10 Coding

E72.22, Arginosuccinic aciduria

Disorder Category

Amino acidemia

Screening

Abnormal Finding

Elevated citrulline and argininosuccinic acid

Tested By

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

Description

Argininosuccinic aciduria is a urea cycle disorder resulting from deficiency of the enzyme argininosuccinate lyase, disrupting the conversion of argininosuccinate to fumarate and arginine. As with most other urea cycle disorders, it is characterized by hyperammonemia and encephalopathy. However, the common finding of chronic liver disease, trichorrhexis nodosa, and systemic hypertension, often despite optimal metabolic management, is unique to argininosuccinic aciduria. Though commonly considered a disease of severe neonatal onset, late-onset cases in childhood to late adulthood have been reported, typically with a hyperammonemic crisis triggered by an acute infection.

Clinical Characteristics

With treatment of argininosuccinic aciduria, normal cognitive and physical development is possible if severe hyperammonemic crises are avoided, particularly in the neonatal period. However, even with optimal metabolic control using currently available therapies, the risk remains for complications including chronic liver disease, neurocognitive deficiencies, trichorrhexis nodosa (caused by arginine deficiency), and systemic hypertension. Episodes of hyperammonemia may still occur, typically triggered by metabolic stress (i.e., fever/infection, fasting) or excess protein intake.
Without treatment, symptoms usually begin within the first few days of life, often before newborn screen results have returned. Patients will initially present with vomiting, refusal of feeds, and lethargy, which can progress to tachypnea, respiratory alkalosis, coma, and even death. Less severe cases may present later in life with the potential for similar symptoms of hyperammonemia.

Initial symptoms of argininosuccinic aciduria may include:
  • Poor appetite
  • Vomiting
  • Irritability
  • Seizures
  • Lethargy/coma
  • Lab findings:
    • Hyperammonemia
    • Elevated transaminases
    • Prolonged PT/PTT
    • Elevated citrulline
    • Elevated argininosuccinic acid (plasma and urine)
Subsequent symptoms may include:
  • Episodic hyperammonemia
  • Liver disease
  • Short, dry, brittle hair (trichorrhexis nodosa)
  • Neurocognitive deficits
  • Seizures
Treatment includes a low-protein diet, arginine supplementation, and the use of nitrogen scavenger medications (sodium benzoate or sodium/glycerol phenylbutyrate). Patients should be monitored periodically with laboratory tests to verify adequate amino acid concentrations and for maintenance of normal ammonia levels.

Incidence

The incidence of argininosuccinic aciduria is approximately 1:300,000 live births. [Therrell: 2014]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family, inform them of the newborn screening result, and evaluate the infant for clinical symptoms (poor feeding, vomiting, lethargy, tachypnea).
  • Immediately consult with Medical Genetics (see NV providers [5]).
  • Measure the blood ammonia and initiate emergency treatment or referral if there is evidence of hyperammonemia or clinical symptoms, such as vomiting, refusal of feeds, lethargy, or seizures. See the ACT Sheet for Elevated Citrulline (ACMG) (PDF Document 346 KB) for other immediate steps to take upon notification of a positive screen.

Confirming the Diagnosis

If the Diagnosis is Confirmed

Resources

Information & Support

Related Portal Content
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

Argininosuccinic Aciduria (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

Argininosuccinate Lyase 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

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

Argininosuccinic Acid Lyase Deficiency - 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.

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 Algorithm for Elevated Citrulline (ACMG) (PDF Document 175 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.

NV ACT Sheet for Elevated Citrulline (ACMG) (PDF Document 117 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 Nevada (NV)

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

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: March 2007; last update/revision: July 2022
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Reviewer: Nancy C. Rose, MD
Authoring history
2019: update: Chelsea Norman, BS, RDN, CDA; Nicola Longo, MD, Ph.D.R
2012: update: 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