On this page
Citrullinaemia type II (citrin deficiency)
Citrullinaemia type II is a rare genetic condition that disrupts a key part of the urea cycle, leading to the build-up of harmful substances. It mainly affects the liver and brain and is more commonly observed in individuals of East Asian descent.
Available at Jeen Health
Clinical tests that include this
Overview
Citrullinaemia type II (CTLN2), or citrin deficiency, is a rare inherited metabolic disorder. It is caused by a problem with the SLC25A13 gene, which provides instructions for making the citrin protein. This protein is crucial for the proper functioning of the urea cycle, a process in the liver that removes toxic ammonia from the body. When citrin is deficient, ammonia and other substances can build up to harmful levels in the blood, affecting various organs, particularly the liver and brain [PMID:17907106].
The condition presents in various ways and at different ages, from early childhood to adulthood. The specific symptoms and their severity can vary widely among affected individuals. While considered rare globally, citrin deficiency has a higher prevalence in certain populations, particularly in East Asia, with a prevalence of about 1 in 17,000 in Japan.
Symptoms & clinical features
The symptoms of citrin deficiency can be broadly grouped into three main types, depending on the age of onset. Neonatal Intrahepatic Cholestasis (NICCD) typically appears in infancy and involves liver problems such as jaundice (yellowing of the skin and eyes), poor weight gain, and abnormal liver function tests. Infants with NICCD may also show a preference for protein-poor and fat-rich foods [PMID:24074212]. These symptoms often improve spontaneously within the first year of life.
Failure to thrive and dyslipidaemia (FTTDCD) can manifest during childhood and is characterised by persistent growth problems and abnormal fat levels in the blood. Later-onset forms, typically appearing in adulthood, are referred to as adult-onset citrullinaemia type II. These adult forms are often more severe and can involve neurological symptoms such as confusion, disorientation, memory loss, seizures, and even coma, often triggered by alcohol intake, certain medications, or surgery. Psychiatric symptoms like aggression, irritability, and insomnia may also be present [PMID:17907106].
Video: Genetics 101
Affected organs
Citrullinaemia type II primarily affects the liver and the brain. The liver is significantly impacted due to its central role in the urea cycle, which is disrupted in this condition. This can lead to liver dysfunction, fatty liver, and in severe cases, liver failure. The build-up of toxic ammonia, which the liver normally processes, can then travel to the brain.
The brain is vulnerable to high ammonia levels, leading to neurological and psychiatric symptoms. These can range from subtle changes in behaviour and cognitive function to more severe manifestations such as encephalopathy, seizures, and coma. Other organs may also be affected indirectly due to the systemic metabolic imbalance, though the primary impact remains on the liver and central nervous system.
Risks & severity
The severity of citrin deficiency is highly variable, even within the same family. In infants, the NICCD form can range from mild, self-resolving liver issues to severe liver failure. While many infants recover from NICCD, they may still be at risk of developing later-onset forms of the disorder, such as FTTDCD or adult-onset citrullinaemia type II [PMID:24074212].
Adult-onset citrullinaemia type II typically presents with more severe and life-threatening symptoms, particularly neurological crises. These crises can be triggered by factors like alcohol consumption, certain medications, or stress, and can lead to rapid neurological decline. If untreated, severe episodes can be fatal. The long-term risks include recurrent neurological episodes and the potential for liver failure, although progression varies greatly between individuals.
Genetic causes
Citrullinaemia type II is caused by pathogenic variants in the SLC25A13 gene. This gene provides the instructions for making a protein called citrin. Citrin is a mitochondrial carrier protein, meaning it helps to transport specific molecules across the inner membrane of mitochondria, which are often called the 'powerhouses' of the cell. Specifically, citrin is involved in moving glutamate into the mitochondria and aspartate out.
This transport is a critical step in several metabolic pathways, including the urea cycle, which processes and removes excess ammonia from the body. Citrin also plays a role in gluconeogenesis (making glucose) and glycolysis (breaking down glucose). When pathogenic changes occur in the SLC25A13 gene, the citrin protein either isn't produced correctly or doesn't function properly. This leads to a build-up of ammonia and other metabolic waste products, causing the symptoms observed in citrin deficiency [PMID:17907106].
- SLC25A13 solute carrier family 25 member 13The SLC25A13 gene provides instructions for producing citrin, a protein crucial for transporting molecules across mitochondrial membranes, particularly in the liver, kidneys, and heart.
