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Screening & Prevention >> Newborn Screening >> Amino Acid Disorders >> Citrullinemia

Citrullinemia

Disorder Category

an amino acid (urea cycle) disorder

Screening

Finding

elevated citrulline

Tested By

tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=100% [Schulze: 2003]

Names

Citrullinemia

Citrullinemia I or type 1 (classic form)

Citrullinuria

Argininosuccinate synthetase deficiency (AS or ASS)

Argininosuccinic acid synthetase deficiency (ASAS)

ICD-9

270.6, Disorder of urea cycle metabolism

Overview

Citrulinemia results from a defect in argininosuccinate synthetase (ASS), the third step in the urea cycle. Timing of clinical manifestations ranges from acute, early onset to assymptomatic to onset during pregnancy. The adult- or late-onset form, Citrullinemia II or Type 2, is more common in people of Japanese descent and is caused by a defect in a mitochondrial transporter unrelated to ASS.

Prevalence

about 1/250,000 live births [Schulze: 2003]

Inheritance

autosomal recessive

Prenatal Testing

DNA, linkage analysis, and enzyme testing by amniocentesis or CVS.

Clinical Characteristics

With treatment preventing serious hyperammonemic episodes, normal IQ and development are possible. Without treatment, classical citrullinemia type I generally presents in the first week after establishing a normal protein diet. Less acute forms may present in childhood, be assymptomatic, or present during pregnancy or postpartum with severe symptoms. Acute symptoms may occur during prolonged fasting, periods of increased energy demands (fever, stress, lack of sleep), and after meals high in protein.

Initial symptoms may include:
  • poor appetite;
  • vomiting;
  • lethargy;
  • increased intracranial pressure;
  • apnea;
  • seizures;
  • coma, possibly leading to death; and
  • lab findings:
    • hyperammonemia;
    • elevated citrulline; and
    • absent argininosuccinic acid.


Symptoms of the milder form in children may include:
  • poor growth,
  • poor appetite,
  • vomiting,
  • headaches,
  • learning disabilities,
  • behavior problems,
  • hyperactivity,
  • balance and coordination problems, and
  • spasticity.

Follow-up on positive screening test

Quantitative plasma ammonia and amino acid analysis, urine for 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 Citrullinemia info for parents, STAR-G);
  • Assist in implementation and maintenance of a low protein diet, provision of arginine and essential amino acid supplements, and therapy with sodium phenylbutyrate;
  • Regular blood tests to monitor amino acid and ammonia levels may be indicated;
  • Sodium benzoate and/or phenylburtyrate/phenylacetate and arginine to manage hyperammonemic crises or dialysis may be indicated;
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Management

Initial consultation with the following service(s): Metabolic Clinic, (801-585-2457); See also Services below; and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management.

Resources

Links

For Professionals

Citrullinemia info for professionals, STAR-G
On the Screening, Technology and Research in Genetics (STAR-G) site, one of a series of Disorder Fact Sheets for Professionals; structured list of information about the condition, with links to more information.

ACT Sheet for Citrullinemia from ACMG (pdf 62kb)
Developed by the American College of Medical Genetics (ACMG), includes recommended responses to positive newborn screening test results, diagnostic evaluation, clinical expectations, and sources of additional information. See the ACMG ACT Sheets and Confirmatory Algorithms (link elsewhere on this page) for more info and sheets on other conditions.

ACMG ACT Sheets and Confirmatory Algorithms
The American College of Medical Genetics (ACMG) has developed ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results. This page contains a table with links to all of the ACT Sheets and related algorithms.

Citrullinemia review, GeneTests.org
Excellent review by Jess G Thoene, MD including clinical description, differential, management, genetic counseling, molecular genetics, and a bibliography.

Citrullinemia Emergency Protocol
A protocol for management of the patient with a positive screen for citrullinemia, from the New England Consortium of Metabolic Programs.

Utah Newborn Screening Program
The site provides information and statistics about the program and related legislation, training for practices, and the conditions screened for.

For Parents

Citrullinemia info for parents, STAR-G
From the Screening, Technology and Research in Genetics (STAR-G) site, providing information for parents about citrullinemia and links to other sites including parent support groups.

Citrullinemia, Genetics Home Reference
Excellent, detailed review aimed at patients and families from the National Library of Medicine's Genetics Home Reference site.

National Urea Cycle Disorders Foundation
The National Urea Cycle Disorders Foundation, a non-profit organization, provides support services and information for families; medical lectures on urea cycle disorders; nutrition and medication resources; and information about events and conferences.

Services

Newborn Screening Programs

Utah Newborn Screening Program, more info...
44 Mario Capecchi Drive
Salt Lake City, UT84114
Phone: 801-584-8256
Fax: 801-536-0966
http://health.utah.gov/newbornscreening

Pediatric Genetics

Metabolic Clinic, more info...
100 Mario Capecchi Drive
Salt Lake City, UT84113
Phone: 801-585-2457
Fax: 585-7252
http://www.ped.med.utah.edu/divisions/divisions.htm

See all Pediatric Genetics services providers (3) in our database.

For other services related to this condition, browse our Services categories or search our database.

Helpful Articles

PubMed search for articles on citrullinemia in the last 5 years.

Authors

Reviewing Author: Nicola Longo MD, PhD, 3/2007
Compiled and edited by: Alfred Romeo RN, PhD, 3/2007
Content Last Updated: 3/2008

Page Bibliography

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract
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