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Argininosuccinic aciduria
This rare genetic disorder affects the urea cycle, a process in the liver that removes excess nitrogen. It leads to the harmful build-up of ammonia in the blood, which can cause serious health problems, particularly affecting the brain.
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Overview
Argininosuccinic aciduria is a rare inherited metabolic disorder that affects how the body removes ammonia, a waste product formed when proteins are broken down. The body's natural process for removing ammonia is called the urea cycle. In argininosuccinic aciduria, there is a fault in one of the enzymes needed for this cycle to work correctly [PMID:30138908]. This leads to ammonia accumulating in the blood, a condition known as hyperammonaemia, which can be toxic, especially to the brain.
This condition is part of a group of disorders known as urea cycle disorders (UCDs). It is typically diagnosed in infancy or early childhood, though milder forms can emerge later in life. The severity of symptoms can vary significantly among affected individuals. Early detection and management are crucial for improving outcomes.
Symptoms & clinical features
Symptoms of argininosuccinic aciduria can range widely, from severe issues appearing shortly after birth to milder problems that become apparent later. In newborns, symptoms often include poor feeding, vomiting, lethargy (lack of energy), irritability, seizures, and an enlarged liver. These signs are often related to the build-up of ammonia, which can become life-threatening if not managed promptly.
In individuals with a later onset or milder form, symptoms might be more subtle or intermittent. These can include developmental delay, learning difficulties, headaches, aversion to protein-rich foods, and brittle hair. Some individuals may experience episodes of hyperammonaemic crisis triggered by illness, stress, or certain medications. Neurological problems, such as intellectual disability and seizures, are common in both severe and milder forms [PMID:20301375].
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Affected organs
While argininosuccinic aciduria affects the body's overall metabolism, the brain is particularly vulnerable to the toxic effects of ammonia build-up. This can lead to neurological problems, including developmental delay, intellectual disability, and seizures. The liver is also central to the condition because the urea cycle primarily operates there. However, the liver cells themselves are generally not damaged in argininosuccinic aciduria, unlike some other metabolic conditions.
Risks & severity
The severity of argininosuccinic aciduria can vary considerably. Some infants experience a severe form with life-threatening hyperammonaemia shortly after birth. This acute presentation requires urgent medical intervention and can result in significant neurological damage if not treated swiftly. At the other end of the spectrum, some individuals have a milder form, with symptoms presenting later in childhood or even adulthood, often triggered by metabolic stress [PMID:30138908].
Lifelong monitoring and management are necessary for all individuals with argininosuccinic aciduria to prevent or minimise hyperammonaemic crises and their neurological consequences. The long-term risks include intellectual disability, seizures, and other neurological issues. The exact prevalence of argininosuccinic aciduria is not well established globally, but it is estimated to affect around 1 in 70,000 live births.
Genetic causes
Argininosuccinic aciduria is caused by changes (also known as pathogenic variants or mutations) in the ASL gene. This gene provides instructions for making an enzyme called argininosuccinate lyase. This enzyme is a critical component of the urea cycle, which is the main pathway for the body to convert excess nitrogen from protein breakdown into urea, which can then be safely excreted [PMID:36830504].
When the ASL enzyme is faulty due to a pathogenic variant, the urea cycle cannot complete its task. This leads to a build-up of argininosuccinic acid and, more importantly, ammonia in the blood. The accumulation of ammonia is toxic, particularly to the brain, leading to the diverse symptoms observed in individuals with argininosuccinic aciduria.
- ASL argininosuccinate lyaseThe ASL gene provides instructions for producing argininosuccinate lyase, an enzyme critical for the body's urea cycle and the production of nitric oxide.
Inheritance pattern
Argininosuccinic aciduria is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered ASL gene, one from each parent, to develop the condition. People who have only one altered copy of the ASL gene are called carriers. Carriers typically do not show symptoms of argininosuccinic aciduria but can pass the altered gene on to their children.
If both parents are carriers of a pathogenic variant in the ASL gene, for each pregnancy, there is a 25% chance of their child inheriting two altered copies and developing the condition. There is also a 50% chance of the child being a carrier, and a 25% chance of the child inheriting two normal copies and not being 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 argininosuccinic aciduria often begins with recognising clinical symptoms, particularly those associated with hyperammonaemia. Initial biochemical tests typically include measuring ammonia levels in the blood, which will be elevated. Additional tests, such as plasma amino acid analysis and urine organic acid analysis, help to identify characteristic patterns of metabolites, including high levels of argininosuccinic acid.
