Arginase Deficiency

Definition

Definition of Arginase Deficiency
Arginase inadequacy is thought to be the least popular of the urea rhythm disorders. It causes the amino acid arginine and ammonia to amass gradually in the blood. Ammonia, which is formed when proteins are broken downward in the system, is poisonous if levels get overly higher. The anxious structure is particularly susceptible to the effects of extra ammonia. The disease is caused by a deficiency of arginase type I in the liver. As an inherited disorder, the age of onset is typically during the neonatal period. Because of its atypical manifestation, the disease may easily be missed in the neonatal period and only recognized in later infancy or early childhood. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency. Arginase deficiency is inherited as an autosomal recessive trait.

Symptoms

Symptoms of Arginase Deficiency

1. Spastic tetraplegia
2. Progressive mental retardation
3. Seizures
4. Hyperactivity
5. Growth failure
6. Arginase deficiency
7. Elevated blood ammonia level
8. Enlarged liver
9. Lack of appetite
10. Vomiting
11. Increased blood level of arginine
12. Muscle stiffness
13. Spasticity
14. Tremor
15. Balance problems
16. Coordination problems
17. Irritability

Causes

Causes of Arginase Deficiency
Arginase deficiency is caused by a mutation in the arginase gene, ARG1.

Diagnosis

Diagnosis of Arginase Deficiency
Clinical findings are not specific, but the disorder may be suspected in instances of progressive loss of developmental milestones and spasticity.

Treatment

Treatment of Arginase Deficiency
The management of individuals with arginase deficiency should closely mirror that described in the Urea Cycle Disorders Overview, with one caveat: individuals with arginase deficiency are less prone to episodes of hyperammonemia and when present, hyperammonemia is more likely to respond to conservative management such as intravenous fluid administration. However, the individual who is comatose and encephalopathic is at high risk for severe brain damage and should be treated accordingly. Arginine supplementation is obviously contraindicated.

Infants should be managed by a team coordinated by a metabolic specialist in a specialized center. In the acute phase, the mainstays of treatment are the following:

1. Rapidly reducing plasma ammonia concentration: The best way to reduce plasma ammonia concentration quickly is by dialysis; the faster the flow rate of dialysate, the faster the clearance of ammonia from the plasma. The method employed depends on the affected individual's circumstances and available resources. Fastest is use of pump-driven dialysis, in which an extracorporeal membrane oxygenation (ECMO) pump is used to drive a hemodialysis (HD) machine. Other methods are hemofiltration (both arteriovenous and venovenous), peritoneal dialysis, and continuous-drainage peritoneal dialysis. Dialysis can usually be discontinued when plasma ammonia concentration falls below 200 µmol/L. Affected individuals often experience a "rebound" hyperammonemia that may require further dialysis, although rarely is this level of intervention required in arginase deficiency.
2. Pharmacologic management to allow alternative pathway excretion of excess nitrogen: Blocking the production of ammonia and the need for ureagenesis is accomplished by diminishing catabolism with adequate non-protein calories and with a combination of the nitrogen scavenger drugs sodium phenylacetate and sodium benzoate. A loading dose of the drugs is followed by maintenance administration, initially intravenously and later orally when the individual is stable. Intravenous forms of these medications are now approved by the FDA and are generally available.
3. Reducing the amount of excess nitrogen in the diet and reducing catabolism through the introduction of calories supplied by carbohydrates and fat. In acutely ill individuals, calories should be provided as carbohydrate and fat, either intravenously as glucose and Intralipid® or orally as protein-free oral formula, such as Mead Johnson 80056® or Ross Formula ProPhree®; however, complete restriction of protein should not exceed 24-48 hours, because depletion of essential amino acids may result in endogenous protein catabolism and nitrogen release. High parenteral glucose plus insulin can be used acutely to diminish endogenous protein catabolism. Individuals should be transitioned from parenteral to enteral feeds as soon as possible. In early treatment, feeding 1.0 to 1.5 g of protein/kg body weight with 50% as essential amino acids is advised, particularly for infants. Older children require and tolerate lower protein intake.
4. Reducing the risk of neurologic damage: Cautionary measures are physiologic stabilization with intravenous fluids (10% dextrose with one-quarter normal saline) and cardiac pressors as necessary while avoiding overhydration and resulting cerebral edema, the duration of which correlates with poor neurologic outcome.

Prognosis

Prognosis of Arginase Deficiency
Prognosis for Arginase deficiency: severity of the condition is variable and symptoms may not occur in mild cases until later in life.

Prevention

Prevention of Arginase Deficiency
The goal should be maintenance of plasma arginine concentration as near normal as possible, consistent with the individual's tolerance for the following interventions:

1. Restriction of dietary protein through use of specialized formulas. In the best of circumstances, the affected individual should be on the minimal protein intake needed to maintain protein biosynthetic function, growth, and normal or near-normal plasma amino acid concentrations. Half or more of dietary protein should be an arginine-free essential amino acid mixture.
2. Administration of oral nitrogen scavenging drugs. Sodium benzoate or sodium phenylbutyrate at a dose of 250 mg/kg/day up to 10 g/day (typically described as per meter sq body surface area) in three divided doses may be used as well (De Deyn et al 1997, Iyer et al 1998).
3. Liver transplantation eliminates the hyperargininemia and presumably the risk for hyperammonemia.