National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Citrullinemia type I


Other Names:
Classic citrullinemia; Argininosuccinate synthetase deficiency; CTNL1; Classic citrullinemia; Argininosuccinate synthetase deficiency; CTNL1; Citrullinuria; ASS deficiency; Citrullinemia 1 See More
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This disease is grouped under:
Citrullinemia type 1 is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. There are four types. The classic, most severe form, occurs in newborns, while a milder, later-onset form occurs in children or adults. There's also a form that occurs during or after pregnancy, and a form with no symptoms.[1][2] In the classic form, symptoms occur right after birth and include excessive sleepiness, poor appetite, vomiting, and irritability. As ammonia builds up, muscle weakness, seizures, coma, and death can occur. Citrullinemia is caused by mutations in the ASS1 gene and is inherited in an autosomal recessive pattern.[1][2][3]

This disorder is diagnosed through newborn screening and additional medical and genetic tests. Treatment includes removal of ammonia in the blood by medications and dialysis, as well as a lifelong low-protein diet. Liver transplantation is possible and, if done early in life, may eliminate the symptoms of the disorder. Left untreated, people with citrullinemia will build up very high levels of ammonia in the blood that can lead to brain damage and eventually death. Treated individuals can have normal growth and development.[1][2][3]
Last updated: 10/30/2018
Without treatment, infants with citrullinemia type 1 build up harmful levels of ammonia in their blood and will develop symptoms within a few days. Symptoms include extreme sleepiness, no appetite, irritability, and vomiting. Later symptoms may include muscle weakness, low or increased muscle tone, breathing problems, seizures, and trouble staying warm. Untreated infants can go into a coma and die within a few weeks.[1][2][3]

The symptoms of the milder forms of citrullinemia may show up later in infancy, childhood or adulthood.[1][2] Untreated children may have poor growth, dry hair, behavior and learning problems. They can develop abnormal tightness of the muscles and strokes. Other symptoms of increased ammonia in the blood include:  
  • Headaches
  • Vomiting
  • Sleepiness
  • Poor appetite
  • Slurred speech
  • Poor coordination
Episodes of high ammonia can occur after going without food for a long time, like after an illness, or after a high-protein meal.[1][4]

Women with the pregnancy-related form of citrullinemia may have vomiting, excessive tiredness, seizures, confusion, and behavior changes. These symptoms can occur during or right after pregnancy.[1][4]

For reasons that are unclear, some people with the gene mutations associated with citrullinemia never have symptoms of the disorder.[1]
Last updated: 10/30/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 22 |
Medical Terms Other Names
Learn More:
HPO ID
5%-29% of people have these symptoms
Stroke 0001297
Percent of people who have these symptoms is not available through HPO
Ataxia 0001251
Autosomal recessive inheritance 0000007
Cerebral edema
Swelling of brain
0002181
Cirrhosis
Scar tissue replaces healthy tissue in the liver
0001394
Coma 0001259
Episodic ammonia intoxication 0001951
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Global developmental delay 0001263
Hepatomegaly
Enlarged liver
0002240
Hyperammonemia
High blood ammonia levels
0001987
Hyperglutaminemia
High plasma glutamine
0003217
Hypoargininemia
Low blood arginine levels
0005961
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Irritability
Irritable
0000737
Lethargy 0001254
Neonatal onset 0003623
Oroticaciduria
High urine orotic acid levels
0003218
Protein avoidance 0002038
Respiratory alkalosis 0001950
Seizure 0001250
Vomiting
Throwing up
0002013
Showing of 22 |
Last updated: 7/1/2020
Citrullinemia type I is caused by mutations in the ASS1 gene.[3] This gene provides instructions for making an enzyme, argininosuccinate synthetase 1 (ASS1), which is responsible for helping breakdown ammonia in the body. Mutations in the ASS1 gene reduce the amount of ASS1 enzyme in the body, leading to increased levels of ammonia in the blood. Ammonia is especially toxic to the nervous system, and high levels can lead to permanent brain damage and neurological problems like seizures and poor coordination.[3][2]
Last updated: 10/30/2018
Citrullinemia type I is inherited in an autosomal recessive pattern, which means both copies of the gene in every cell have mutations.[3][1][2]  This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this.

