What is Arginase Deficiency?
Arginase deficiency, also known as argininemia, is a genetic disorder that leads to a build-up of arginine and an excess of ammonia in the body. The levels of ammonia can change depending on the patient’s age and health condition. Symptoms include slow growth, delayed development, and problems with memory and thinking. If not treated on time, it could cause deterioration.
Usually, this condition is spotted in babies when they are born through a test called newborn screening (NBS). The test shows higher levels (as much as four times) of arginine. The way this condition is managed is similar to how some related disorders of the urea cycle (a cycle of processes in the body that gets rid of nitrogen waste) are dealt with, even if there’s mild or no excess of ammonia. But if there’s too much ammonia, treatments that reduce ammonia work well. Long-term treatment typically includes a diet with limited protein combined with medicines that get rid of excess nitrogen.
What Causes Arginase Deficiency?
ARG1 is a gene that creates a protein, named the arginase enzyme. This enzyme is mainly found in the liver and plays an important role in the final step of the urea cycle, a process that gets rid of ammonia in the body. If there are issues with both copies of this ARG1 gene, the arginase enzyme becomes unstable.
Another gene, ARG2, also contributes to arginase activity. This gene is primarily found in the mitochondria of certain tissues outside the liver, notably in the kidneys, but also in smaller amounts in the brain and digestive tract. However, it doesn’t produce enough to make up for any problems caused by defects in ARG1.
Risk Factors and Frequency for Arginase Deficiency
Arginase deficiency is a very rare metabolic disorder, with approximately 0.5 to 1 case in every 1,000,000 people. It cannot be precisely predicted who will be affected by this disorder as no specific genetic indications have been found yet.
Signs and Symptoms of Arginase Deficiency
Arginase deficiency, also known as argininemia, is a rare condition that doesn’t often show symptoms in newborns or infants. However, after 1 to 3 years of age, patients may experience periods of high ammonia levels in the blood triggered by illness, a diet high in protein, or certain medications like valproate. This high ammonia level is generally detected when the patient has a significant incident.
As these patients grow, they tend to exhibit reduced growth, spastic diplegia (a strong symptom of the condition), and stagnation or decline in mental development. Some specific cognitive manifestations that have been noted include learning disabilities, attention deficit hyperactivity disorder (ADHD), aggressive behavior, disorder of development, problems with remembers, and difficulties with fine motor skills. The last two are especially common in adult patients.
- Reduced growth
- Spastic diplegia
- Decline in mental development
- Learning disabilities
- ADHD
- Aggressive behavior
- Development disorder
- Recollecting memory problems
- Difficulties with fine motor skills
Though less common, patients can sometimes experience symptoms outside of the nervous system, which can include mild to severe liver problems and bone issues. If the disease is not treated, patients can develop severe complications related to the symptoms mentioned before. Some complications that can be found through brain scans include seizures, smaller-than-normal head size (microcephaly), and shrinkage of the brain tissue (cortical atrophy).
Testing for Arginase Deficiency
Newborn screening programs across the country often test for elevated levels of arginine, a type of amino acid. However, not all states include this test in their screening process. As a result, if individuals from these states start to fall behind in their developmental progress, it may point towards a potential issue with high arginine levels.
When a newborn screening test does indicate high arginine levels, more tests are needed. These include checking the levels of ammonia in the blood, measuring plasma amino acids, and testing for orotic acid in the urine.
Detections of high arginine levels (typically four times the normal amount), ammonia levels above 200 micrograms/dL (if present), and increased orotic acid could suggest a potential problem. To confirm this, doctors usually conduct a more specific analysis of the arginase enzyme in red blood cells, or they may run tests on a gene known as ARG1. The latter is often the first definitive step in diagnosis, as it’s harder to analyze the enzyme.
This initial testing phase is crucial because there are other disorders related to the urea cycle, a process in the body that helps get rid of excess nitrogen, which can benefit from arginine. In these cases, arginine is beneficial as it helps reduce ammonia levels by increasing the levels of another amino acid called citrulline, and aids in the expulsion of ammonia molecules from the body.
Treatment Options for Arginase Deficiency
In severe cases of a condition called hyperammonemia, treatment usually involves giving patients fluids through an IV. Certain medications like sodium phenylacetate or sodium benzoate, known as nitrogen scavengers, can also be used. It might be necessary to limit the patient’s protein intake while increasing their intake of non-protein energy sources like fats and carbohydrates.
If an IV is used with carbohydrates, a 10% dextrose solution with the right amount of sodium and/or potassium should be used depending on the patient’s age. It’s important not to give too much fluid because that can cause brain swelling. Avoiding protein should not last more than 24 to 48 hours as it can lead to further health problems.
In cases where high ammonia levels in the blood don’t respond to these methods, doctors can consider dialysis, either continuous renal replacement therapy or traditional hemodialysis. Dialysis should be stopped once ammonia levels fall to 250 micrograms/dL or lower. If seizures are a symptom, the use of medications such as phenobarbital or carbamazepine may be considered. However, a drug called valproate should not be used because it can raise the level of ammonia in the blood.
In terms of long-term care, protein intake should be limited to the minimum needed for basic body functions and development. A significant part of the dietary protein should contain arginine, an essential amino acid necessary for the function of certain cells. The amount of protein needed varies with age, with infants needing between 1 to 1.5 grams of protein per kilogram of body weight.
Some experts recommend taking supplements of an amino acid called ornithine. This can increase ornithine levels in the liver and prevent high ammonia levels. It may also block the creation of harmful compounds in the brain.
In cases where hyperammonemia reoccurs often, a liver transplant may be considered as an ultimate treatment option. Infants should be seen by a doctor monthly, and as they grow older, their visits can be less frequent. During these visits, the doctor should monitor liver function, arginine levels, muscle stiffness, and overall development.
It’s often preferable to use medications that don’t rely on the liver to be broken down. For example, ibuprofen may be a better choice than acetaminophen. Similarly, alternatives to the drug valproate may be chosen because valproate can increase ammonia levels.
Research is ongoing to find better treatments, or even potential cures, for conditions causing hyperammonemia. Techniques studied include enzyme replacement therapy, modifying the genes, and using specific forms of stem cells. Some of these efforts have seen promising results, but they’re still in the early stages and not yet ready for use in patients.
What else can Arginase Deficiency be?
Arginase deficiency can still be highly suspected even when the levels of arginine, an amino acid, are higher compared to other amino acids. This can even look normal when babies are screened or when an amino acid profile is conducted. It’s also crucial to think about other possible conditions related to the urea cycle, especially if there is an excess of ammonia in the blood without an apparent abnormality in the profiles of amino acids.
What to expect with Arginase Deficiency
The future health outlook for many patients remains uncertain due to the rarity of the disorder and inadequate follow-up. However, it’s known that most patients experience moderate to severe neurological damage, leading to poor quality of life if the impact is extensive.
Possible Complications When Diagnosed with Arginase Deficiency
If children with this condition do not receive treatment, they can develop seizures, become overly stiff and rigid, have stunted growth, and experience intellectual disabilities. Nowadays, most infants with this condition are found at birth via newborn screening. However, this is not yet a standard practice everywhere.
Preventing Arginase Deficiency
It’s important for parents to understand that if their child is affected by this condition, regular blood tests will need to be carried out. These tests will check levels of ammonia and arginine in the child’s blood and verify that the liver is working properly. High levels of ammonia or arginine require immediate attention.
It’s also recommended for those who have the disease and their relatives to seek advice about their inherited genes. This is often referred to as genetic counseling and provides valuable insights about the disease’s progression and management.
