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Citrullinaemia type I
This condition is part of a group of disorders known as urea cycle disorders. It can lead to the build-up of harmful substances, particularly ammonia, primarily affecting infants and, in some cases, adults. Early diagnosis and management are important to prevent serious health issues.
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Overview
Citrullinaemia type I, also known as classic citrullinaemia, is a rare genetic condition where the body cannot effectively process and remove ammonia. Ammonia is a toxic compound produced when proteins are metabolised. Normally, the urea cycle, a series of biochemical reactions, converts ammonia into urea, which is then excreted from the body via urine. In individuals with Citrullinaemia type I, a specific enzyme in this cycle does not work correctly, leading to a build-up of ammonia and other by-products in the blood [PMID:33994119].
This condition is part of a broader group of disorders called urea cycle disorders. It typically presents in infancy, often within the first few days of life, but can sometimes have a later onset, including in adulthood. The severity of symptoms can vary widely among affected individuals.
Symptoms & clinical features
Symptoms of Citrullinaemia type I are mainly related to the accumulation of ammonia in the body, particularly in the brain. In newborns, these symptoms can appear rapidly and include poor feeding, vomiting, lethargy (extreme tiredness), irritability, and seizures. If left untreated, high ammonia levels can lead to brain damage, coma, and can be life-threatening [PMID:20301389].
In individuals with a later onset, symptoms may be milder and can include recurrent vomiting, intellectual disability, developmental delay, learning difficulties, and neurological problems such as seizures or ataxia (problems with coordination and balance). Some individuals may experience periods of symptom worsening, often triggered by illness, stress, or high protein intake.
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Affected organs
The primary organ affected by Citrullinaemia type I is the brain, due to its high sensitivity to elevated ammonia levels. High ammonia concentrations can cause swelling and damage to brain cells, leading to the severe neurological symptoms observed. The liver is also involved, as it is the main site where the urea cycle takes place. Although the liver may not be directly damaged by the condition in the same way as the brain, its inability to perform its detoxifying function within the urea cycle is central to the disorder.
Risks & severity
Citrullinaemia type I is considered a serious condition, especially when symptoms appear early in life. The severity of the condition depends on how active the affected enzyme is. Newborns with very little enzyme activity can experience rapid and severe ammonia build-up, leading to significant brain damage if not treated promptly. Long-term complications for those with early-onset disease can include intellectual disability, developmental delays, and neurological issues despite treatment.
For those with a later or milder onset, the risks are still significant, particularly during metabolic crises triggered by infection, surgery, or dietary issues. These crises can lead to acute encephalopathy (brain dysfunction) due to sudden increases in ammonia. The exact prevalence of Citrullinaemia type I is approximately 1 in 57,000 live births, but this can vary by population [PMID:37517173].
Genetic causes
Citrullinaemia type I is caused by pathogenic variants in the ASS1 gene. The ASS1 gene provides instructions for making an enzyme called argininosuccinate synthase 1. This enzyme is crucial for one of the steps in the urea cycle, where it helps convert citrulline and aspartate into argininosuccinate.
When there are disease-causing changes in the ASS1 gene, the argininosuccinate synthase 1 enzyme either does not function correctly or is present in insufficient amounts. This disrupts the urea cycle, preventing the efficient removal of ammonia from the body and leading to its accumulation along with specific amino acids like citrulline. The build-up of ammonia is toxic, particularly to the brain.
- ASS1 argininosuccinate synthase 1The ASS1 gene provides instructions for making argininosuccinate synthase 1, an enzyme vital for the urea cycle, which helps remove waste nitrogen from the body.
Inheritance pattern
Citrullinaemia type I is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered ASS1 gene - one from each parent - to develop the condition. People who have only one copy of the altered gene are called carriers; they do not typically show symptoms of Citrullinaemia type I 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 the child will be a carrier, and a 25% chance the child will inherit two working copies of the gene 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 Citrullinaemia type I is often suspected based on elevated ammonia levels in blood tests, especially in a newborn presenting with typical symptoms. Specific metabolic tests, such as amino acid analysis in blood and urine, can reveal high levels of citrulline, which is characteristic of the condition. In some regions of the UK, Citrullinaemia type I may be included in newborn screening programmes, which can lead to early detection before symptoms appear.
