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Argininaemia
This rare condition results from changes in the *ARG1* gene, causing a build-up of arginine and ammonia in the blood. It can lead to neurological problems and developmental delays, typically affecting infants and children.
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Overview
Argininaemia is a rare genetic condition affecting metabolism, specifically the urea cycle. It is caused by a deficiency in the arginase 1 enzyme, which is crucial for converting arginine into urea and ornithine [PMID:33678083]. This enzyme deficiency leads to an accumulation of arginine in the blood and other body tissues, and can also result in elevated ammonia levels, known as hyperammonaemia. The condition typically presents in early childhood, affecting development and neurological function. It is classified as an inborn error of metabolism.
Because arginine plays various roles in the body, its high concentration can have widespread effects. The urea cycle is essential for removing toxic ammonia, a by-product of protein metabolism, from the body. When this cycle is disrupted, ammonia levels can rise, which is particularly damaging to the brain.
Symptoms & clinical features
Symptoms of argininaemia can vary in severity and typically appear in infancy or early childhood. Common signs include developmental delay, learning difficulties, and spastic paraparesis (weakness and stiffness in the legs) [PMID:20301323]. Children may also experience seizures and challenges with movement. Growth can also be affected, leading to shorter stature.
In some cases, individuals may experience episodes of hyperammonaemia, where ammonia levels in the blood become dangerously high. Such episodes can cause vomiting, lethargy, irritability, and in severe cases, coma, though this is less common or severe than in some other urea cycle disorders. Early recognition and management are important to mitigate the long-term impact of the condition.
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Affected organs
The primary organs affected by argininaemia are the brain and the central nervous system. The accumulation of toxic substances, especially ammonia, has a profound impact on neurological development and function, leading to symptoms like developmental delay, seizures, and spasticity. The liver is also involved as it is the main site of the urea cycle, where the arginase 1 enzyme normally functions. However, liver function itself is usually not severely impaired in argininaemia.
Risks & severity
The severity of argininaemia can vary among individuals, even within the same family. Without early diagnosis and treatment, the accumulation of arginine and ammonia can lead to progressive neurological damage, potentially resulting in severe intellectual disability and physical disabilities [PMID:20301323]. Spastic paraparesis is a common and often progressive feature, affecting mobility. The exact prevalence of argininaemia is not well established, but it is considered a rare condition.
While severe hyperammonaemic crises are less frequent than in some other urea cycle disorders, persistent elevated arginine can still cause significant long-term health problems. Early intervention and consistent management are key to improving outcomes and reducing the risk of complications.
Genetic causes
Argininaemia is caused by pathogenic variants in the *ARG1* gene. This gene provides instructions for making the arginase 1 enzyme, which is primarily found in the liver. The arginase 1 enzyme is the final enzyme in the urea cycle, responsible for breaking down the amino acid arginine into urea and ornithine. Urea is then excreted from the body via the urine.
When variants in *ARG1* disrupt the function of the arginase 1 enzyme, arginine cannot be broken down effectively, leading to its accumulation in the blood. This build-up, along with the disruption of the urea cycle, can also lead to increased ammonia levels. The subsequent toxicity of these compounds, particularly ammonia, primarily affects the brain and central nervous system.
- ARG1 arginase 1
Inheritance pattern
Argininaemia has an autosomal recessive pattern of inheritance. This means that an individual must inherit two copies of the pathogenic gene variant - one from each parent - to develop the condition. People who inherit only one copy of the variant are called carriers; they typically do not show symptoms of argininaemia themselves.
If both parents are carriers of an *ARG1* gene variant, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two copies of the variant and develop argininaemia. There is also a 50% chance that the child will be a carrier like their parents, and a 25% chance that the child will not inherit any pathogenic variants.
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 argininaemia typically begins with clinical suspicion prompted by characteristic symptoms. Biochemical tests, such as blood and urine analyses, can show elevated levels of arginine and ammonia, and often a distinctive amino acid profile. These findings usually suggest argininaemia.
