Disease Profile

Citrullinemia type II

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

Adult

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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)

Citrullinemia type 2; Adult-onset citrullinemia type 2; CTLN2;

Categories

Congenital and Genetic Diseases; Digestive Diseases; Metabolic disorders;

Summary

Adult-onset citrullinemia type II is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. The condition chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. These signs and symptoms can be life-threatening. The signs and symptoms appear during adulthood and are triggered by certain medications, infections, surgery, and alcohol intake. The features of adult-onset type II citrullinemia may also develop in people who as infants had a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). In many cases, the signs and symptoms of NICCD resolve within a year. Years or even decades later, however, some of these people develop the characteristic features of adult-onset type II citrullinemia. Adult-onset citrullinemia type II is caused by mutations in the SLC25A13 gene. This condition is inherited in an autosomal recessive pattern.[1]

Symptoms

Adult-onset citrullinemia type II chiefly affects the nervous system, causing neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. These signs and symptoms can be life-threatening. The signs and symptoms of this disorder appear suddenly during adulthood, usually between ages 20 and 50 years. The symptoms appear to be triggered by certain medications, infections, surgery, and alcohol intake.[1][2] Many individuals with adult-onset citrullinemia type II are fond of protein-rich and/or fatty foods and have an aversion to carbohydrate-rich foods. Pathologic findings include fatty infiltration and mild fibrosis of the liver despite little or no liver dysfunction.[2]

The features of adult-onset type II citrullinemia may also develop in people who as infants had a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). In many cases, the signs and symptoms of NICCD resolve within a year. Years or even decades later, however, some of these people develop the characteristic features of adult-onset type II citrullinemia.[1][2]

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
80%-99% of people have these symptoms
Acute hyperammonemia
0008281
Decreased body mass index
0045082
Elevated plasma citrulline
0011966
Hepatic steatosis
Fatty infiltration of liver
Fatty liver

[ more ]

0001397
30%-79% of people have these symptoms
Abnormal eating behavior
0100738
Aggressive behavior
Aggression
Aggressive behaviour
Aggressiveness

[ more ]

0000718
Asterixis
0012164
Delirium
0031258
Delusions
0000746
Drowsiness
Sleepy
0002329
Elevated hepatic transaminase
High liver enzymes
0002910
Fluctuations in consciousness
0007159
Hallucinations
Hallucination
Sensory hallucination

[ more ]

0000738
Hepatomegaly
Enlarged liver
0002240
Hypertriglyceridemia
Increased plasma triglycerides
Increased serum triglycerides
Increased triglycerides

[ more ]

0002155
Hypoalbuminemia
Low blood albumin
0003073
Hypoproteinemia
Decreased protein levels in blood
0003075
Irritability
Irritable
0000737
Lethargy
0001254
Memory impairment
Forgetfulness
Memory loss
Memory problems
Poor memory

[ more ]

0002354
Night sweats
0030166
Restlessness
0000711
Seizure
0001250
Sleep terror
0030765
Tremor
0001337
5%-29% of people have these symptoms
Cerebral edema
Swelling of brain
0002181
Coma
0001259
Decreased HDL cholesterol concentration
Decreased circulating high-density lipoprotein cholesterol
Decreased HDL cholesterol
Low HDL-cholesterol

[ more ]

0003233
Delayed menarche
Delayed start of first period
0012569
Diarrhea
Watery stool
0002014
Echolalia
Echoing another person's speech
0010529
Enuresis
0000805
Global developmental delay
0001263
Hepatic encephalopathy
0002480
Hepatic fibrosis
0001395
Hepatocellular carcinoma
0001402
Hyperactivity
More active than typical
0000752
Hypercholesterolemia
Elevated serum cholesterol
Elevated total cholesterol
Increased total cholesterol

[ more ]

0003124
Insomnia
Difficulty staying or falling asleep
0100785
Mania
Manic
0100754
Pancreatitis
Pancreatic inflammation
0001733
Psychosis
0000709
Vomiting
Throwing up
0002013
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Confusion
Disorientation
Easily confused
Mental disorientation

[ more ]

0001289
Hyperammonemia
High blood ammonia levels
0001987

Diagnosis

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.
    • 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

      Liver transplantation for adult-onset citrullinemia type II prevents hyperammonemic crises, corrects metabolic disturbances, and eliminates preferences for protein-rich foods. Administration of arginine decreases blood ammonia concentration. Reduction in calorie and/or carbohydrate intake can lessen high triglycerides. Individuals with adult-onset citrullinemia type II are encouraged to consume a diet rich in lipids and protein and low in carbohydrates. This may help to prevent hyperammonemia.[2]

      Additional information related to the treatment of adult-onset citrullinemia type II can be accessed through eMedicine.

      Management Guidelines

      • GeneReviews provides a current, expert-authored, peer-reviewed, full-text article urea cycle disorders in general that you may find helpful. GeneReview articles describe the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.

        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 II. This website is maintained by the National Library of Medicine.

            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 II. Click on the link to view a sample search on this topic.

              References

              1. Citrullinemia. Genetics Home Reference (GHR). 2017; https://ghr.nlm.nih.gov/condition/citrullinemia.
              2. Kobayashi K, Saheki T. Citrin Deficiency. GeneReviews. July 31, 2014; https://www.ncbi.nlm.nih.gov/books/NBK1181/.
              3. Citrullinemia, Type II. baby's first test. https://www.babysfirsttest.org/newborn-screening/conditions/citrullinemia-type-ii. Accessed 12/28/2016.