Confirmation of the diagnosis is made through genetic testing, which identifies pathogenic variants in the ASL gene. In the UK, genetic testing for suspected inherited metabolic conditions like argininosuccinic aciduria falls under the NHS Genomic Medicine Service (GMS) pathways. Referrals for genetic testing are typically made by specialist paediatricians, metabolic consultants, or clinical geneticists, using R-codes such as R4 (Neurological disorders with a monogenic cause) or R101 (Inherited metabolic disorders). Newborn screening programmes in some regions may also identify individuals at risk.
Management & lifestyle
Management of argininosuccinic aciduria focuses on preventing or treating hyperammonaemia and providing nutritional support. This typically involves a lifelong, carefully managed diet that restricts protein intake to reduce the amount of nitrogen the body needs to process. Certain amino acid supplements and medicines that help by-pass the urea cycle and remove excess nitrogen from the body may also be prescribed.
During times of illness or metabolic stress, individuals with argininosuccinic aciduria may require urgent hospitalisation to prevent or treat acute hyperammonaemic crises. This can involve intravenous fluids, glucose, and medications to lower ammonia levels. Regular monitoring of blood ammonia and amino acid levels is essential. Management plans are highly individualised and are developed and overseen by a multidisciplinary team, usually including metabolic consultants, dietitians, and genetic counsellors, within the NHS framework. Genetic counselling is also offered to affected families.
UK care pathway
In the UK, individuals suspected of having argininosuccinic aciduria are generally referred to specialist NHS metabolic centres. Diagnosis is typically confirmed through genetic testing, which is requested by clinical geneticists or specialist consultants via the NHS Genomic Medicine Service, often using R-codes relevant to inherited metabolic disorders. Following diagnosis, care is managed by a multidisciplinary team, and genetic counsellors are available to provide support and information to families regarding inheritance patterns and family planning.
Frequently asked questions
What happens if argininosuccinic aciduria is not treated?
Without treatment, the build-up of ammonia can become toxic and cause severe neurological damage. This can lead to intellectual disability, developmental delay, seizures, and in severe cases, be life-threatening.
Can argininosuccinic aciduria be cured?
Currently, there is no cure for argininosuccinic aciduria. However, with lifelong dietary management, medications, and careful monitoring, the symptoms can often be managed effectively, helping to prevent serious complications.
Is it possible to have a mild form of argininosuccinic aciduria?
Yes, the severity of argininosuccinic aciduria can vary. Some individuals have a milder form where symptoms might appear later in childhood or adulthood, often triggered by illness or stress. These individuals also require careful management.
What kind of diet is required for someone with argininosuccinic aciduria?
Individuals typically require a carefully managed, low-protein diet to reduce the amount of ammonia produced. This is often supplemented with specific amino acids and medications specified by a metabolic dietitian and consultant.
How common is argininosuccinic aciduria?
Argininosuccinic aciduria is a rare condition. Exact figures vary, but it is estimated to affect approximately 1 in 70,000 live births globally.
References
- Winchester S, Singh PK, Mikati MA. Ataxia. Handbook of clinical neurology. 2013. PMID: 23622331
- Adam MP, Bick S, Mirzaa GM. Argininosuccinate Lyase Deficiency. 1993. PMID: 21290785
- Nagamani SC, Lee B, Erez A. Optimizing therapy for argininosuccinic aciduria. Molecular genetics and metabolism. 2012. PMID: 22841516
- Gurung S, Timmermand OV, Perocheau D. mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria. Science translational medicine. 2024. PMID: 38198573
- Posset R, Garbade SF, Gleich F. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Genetics in medicine : official journal of the American College of Medical Genetics. 2024. PMID: 38054409
- Baruteau J, Diez-Fernandez C, Lerner S. Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects. Journal of inherited metabolic disease. 2019. PMID: 30723942
- Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. American journal of medical genetics. Part C, Seminars in medical genetics. 2011. PMID: 21312326
- Zielonka M, Kölker S, Garbade SF. Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders. Molecular genetics and metabolism. 2024. PMID: 39299137