Citrullinemia type I is a genetic, metabolic condition where there is a build up of ammonia (a toxic by-product of protein metabolism) in the blood. 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.

Citrullinemia type I is a urea-cycle disorder, in which one of the urea cycle enzymes (argininosuccinate synthetase;  ASS) is not working properly and fails to combine citrulline and asparate to form arginosuccinate. This prevents ammonia from being completely converted to urea, leading to build-up of citrulline and ammonia. High levels of ammonia in the blood (hyperammonemia) 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 hyperammonemia is not treated promptly, it can be life-threatening. Even with prompt treatment of the hyperammonemia, children may have developmental delay, intellectual disability, and other complications.

Symptoms and severity of citrullinemia type I can vary widely between individuals, ranging from:

• 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 hyperammonemia)

In Australia, citrullinemia type I, in particular the classic form, is often detected shortly after birth via newborn bloodspot screening (NBS) programs. For individuals who are not screened at birth or not detected by NBS, citrullinemia type I is often diagnosed after symptoms develop. Early detection and management of citrullinemia type I prior to development of symptoms is important to prevent hyperammonemia and long term damage as well as life-threatening complications.

Synonyms: 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

Rare diseases typically display a high level of symptom complexity. There is often a wide range of symptoms and the symptoms may vary between individuals in terms of its presentation, severity, duration and impact.

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.

Citrullinemia type I is a genetic condition. It is caused by disease-causing genetic changes (variants) in the ASS1 gene. 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. Citrullinemia type I is an autosomal recessive condition, 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

Screening

In Australia, citrullinemia 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 citrullinemia type I. If the test results suggest that there is a risk of the baby having one of 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 citrullinemia 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, citrullinemia type I is often diagnosed after symptoms develop.

Diagnosis of citrullinemia 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 confirmed by genetic testing.

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 other urea cycle disorders such as carbamoyl-phosphate synthetase 1 deficiency, argininosuccinic aciduria (ASA), ornithine transcarbamylase deficiency, arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency.

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

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.

Healthcare professionals involved in the clinical care of individuals with citrullinemia 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.

For many rare diseases, 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. 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. Palliative care 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. For 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

If you know of any relevant clinical care guidelines, please let us know via the  Contribute page.

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.

If you know of any relevant emergency management guidelines or information relevant to emergency care, please let us know via the  Contribute page.

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.

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in any clinical trials with your medical team to determine suitability and eligibility.

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.

Citrullinemia 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, including families and carers, 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 people 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 Citrullinemia 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. If you would like to see more information added to this page, please reach out via the Contact form. If you would like to share relevant resources for this condition, please visit the Contribute page.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.