Rare Immunology News

Disease Profile

Citrullinemia type I

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Neonatal

ICD-10

E72.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Classic citrullinemia; Argininosuccinate synthetase deficiency; CTNL1;

Categories

Newborn Screening

Summary

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 lowprotein 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]

Symptoms

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 highprotein 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]

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.

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

Cause

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]

Diagnosis

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. 

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.

      Treatment

      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 lowprotein 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]

      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

        Organizations

        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

          Learn more

          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

          • 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.
          • Genetics Home Reference (GHR) contains information on Citrullinemia type I. This website is maintained by the National Library of Medicine.
          • 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.

              References

              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; https://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.

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