Confirmation of the diagnosis involves genetic testing to identify pathogenic variants in the *ARG1* gene. Genetic testing for argininaemia is available within the NHS Genomic Medicine Service (GMS) under specific R-codes for metabolic disorders. Referral to a clinical genetics service or a metabolic specialist is usually required for genetic testing and counselling. Newborn screening programmes in the UK do not universally screen for argininaemia at present, but it may be detected through expanded newborn screening where available.
Management & lifestyle
Management of argininaemia focuses on reducing arginine and ammonia levels in the body to prevent neurological damage and manage symptoms. This often involves a specialised diet, specifically a protein-restricted diet, to limit the intake of arginine. Dietary management may also include supplements of essential amino acids and energy sources to ensure adequate nutrition and prevent catabolism.
Medications may be used to help remove excess ammonia from the body. Regular monitoring of blood arginine and ammonia levels is crucial to adjust treatment as needed. Physiotherapy, occupational therapy, and speech and language therapy are often important to manage developmental delays and motor difficulties. Management is coordinated through specialist metabolic teams within the NHS.
UK care pathway
In the UK, individuals suspected of having argininaemia are typically referred to a specialist metabolic centre or clinical genetics service within the NHS. Genetic testing, covered by the NHS Genomic Medicine Service (GMS) through specific R-codes, can confirm the diagnosis. A genetic counsellor will provide information about the condition, inheritance patterns, and implications for family members. Care is multidisciplinary, involving paediatricians, metabolic specialists, dietitians, and various therapists.
Frequently asked questions
What happens if argininaemia is not treated?
Untreated argininaemia can lead to the build-up of harmful substances like arginine and ammonia in the blood, which can cause progressive neurological damage. This can result in severe developmental delays, intellectual disability, seizures, and difficulties with movement like spastic paraparesis.
Can argininaemia be detected during pregnancy?
Yes, if a family has a known history of argininaemia and the genetic variant has been identified, prenatal diagnosis is possible. This involves testing samples taken during pregnancy, such as chorionic villus sampling or amniocentesis, to check for the *ARG1* gene variants.
What kind of diet is required for argininaemia?
Individuals with argininaemia typically require a specialised low-protein diet to limit the intake of arginine. This diet is carefully managed by a specialist dietitian to ensure adequate nutrition while preventing the accumulation of harmful substances. This may include special protein-free or low-protein foods and specific amino acid supplements.
Will my children inherit argininaemia?
Argininaemia is inherited in an autosomal recessive pattern. If you have argininaemia, your children will inherit one copy of the *ARG1* gene variant from you. Unless your partner is also a carrier or has argininaemia, your children will be carriers but are unlikely to develop the condition themselves. Genetic counselling can provide personalised risk assessments.
Is there a cure for argininaemia?
There is currently no cure for argininaemia, but it is a manageable condition. Treatment focuses on lifelong management to control arginine and ammonia levels through dietary modifications and, in some cases, medications. Early diagnosis and consistent adherence to treatment can significantly improve outcomes and help prevent severe complications.
References
- Edwards RL, Moseley K, Watanabe Y. Long-term neurodevelopmental effects of early detection and treatment in a 6-year-old patient with argininaemia diagnosed by newborn screening. Journal of inherited metabolic disease. 2009. PMID: 19562505
- Duff C, Alexander IE, Baruteau J. Gene therapy for urea cycle defects: An update from historical perspectives to future prospects. Journal of inherited metabolic disease. 2024. PMID: 37026568
- 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
- Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta paediatrica (Oslo, Norway : 1992). 2008. PMID: 18616627
- Endres W, Schaller R, Shin YS. Diagnosis and treatment of argininaemia. Characteristics of arginase in human erythrocytes and tissues. Journal of inherited metabolic disease. 1984. PMID: 6429443
- Santos Silva E, Martins E, Cardoso ML. Liver transplantation in a case of argininaemia. Journal of inherited metabolic disease. 2001. PMID: 11916327
- Baumgartner MR, Rabier D, Nassogne MC. Delta1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline. European journal of pediatrics. 2005. PMID: 15517380
- Konarska L, Tomaszewski L, Colombo JP. Human salivary arginase and its deficiency in argininaemia. Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie. 1985. PMID: 4020330