Home > Newborn Disorders > Citrullinemia
Citrullinemia
Screening
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)
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, depending on the residual enzyme activity left by the specific mutations. Milder forms of the disease are triggered by catabolic state or excess dietary proteins and can present with acute hyperammonemia, psychotic changes or acute liver failure . There is a second form of citrullinemia, called Type 2, that is more common in people of Japanese descent. This is caused by a defect in a mitochondrial transporter unrelated to ASS and can result in nenonatal cholestasis or in adult-onset disease. It is extremely important to distinguish the two forms since treatment is completely different. [Salek: 2010]Prevalence
about 1/250,000 live births [Schulze: 2003]Prenatal Testing
DNA sequencing for both types of citrullinemia on samples obtained 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 of life. Less acute forms may present later in life (childhood, pregnancy) with severe symptoms during prolonged fasting, periods of increased energy demands (fever, stress, lack of sleep), and after meals high in protein. There are even milder forms with only mildly increased citrulline that might remain asymptomatic for life (periodic monitoring without therapy is recommended in these forms). Citrullinemia type 2 (citrin deficiency) can cause intrahepatic cholestasis in the neonatal period that usually improves over time [Saheki: 2010]. Adults with this condition can have acute liver failure and hyperammonemia.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 glutamine
- 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
Symptoms of citrullinemia in aduts may include:
- Psychotic changes
- Acute liver failure
Therapy consists in protein restriction, the administration of arginine supplements and nitrogen scavengers (phenylbutyrate, phenylacetate, benzoate) in citrullinemia type 1. By contrast, a diet low in carbohydrates is indicated in citrullinemia type 2.
Follow-up on positive screening test
Quantitative plasma ammonia and amino acid analysis, urine for orotic acid, DNA testing for the ASS or citrin gene as indicated.Primary care management
Upon notification of the + screen
- Contact the family and evaluate the infant for poor feeding, vomiting, lethargy, tachypnea;
- Provide emergency treatment/referral for symptoms of vomiting, hypotonia, tachypnea, seizures, or signs of liver disease (see
the ACT Sheet for elevated citrulline (ACMG)
(
346 KB)
for additional information);
- To confirm the diagnosis, work with the following service(s): Utah Newborn Screening Program, (801-584-8256); See also Services below;
- For evaluation and ongoing collaborative management, consult the following service(s): Medical Genetics, (801-231-3599); See also Services below;
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 Collaboration
Initial consultation with the following service(s): Medical Genetics, (801-231-3599); 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
Information & Support
For Professionals
Citrullinemia info for professionals (STAR-G)
From the Screening, Technology and Research in Genetics (STAR-G) program, 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 elevated citrulline (ACMG)
( 346 KB)
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.
ACT Sheets and Confirmatory Algorithms (ACMG)
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.
Neonatal Hyperammonemia Emergency Protocol (NECMP)
A guideline for healthcare professionals treating the sick neonate with hyperammonemia; 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.
Infant/Child Hyperammonemia Acute Illness Protocol (NECMP)
( 57 KB)
A guideline for healthcare professionals treating the sick infant/child who has previously been diagnosed with citullinemia;
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.
Citrullinemia (GeneReviews)
Excellent review by Jess G Thoene, MD including clinical description, differential, management, genetic counseling, molecular
genetics, and a bibliography.
Resources for citrullinemia (NLM)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more; from the National
Library of Medicine and the Genetic Alliance.
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 and Patients
Citrullinemia info for parents (STAR-G)
From the Screening, Technology and Research in Genetics (STAR-G) program, 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.
National Newborn Screening & Genetics Resource Center
Provides information for families and professionals about genetic screening; links to support and advocacy groups; links to
state genetic contacts; newsletters; fact sheets; data reports; publications; and more.
Services
Newborn Screening Programs
Utah Newborn Screening Program,
more info...
44 Mario Capecchi Drive
Salt Lake City, UT 84114
Phone: 801-584-8256
Fax: 801-536-0966
http://health.utah.gov/newbornscreening
Pediatric Medical Genetics
See all Pediatric Medical 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, 3/2011 |
| Compiled and edited by: | Alfred Romeo RN, PhD, 3/2007 |
| Content Last Updated: | 3/2011 |
Page Bibliography
Saheki T, Inoue K, Tushima A, Mutoh K, Kobayashi K.
Citrin deficiency and current treatment concepts.
Mol Genet Metab.
2010;100 Suppl 1:S59-64.
PubMed abstract
The historical aspects of citrin and citrin deficiency and current treatment concepts for citrin deficiency are described.
Developing novel therapeutics based on the pathophysiology, such as sodium pyruvate, are discussed.
Salek J, Byrne J, Box T, Longo N, Sussman N.
Recurrent liver failure in a 25-year-old female.
Liver Transpl.
2010;16(9):1049-53.
PubMed abstract
Urea cycle defects such as Citrullinemia type I are not generally considered causes of ALF in adults and are described rarely
in children beyond the neonatal period. Prompt diagnosis and treatment can enable the patient to recover fully.
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