Citrullinaemia type I is a genetic, metabolic condition where there is a build-up of ammonia in the blood.¹ Ammonia is produced when the body breaks down protein from food, and is toxic at high levels. The body’s liver normally converts ammonia into urea (which is then excreted from the body in urine) through a metabolic process called the urea cycle.

Citrullinaemia type I is a urea-cycle disorder, in which one of the urea cycle enzymes, argininosuccinate synthetase (ASS), does not work properly.^2,3 This enzyme is involved in the third step of the urea cycle and is responsible for combining citrulline and aspartate to form arginosuccinate.^2,4 When this step is blocked, ammonia cannot be fully converted into urea for removal from the body, leading to build-up for citrulline and ammonia. High levels of ammonia in the blood (hyperammonaemia) can be toxic, particularly to the body’s nervous system. This can result in symptoms such as lethargy, vomiting, seizures and coma in babies in severe cases and if the hyperammonaemia is not treated promptly, it can be life-threatening. Even with prompt treatment of the hyperammonaemia, children may have developmental delay, intellectual disability, and other complications.

Symptoms and severity of citrullinaemia type I can vary widely between individuals, ranging from:^2,3

• classic form (neonatal acute form)
• non-classic form (milder, late-onset form)
• a form in which symptoms present at pregnancy or post-partum
• asymptomatic form (no symptoms or no hyperammonaemia)

In Australia, citrullinaemia type I, in particular the classic form, is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Additional testing is required to confirm the diagnosis. For individuals who are not screened at birth or not detected by NBS, citrullinaemia type I is often diagnosed after symptoms develop. Early detection and management of citrullinaemia type I prior to development of symptoms is associated with better outcomes.²

Synonyms:² Argininosuccinate synthetase deficiency; Argininosuccinic acid synthetase deficiency; ASS deficiency; Classic citrullinemia; CTLN1

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:247525 Citrullinemia type I

ICD-11: 5C50.A3 Citrullinaemia

Symptoms of citrullinaemia type I vary widely between individuals and have been described as the following forms:

Classic form (neonatal acute form)

Symptoms often present within the few first days or week of life. Babies may display symptoms such as extreme tiredness and lack of energy (lethargy), vomiting, poor feeding or refusal to feed and irritability.^2,3 They may develop liver failure and cerebral edema (swelling in the brain due to build-up of fluid). If left untreated, the hyperammonaemia (high levels of ammonia in the blood) lead to seizures, coma and early death. Episodes of hyperammonaemia can also have long-term effects such as developmental delay and intellectual disability.

Non-classic form (milder, late-onset form)

Symptoms present later than the classic form and may include lethargy, sleepiness, headaches or migraine-like episodes, slurred speech and ataxia (loss of ability to control movement of muscles, affecting balance and coordination).³ Similar to the classic form, there may also be liver failure and if left untreated, the hyperammonaemia can lead to seizures, coma and early death.

Onset of symptoms at pregnancy or post-partum

Severe symptoms may only present during pregnancy or after pregnancy during the postpartum period. Individuals may develop hyperammonaemia and have symptoms such as headaches, dizziness, confusion, seizures and in severe cases, it may lead to coma and early death.^2,5 Hyperemesis gravidarum (severe nausea and vomiting during pregnancy) with acute kidney failure, and post-partum psychosis has also been reported.^3,5

Asymptomatic form (no symptoms or no hyperammonaemia)

It is reported that there are some individuals that do not have any symptoms or hyperammonaemia, even without treatment.^2,3

Please speak to your medical team to learn more about the symptoms of this condition.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

Citrullinaemia type I is a genetic condition. It is caused by disease-causing genetic changes (variants) in the ASS1 gene.^1-3 The ASS1 gene is responsible for producing an enzyme called  argininosuccinate synthetase (ASS).

All individuals have two copies (alleles) of the ASS1 gene – one copy inherited from each parent. Citrullinaemia type I is an autosomal recessive condition,^1-3 which means both copies of the ASS1 gene must have the disease-causing genetic variants. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Newborn screening

In Australia, citrullinaemia type I, in particular the classic form, is usually detected via the newborn bloodspot screening (NBS) programs.  Shortly after birth and with parental consent, a nurse or midwife will collect the baby’s blood via a heel prick blood test. The healthcare provider will then send it to a specific laboratory to test for a range of rare conditions, including citrullinaemia type I. If the test results suggest that there is a risk of the baby having one of the screened conditions, laboratory staff will promptly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing to confirm if the baby actually has the condition. The healthcare providers will also organise for the baby to receive urgent care if required. Depending on your state or territory, parents may or may not receive a notification if the test results are clear. You can find out more about NBS in your state or territory at Australian Government Department of Health, Disability and Ageing: Delivering newborn bloodspot screening programs.

Newborn bloodspot screening is a reliable way to check for certain rare conditions early in life. Although it’s extremely rare, cases can sometimes be missed. If you are concerned your baby may have a condition that they have already been screened for, you should contact a medical professional.