Affected people inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

•  25% chance to be affected
•  50% chance to be an unaffected carrier like each parent
•  25% chance to be unaffected and not a carrier
Last updated: 10/30/2018
Citrullinemia can be diagnosed through newborn screening.[1][4] Every state in the US offers newborn screening for this disorder.[4] When a baby tests positive for citrullinemia on a newborn screen, the diagnosis needs to be confirmed through specific medical test. Genetic testing can help identify the gene mutation in the family.[1][4]

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person's medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional. 
Last updated: 10/30/2018

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Newborn Screening

  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
  • Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
  • The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.
  • National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

For infants and children with high levels of ammonia, medications are necessary to remove the excess ammonia from the blood. Dialysis can also be used to clear ammonia from the blood. For long-term treatment, people with citrullinemia type 1 are put on a special low-protein diet and are given medications and supplements that help keep their ammonia levels low. Infants are given a special low-protein formula instead of breast milk or regular formula. it is recommended that people with citrullinemia remain on this diet for the rest of their life. Citrullinemia can also be treated with a liver transplant which is usually done before one year of age.[4][5][6]

Last updated: 10/30/2018

Management Guidelines

  • The NORD Physician Guide for Citrullinemia type I was developed as a free service of the National Organization for Rare Disorders (NORD) and it's medical advisors.  The guides provide a resource for clinicians about specific rare disorders to facilitate diagnosis and treatment of their patients with this condition. 
  • Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition.  

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

  • Glycerol phenylbutyrate (Brand name: Ravicti) - Manufactured by Horizon Pharma, Inc.
    FDA-approved indication: Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients at least 2 months of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).
    National Library of Medicine Drug Information Portal
With treatment, people with citrullinemia type 1 can have normal growth and development. However, episodes of high ammonia can cause brain and nerve damage that cannot be repaired. This type of brain damage can cause permanent learning and intellectual disabilities, as well as problems with muscle control and coordination.[4]
Last updated: 10/30/2018
Citrullinemia type 1 occurs equally in both males and females and in all ethnic groups. It has been estimated that about 1 in 44,300 to 1 in 200,000 individuals worldwide have citrullinemia type 1.[6]
Last updated: 10/30/2018

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Patient Registry

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Financial Resources

  • Good Days provides help to patients with life-altering conditions. Assistance includes help with the cost of medications and travel.
  • The HealthWell Foundation provides financial assistance for underinsured patients living with chronic and life-altering conditions. They offer help with drug copayments, deductibles, and health insurance premiums for patients with specific diseases. The disease fund status can change over time, so you may need to check back if funds are not currently available.

Education Resources

  • The Genetics Education Materials for School Success (GEMSS) aims to assure that all children with genetic health conditions succeed in school-life. Their Web site offers general and condition-specific education resources to help teachers and parents better understand the needs of students who have genetic conditions.

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Citrullinemia type I. This website is maintained by the National Library of Medicine.
  • MedlinePlus.gov provides more information on urea cycle disorders in general. MedlinePlus is a Web site designed by the National Library of Medicine to help you research your health questions.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
  • The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Citrullinemia type I. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Citrullinemia type 1. National Organization for Rare Disorders (NORD). Updated 2016; https://rarediseases.org/rare-diseases/citrullinemia-type-1. Accessed 10/23/2018.
  2. Quinonex SC, Thoene JG. Citrullinemia Type I. GeneReviews. Updated Sept 1, 2016; https://www.ncbi.nlm.nih.gov/books/NBK1458.
  3. Citrullinemia. Genetics Home Reference (GHR). 2017; https://ghr.nlm.nih.gov/condition/citrullinemia.
  4. Citrullinemia. Screening, Technology and Research in Genetics (STAR-G). Updated Feb. 18, 2016; http://www.newbornscreening.info/Parents/aminoaciddisorders/ASAS.html.
  5. Vara R, Dhawan A, Deheragoda M, et al. Liver transplantation for neonatal-onset citrullinemia.. Pediatr Transplant. Jun 2018; 22:e13191. https://www.ncbi.nlm.nih.gov/pubmed/29726081.
  6. Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H. Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options. Biochem Genet. Apr 2018; 56(1-2):7-21. https://www.ncbi.nlm.nih.gov/pubmed/29094226.