Arginase deficiency is an inborn error of metabolism that results from a defect in the urea cycle. This cycle is a series of biochemical reactions that occur in the body in order to remove ammonia from the bloodstream.
During normal cellular function, proteins are broken down into nitrogen waste products and put into the blood stream as ammonia. The urea cycle transforms this toxin into urea, which can be safely removed by the kidneys as urine. Lack of an enzyme from the urea cycle, such as arginase, can result in the buildup of toxins in the body. There are six diseases that belong in the group of urea cycle disorders. Arginase is thought to be the rarest of these disorders.
The enzyme arginase is the last step of the urea cycle, where it turns arginine into ornithine and urea. If a person is born with arginase deficiency then they build up arginine in their blood. This is called argininemia. Since earlier steps in the urea cycle are left intact, patients may or may not build up ammonia in the blood. Commonly, the build up of arginine presents as a central nervous system disease or developmental delay in young children.
Arginase deficiency is an autosomal recessive trait. Thus, both parents of an affected child would have to be carriers of the gene . There are two genetically distinct arginases in the human body. The arginase that is expressed in the liver and in red blood cells is the one that is lost in arginase deficiency. This gene has been mapped to the long arm of chromosome 6, specifically 6q23. Twenty different mutations have been found in patients with the disease.
Like other autosomal recessive diseases, arginase deficiency remains rare. The first signs of this disease tend to occur while the patient is still very young. A child may have a normal birth, infancy, and may not show any signs of the disease for quite a few years. There is no gender or racial difference (men and women are both as likely to have the disease), but its absolute incidence rate cannot be known, due its rarity and the lack of statistics. Its incidence is well below one per 200,000.
Signs and symptoms
The onset of this disease tends to be subtle. While the first symptoms of this disease show up while the patient is still a baby, some infants are said to be normal before beginning to have the symptoms. In many cases, the disease is not found at first, and the child is labeled as having 'cerebral palsy' (a general term for neurologic problems that result in altered development—often starting at birth). The symptoms include: loss of normal developmental milestones (the child does not perform tasks at the usual age—walking and speaking, for example); poor feeding; not being able to eat proteins (i.e. a high protein meal makes symptoms worse); fussy behavior; lessened alertness; choreoathetotic movements (strange, uncontrollable writhing movements of limbs); spasticity of lower limbs (weakness and stiffness of legs); incoordination; tremors; seizures; and mental retardation. Affected children may also have an enlarged liver from the buildup of toxins.
Diagnosis is made after children present with symptoms. The illness should be thought for children who have both a developmental delay and stiffness of the ankles and legs that interfere with walking. It should also be thought of anytime that other urea cycle disorders are considered. The lab test of choice is to measure arginase activity in red blood cells. If patients are truly deficient then they will have below normal activity levels. In patients in which there is a high chance of disease and only mildly elevated levels of arginine in the blood, more testing should be done. In other urea cycle disorders, patients tend to have hyperammonemia (a high amount of ammonia in the blood), but in arginase deficiency the ammonia levels are rarely raised. No prenatal diagnosis is currently done. If patients have one child with this disease, then they can be counseled about risk of disease in future children. Since this disease is inherited in an autosomal recessive pattern, each time carrier parents have a child there is a 25% chance that they will have an affected child.
Treatment and management
Treatment of arginase deficiency is similar to treatment methods for other urea cycle disorders. One would want to decrease, as much as one could, the amount of arginine that is building up. This is done through control of protein intake in foods. Arginine is one of the twenty amino acids that make up proteins, and if its intake is stopped, then the amount that can build up in a patient will be lessened. Supplements of essential amino acids (amino acids that cannot be made by the body and must be obtained through food) are given so that children do not become ill from malnourishment.
Other symptoms can also be controlled. For example, patients who have seizures should be treated with an anti-seizure medication. Also, physical therapy can be helpful for patients with stiff legs and problems walking.
The long-term effects of arginase deficiency are better than that for other urea cycle disorders. With proper food intake, children can have much milder symptoms. Often, though, the disease is not found until after severe problems have occurred. Data about patients that live until they are adults is limited, but many cases of patients living through teenage years have been reported. Hence, prognosis is clearly related to how early the disease can be found. This means that it is a very good idea for children to get tested when this group of symptoms are present.
Behrman, Richard, et al. Nelson Textbook of Pediatrics. Philadelphia, Pennsylvania: W. B. Saunders Company, 2000.
Lindor, Noralane, et al., "Initial Assessment of Infants and Children With Suspected Inborns Errors of Metabolism" Mayo Clinical Proceedings 70, no. 10 (October 1995): 987-988.
Scheuerle, Angela, et al., "Arginase Deficiency Presenting as Cerebral Palsy" Pediatrics 91, no. 5 (May 1993): 995-996.
Roth, Karl. "Arginase Deficiency from Pediatrics/Genetics and Metabolic Disease." eMedicine. <http://www.emedicine.com/ped/GENETICS_AND_METABOLIC_DISEASE.htm.>.
Benjamin M. Greenberg