Diagnosis

A diagnosis of citrullinaemia type I may be suspected based on an abnormal result from NBS but additional tests or a clinical examination will be required to confirm a diagnosis. For individuals who are not screened at birth or if undetected during NBS screening, citrullinaemia type I is often diagnosed after symptoms develop.

Diagnosis of citrullinaemia type I may be made based on clinical evaluation of symptoms, laboratory tests on blood samples to detect for increased levels of ammonia and citrulline (and absence of argininosuccinate), and confirmed by genetic testing.^2,3

As part of the diagnostic process, doctors may do a differential diagnosis, which is to rule out other conditions that have similar symptoms, such as carbamoyl-phosphate synthetase 1 deficiency, argininosuccinic aciduria (ASA), ornithine transcarbamylase deficiency, arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency, pyruvate carboxylase deficiency, dihydrolipoamide dehydrogenase (DLD) deficiency and citrullinaemia type II.^2,3

Please speak to your medical team to learn more about the available pathways for diagnosis of this condition.

Management of citrullinaemia type I focuses on prompt management of hyperammonaemia, prevention of episodes of hyperammonaemia including through long-term dietary management, and management of complications.^2,3 Hyperammonaemia can be life-threatening and requires urgent medical treatment. Long-term dietary management often involves a protein-restricted diet, alongside arginine supplementation. The tolerated amount of protein in diets may vary between individuals and may change over time. It should be managed by a metabolic nutritionist. Nitrogen scavenging medications may be used to remove nitrogen from the body.  Strategies to manage symptoms and complications may include management of seizures, physiotherapy, occupational therapy and speech therapy.

Liver transplantation may be an option for some individuals and will remove the need for long-term dietary protein restriction, but it cannot reverse any neurological damage that had occurred.^2-4

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities. For many rare diseases, treatment options may be limited. Participation in a clinical trial may provide access to new or emerging therapies.

Healthcare professionals involved in the clinical care of individuals with citrullinaemia type I may include general practitioners (GP), paediatricians, geneticists, metabolic physicians, genetic counsellors, neurologists, metabolic dieticians, physiotherapists, speech therapists, occupational therapists, and other metabolic specialists and care team. The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.  

Metabolic Dietary Disorders Association (MDDA): Metabolic Clinics include a list of metabolic clinics in Australia that provide comprehensive diagnostic and management services for children and adults with inborn errors of metabolism.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

This may not be applicable to all rare diseases but for many, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

The ASIEM Low Protein Handbook for Urea Cycle Disorders has been prepared by members of the Australasian Society for Inborn Errors of Metabolism (ASIEM), a special interest group of the Human Genetics Society of Australasia (HGSA), and was published in 2007.

The following guidance is available from international experts outside Australia; however, there may be information that is not relevant or applicable to the Australian context, and may not be up to date:

• Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision, published in 2019, is an update of the 2012 guidelines involving a 17-expert panel assembled from eight different European countries and Israel.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

In addition, individuals, their parents, families and carers often develop extensive expertise on their specific rare disease. It is important to recognise that they can contribute valuable knowledge about their rare condition. Rare diseases often impact individuals differently, so it’s important to consider a person’s lived experience.

Below are some considerations for the emergency management of individuals living with citrullinaemia type I, including when presenting to emergency departments:^,2,3

• people with citrullinaemia type I are at risk of hyperammonaemia, which can be life-threatening and requires urgent medical treatment
• there is also risk of liver failure, acute encephalopathic crises and increased intracranial pressure
• excessive protein intake and prolonged fasting should be avoided
• metabolic specialist team to be consulted in the planning of emergency surgeries or procedures

Metabolic Dietary Disorders Association (MDDA): Latest Research Updates has information about key areas of ongoing research for various inborn errors of metabolism conditions, including urea cycle disorders.

Australian Organisation:

Metabolic Dietary Disorders Association (MDDA)
Website: https://mdda.org.au/

Metabolic Dietary Disorders Association Inc (MDDA) is the national peak consumer body dedicated to supporting, educating, connecting, and representing all individuals their families and carers living with Inborn Errors of protein Metabolism (IEpM).

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

Citrullinaemia type I vary between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

• The ASIEM Low Protein Handbook for Urea Cycle Disorders
• Fruit and Vegetables Counting Lists
• Protein Counting List

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information on Citrullinaemia type I can be found at: 

• Metabolic Dietary Disorders Association (MDDA): Citrullinaemia (CIT)
• Genetic and Rare Diseases (GARD) Information Center: Citrullinemia type i
• National Organization for Rare Disorders (NORD): Citrullinemia Type 1
• The ASIEM Low Protein Handbook for Urea Cycle Disorder

GeneReviews^®: Citrullinemia Type I

Orphanet: Citrullinemia type I

Online Mendelian Inheritance in Man (OMIM): # #215700 – Citrullinemia, Classic

Human Phenotype Ontology (HPO): Citrullinemia type I

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

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