Citrullinemia Type I

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Argininosuccinate synthetase (ASS) deficiency
Argininosuccinic acid synthetase deficiency
Classic citrullinemia

ICD-10 Coding

E72.23, Citrullinemia

Disorder Category

Amino acidemia

Screening

Abnormal Finding

Elevated citrulline

Tested By

Tandem mass spectrometry (MS/MS)

Description

Citrullinemia results from a deficiency of argininosuccinate synthetase (ASS), disrupting the 3rd step of the urea cycle, the pathway that converts ammonia to urea. Clinical manifestations are highly variable with a neonatal form of the condition typically presenting in the first few days of life with lethargy, poor feeding, and vomiting secondary to hyperammonemia. In the late-onset non-classical form of citrullinemia, symptoms which are typically milder can develop any time from infancy to adulthood.. Recurrent episodes of metabolic decompensation and hyperammonemia are triggered by catabolism (due to fasting or illnesses) or excess protein intake. Treatment is available in the form of strict dietary changes and nitrogen scavenging medications.

Clinical Characteristics

With treatment, individuals are still at risk for life-threatening episodes of hyperammonemia, although the risk is significantly decreased. Additionally, long-term outcomes regarding growth/development, liver function, and intellect are significantly improved. Therapy typically involves a mixture of a protein-restricted diet and nitrogen scavenging medications managed by a metabolic specialist. More severe cases may also warrant liver transplantation. [Bourdeaux: 2007] [Perito: 2014]

Without treatment, citrullinemia type I characteristically presents with neonatal onset hyperammonemia along with associated complications of lethargy, poor feeding, and progressive neurological compromise. [Bachmann: 2003] This may be a metabolic emergency, so acute management under the supervision of a metabolic geneticist may be necessary if symptomatic. Less acute later-onset forms may present anytime from infancy to adulthood and are triggered by fasting, increased energy demands (fever, stress, lack of sleep), and excess protein intake. Women also may first experience symptoms in the postpartum period following pregnancy.

Initial neonatal symptoms may include:
  • Poor appetite
  • Vomiting
  • Lethargy
  • Seizures
  • Coma
  • Tachypnea
  • Signs of liver disease
Infancy to adult-onset symptoms may include:
  • Poor growth
  • Vomiting
  • Headaches/Migraines
  • Learning disabilities
  • Behavior problems
  • Postpartum psychosis
  • Hepatic dysfunction

Incidence

Approximately 1 in 50,000-100,000 live births [Brusilow: 2001] [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, lethargy, and tachypnea
  • Provide emergency treatment/referral for symptoms of vomiting, hypotonia, tachypnea, seizures, or signs of liver disease. Plasma ammonia and lactate levels may be indicated. See the ACT Sheet for Elevated Citrulline (ACMG) (PDF Document 346 KB).

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see NM providers [1]).
  • In affected individuals, plasma amino acids will identify the elevated citrulline level. However, there are other inborn errors of metabolism in which citrulline may be elevated and must be differentiated for management purposes. Urine amino acids may also be tested. An ammonia level should also be checked if symptomatic and/or the newborn screen positive predictive values are sufficiently high enough to suspect a true positive result. Confirmation can be made with genetic testing and to differentiate the various types of disorders caused by an elevated citrulline.

If the Diagnosis is Confirmed

Resources

Information & Support

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 - You Are Not Alone; 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

Citrullinemia Type 1 (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.

Communicating Newborn Screening Results to Families (ACHDNC) (PDF Document 289 KB)
One-page guide to help clinicians effectively communicate positive newborn screening results to parents; Advisory Committee on Heritable Disorders in Newborns and Children.

For Parents and Patients

Citrullinemia - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

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

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.

Tools

Confirmatory Algorithm for Citrulline Elevated (ACMG) (PDF Document 210 KB)
Graphical algorithm for responding to finding an elevated citrulline level on newborn screening; from the American College of Medical Genetics and Genomics.

NM 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 New Mexico (NM)

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.

Authors & Reviewers

Initial publication: March 2007; last update/revision: April 2022
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Reviewer: Nancy C. Rose, MD
Authoring history
2012: revision: Kimberly Hart, MS, LCGCR
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Bachmann C.
Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation.
Eur J Pediatr. 2003;162(6):410-6. PubMed abstract

Bourdeaux C, Darwish A, Jamart J, Tri TT, Janssen M, Lerut J, Otte JB, Sokal E, de Ville de Goyet J, Reding R.
Living-related versus deceased donor pediatric liver transplantation: a multivariate analysis of technical and immunological complications in 235 recipients.
Am J Transplant. 2007;7(2):440-7. PubMed abstract

Brusilow SW, Horwich AL.
The Metabolic & Molecular Bases of Inherited Diseases: Urea Cycle Enzymes (Chapter 85).
8 ed. Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B,; 2001.

Perito ER, Rhee S, Roberts JP, Rosenthal P.
Pediatric liver transplantation for urea cycle disorders and organic acidemias: United Network for Organ Sharing data for 2002-2012.
Liver Transpl. 2014;20(1):89-99. 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