Arginase deficiency

Arginase deficiency is caused by mutations in the ARG1 gene, which provides instructions for making an enzyme called arginase. This enzyme plays a key role in the urea cycle, a sequence of reactions that process the excess nitrogen released when the body uses protein. Arginase controls the final step of the urea cycle, which removes nitrogen from arginine and makes a compound called urea. Urea is released by the kidneys in urine.

Mutations in ARG1 cause absent or reduced levels of functional arginase. As a result, arginine is not broken down properly, urea cannot be produced, and excess nitrogen builds up in the blood as ammonia. Increased levels of ammonia and arginine are thought to cause the many signs and symptoms associated with arginase deficiency.

Compared to other urea cycle disorders, ammonia levels are not as high in arginase deficiency. Typically, ammonia levels are only mildly elevated or even normal in arginase deficiency. Some researchers believe that there may be other factors besides ammonia level involved in the cause of the neurological symptoms of arginase deficiency.

A diagnosis of arginase deficiency is often suspected based on the person's signs and symptoms. Special blood tests to measure levels of arginine and ammonia may then be ordered. A diagnosis of arginase deficiency is confirmed when genetic testing identifies a disease-causing mutation in each copy of the ARG1 gene or a blood test demonstrates reduced arginase enzyme activity in the red blood cells.

In some cases, arginase deficiency in a newborn may be suspected if elevated levels of arginine are found through newborn screening. For more information on newborn screening, including which conditions are screened for in each state, visit Baby's First Test.

Arginase deficiency is inherited in an autosomal recessive manner. This means that to be affected, a person must have a disease-causing mutation in both copies of the gene associated with arginase deficiency. The parents of a person with arginase deficiency usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the metabolic disorder. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the genetic disorder, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the genetic disorder AND not be a carrier.

The long-term outlook (prognosis) for people with arginase deficiency varies from person to person. It depends on many factors, including the severity of the disorder, the person's ability to follow the strict diet recommendations, and the response to treatment. For example, some children appear to have more severe intellectual disability while others are more physically affected (e.g. severe spasticity with joint contractures). It is thought that approximately 75% of people with arginase deficiency live long lives.

If the disorder is not diagnosed or if a person with arginase deficiency is unable to follow the strict diet, the prognosis is poor and may include severe intellectual disability and muscle stiffness, loss of the ability to walk, and loss of bladder and bowel control. However, even with treatment, the outcome can vary. In some cases, treatment has been shown to significantly lower arginine levels in both the blood and the cerebrospinal fluid, with some people even having near normal levels. With this response, continued treatment would be expected to improve long-term outlook and prevent progression of neurological symptoms. However, some people with arginase deficiency who follow the recommended treatment regimen may continue to have high levels of arginine in their blood, which can be associated with symptoms that worsen over time. In fact, one older study found that 50% of people with arginase deficiency who are compliant with treatment see an improvement in symptoms, 25% have symptoms that remain the same, and 25% experience a progression of the metabolic disorder.

Nonetheless, early diagnosis in the clinical course allows for improved outcome in most cases. Following a low-protein diet is essential for a better prognosis. Patients and caregivers need to be instructed to seek early medical attention for illnesses, such as fever, because hyperammonemia, although uncommon in this disease, can occur.

The main goals in the treatment of arginase deficiency are to lower arginine levels and to prevent buildup of ammonia in the blood (hyperammonemia). People with arginase deficiency must be closely supervised by a medical team with experience treating metabolic disorders. They may need frequent blood tests to check arginine levels.

Because arginine is a building block of protein, people with arginase deficiency must follow a diet that is very low in protein. It is often recommended they eat the minimal amount of protein needed to maintain good health, which varies based on many factors including age and weight. Protein is found in high amounts in meat, fish, beans, dairy products, eggs and nuts. However, it also occurs in foods like pasta, fruit and vegetables. Under the guidance of a metabolic dietitian, people with arginase deficiency must closely monitor all the protein they eat. They are often advised to drink special formulas and/or buy medical foods in which the protein levels are tailored to fit their needs. People with arginase deficiency may also need to take certain medications (called nitrogen-scavenging drugs) to reduce their levels of arginine.

If people with arginase deficiency have episodes of hyperammonemia, they may be given intravenous (IV) fluids. During an episode of severe hyperammonemia, people with arginase deficiency are generally treated in the hospital. They may require dialysis, nitrogen-scavenging medications, intravenous (IV) fluids, or other treatments. These treatments are given to quickly reduce blood ammonia levels and prevent brain damage.

The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.