Inheritance pattern
Citrullinaemia type II is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of the altered SLC25A13 gene - one from each parent - to develop the condition. Individuals who inherit only one copy of the altered gene are called carriers. Carriers typically do not show symptoms of citrin deficiency but can pass the altered gene on to their children.
If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two altered gene copies and develop the condition, a 50% chance their child will be a carrier, and a 25% chance their child will inherit two typical gene copies and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of citrin deficiency typically involves a combination of clinical evaluation and biochemical and genetic testing. Blood tests may show elevated levels of citrulline, ammonia, and other amino acids, which are indicators of a urea cycle disorder. Liver function tests may also be abnormal, particularly in the infantile form (NICCD).
Genetic testing is used to confirm the diagnosis by identifying pathogenic variants in the SLC25A13 gene. This testing is crucial for a definitive diagnosis and can be offered through the NHS Genomic Medicine Service (GMS) after a referral from a specialist clinician. The relevant NHS National Genomic Test Directory R-code for testing for citrullinaemia type II is R33. Genetic counsellors can help explain the testing process, results, and implications for family members.
Management & lifestyle
Management of citrin deficiency focuses on dietary modifications and supportive care to reduce the build-up of toxic substances and manage symptoms. For infants with NICCD, treatment may involve a special formula with a medium-chain triglyceride (MCT) oil supplement and sometimes lactose-free milk. These dietary changes aim to provide adequate nutrition while reducing the metabolic burden on the liver. The symptoms in NICCD often resolve spontaneously with these interventions [PMID:24074212].
For adult-onset forms, ongoing dietary management often involves a diet low in carbohydrates and high in fat and protein, though individual dietary needs may vary significantly. Avoidance of alcohol and certain medications that can trigger metabolic crises is also important. In severe cases, particularly with recurrent neurological crises or liver failure, liver transplantation may be considered. Regular monitoring by a specialist metabolic team, including dietitians and genetic counsellors, is essential to tailor management strategies and prevent complications.
UK care pathway
In the UK, individuals suspected of having an inherited metabolic condition like citrin deficiency would typically be referred by their GP or another specialist to a clinical genetics service or a specialist metabolic centre. These services can arrange for appropriate diagnostic tests, including genetic testing through the NHS Genomic Medicine Service (GMS). The NHS National Genomic Test Directory includes testing for citrullinaemia type II under R-code R33. Genetic counsellors play a vital role in providing information and support to individuals and families throughout the diagnostic and management process, helping them understand the condition and its implications.
Frequently asked questions
What is the main difference between Citrullinaemia type I and type II?
While both conditions involve high levels of citrulline, Citrullinaemia type I is caused by a different gene (ASS1) and affects a different enzyme in the urea cycle. Citrullinaemia type II, or citrin deficiency, is due to problems with the SLC25A13 gene and impacts a transport protein essential for the urea cycle and other metabolic functions. These genetic differences lead to distinct clinical presentations and management.
Can citrin deficiency be cured?
Currently, there is no cure for citrin deficiency. Management focuses on controlling symptoms and preventing complications through strict dietary measures, avoiding triggers like alcohol, and supportive medical care. In severe cases of adult-onset disease or liver failure, a liver transplant may be considered as it can replace the deficient citrin function.
Is citrin deficiency more common in certain populations?
Yes, citrin deficiency is notably more common in individuals of East Asian descent, particularly in Japan, where it has a prevalence of about 1 in 17,000 births. It is considered rare in most other parts of the world.
What kind of diet is recommended for someone with citrin deficiency?
Dietary recommendations vary depending on the age of onset and severity of the condition. For infants with NICCD, special formulas with medium-chain triglycerides (MCT) and sometimes lactose-free options may be used. For older children and adults, a low-carbohydrate, high-fat, and adequate-protein diet is often recommended to support metabolic pathways and reduce ammonia build-up. A specialist dietitian will provide personalised advice.
If I am a carrier, what does that mean for my family?
If you are a carrier for citrin deficiency, it means you have one copy of the altered SLC25A13 gene but typically do not have symptoms. If your partner is also a carrier, there is a 25% chance with each pregnancy that your child could inherit two altered copies and develop the condition. Genetic counselling can help you understand these risks and discuss options for family planning.