Confirmation of the diagnosis involves genetic testing to identify pathogenic variants in the ASS1 gene. This testing can be arranged through the NHS Genomic Medicine Service (GMS) by clinical genetics specialists or other relevant clinicians, often following referral from a GP or paediatrician. The relevant R-codes for genetic testing for urea cycle disorders, including Citrullinaemia type I, would guide these diagnostic pathways.
Management & lifestyle
Management of Citrullinaemia type I focuses on reducing ammonia levels in the blood and preventing metabolic crises. This typically involves a lifelong, carefully managed diet that is low in protein to limit ammonia production. In some cases, specific amino acid supplements or medications that help the body remove nitrogen compounds (such as ammonia scavengers) may be prescribed.
Regular monitoring of blood ammonia and amino acid levels is essential, particularly during times of illness or stress, as these can trigger a metabolic crisis. Management plans are highly individualised and developed by a team of specialists, including metabolic consultants, dietitians, and genetic counsellors. In severe cases, liver transplantation may be considered as a potential treatment option, as it provides a source of functionally active argininosuccinate synthase 1 enzyme.
UK care pathway
In the UK, individuals suspected of having or diagnosed with Citrullinaemia type I will typically enter the NHS Genomic Medicine Service pathway. Referrals are often made by general practitioners, paediatricians, or other specialists to a clinical genetics service. Clinical geneticists and genetic counsellors play a key role in confirming the diagnosis through genetic testing, explaining the condition, and discussing inheritance patterns and family planning options. The NHS National Genomic Test Directory outlines the available R-codes for testing this and other rare conditions, ensuring appropriate and consistent access to genetic diagnostics across England.
Frequently asked questions
What is the urea cycle and why is it important?
The urea cycle is a process that occurs mainly in the liver, responsible for converting toxic ammonia, a by-product of protein breakdown, into urea. Urea is then safely removed from the body through urine. This cycle is vital for preventing the build-up of harmful ammonia in the blood, which can cause severe health problems, especially for the brain.
How is Citrullinaemia type I inherited?
Citrullinaemia type I is inherited in an autosomal recessive manner. This means a child needs to receive one copy of the altered ASS1 gene from each parent to be affected. Parents who carry one altered copy usually do not have symptoms themselves. Genetic counselling can help families understand the inheritance risks.
Can Citrullinaemia type I be detected before birth?
For families with a known genetic cause of Citrullinaemia type I, prenatal diagnosis may be available through chorionic villus sampling or amniocentesis. This involves testing foetal cells for the specific genetic changes in the ASS1 gene. Pre-implantation genetic testing (PGT) may also be an option for carrier couples, where embryos are tested before implantation.
What is a 'metabolic crisis' in Citrullinaemia type I?
A metabolic crisis refers to a sudden worsening of symptoms due to a rapid increase in ammonia levels. This can be triggered by factors like infections, fever, dehydration, or consuming too much protein. During a crisis, symptoms can include vomiting, extreme tiredness, confusion, and seizures, requiring urgent medical intervention.
Is there a cure for Citrullinaemia type I?
Currently, there is no definitive cure for Citrullinaemia type I. Management focuses on preventing and treating high ammonia levels through lifelong dietary management, medications, and close medical supervision. In some severe cases, liver transplantation can be a treatment option that may significantly improve outcomes for affected individuals.
References
- Glamuzina E, Marquis-Nicholson R, Knoll D. Citrullinaemia type I: a common mutation in the Pacific Island population. Journal of paediatrics and child health. 2011. PMID: 21244552
- Rabinovich S, Adler L, Yizhak K. Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. Nature. 2015. PMID: 26560030
- Aras-Col T, Zubarioglu T, Uygur E. Neonatal Citrullinaemia Type I Complicated by Hyperinsulinaemic Hypoglycaemia: Challenges in Managing Dual Metabolic Pathways. Journal of paediatrics and child health. 2026. PMID: 42568312
- Han LS, Ye J, Qiu WJ. Selective screening for inborn errors of metabolism on clinical patients using tandem mass spectrometry in China: a four-year report. Journal of inherited metabolic disease. 2007. PMID: 17347912