Arginase Deficiency

Updated: Jan 07, 2019
  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
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Arginase deficiency is thought to be the least common of the urea cycle disorders. This entity also manifests itself in a fashion somewhat different from other disorders in the group (see Physical). Two separate isozymes of the enzyme arginase have been reported. [1] Type I is found in the liver and contributes the vast majority of hepatic arginase activity, whereas type II is inducible and found in extrahepatic tissues. The disease is caused by a deficiency of arginase type I in the liver.



The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle takes place in mitochondria; mitochondrial dysfunction may impair urea production and result in hyperammonemia (see Hyperammonemia). Overall, the rate of synthesis of N -acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle, regulates the activity of the cycle.

The reaction normally mediated by arginase is the terminal step in the urea cycle, which liberates urea with regeneration of ornithine (see the image below). Consequently, as in argininosuccinic aciduria, both waste nitrogen molecules normally eliminated by the urea cycle are incorporated into the arginine substrate molecule in the reaction.

Compounds that comprise the urea cycle are sequent Compounds that comprise the urea cycle are sequentially numbered, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS), in this step. Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.

The severe hyperammonemia observed in other urea cycle defects is rarely observed in patients with arginase deficiency for at least 2 identifiable reasons. The first reason is that formed arginine, which contains 2 waste nitrogen molecules, can be released from the hepatocyte and excreted in urine. The second reason may be attributed to the inducibility of the type II isozyme in peripheral tissues, which can attack the arginine released by the hepatocyte and produce urea and ornithine. The ornithine returns to the liver for use in the urea cycle, while the urea is excreted. A 4-fold increase in renal type II arginase has been demonstrated in an affected patient.

The distinct tendency to develop spastic diplegia in patients with arginase deficiency, as compared with patients with other urea cycle disorders, suggests a specific pathogenic mechanism at the CNS level, apart from the generalized toxicity of hyperammonemia. [2] The nature of this mechanism remains unelucidated, but some workers have pointed to an accumulation of guanidino compounds that could interfere with GABAergic transmission. These compounds have also been shown to inhibit the cerebral cortical sodium-potassium adenosine triphosphatase (ATPase) of rats at concentrations comparable with those seen in affected humans. The ATPase is essential to maintenance of the electrochemical gradient of neurons, and its inhibition may be involved in the pathogenesis of the seizure disorder associated with this disease. A 2016 study suggests an adverse effect of arginase-1 deficiency on level 5 cortical motor neurons, as well as diminished synaptic transmission in a neonatal mouse model, recoverable by gene therapy. [3]




United States

The incidence of arginase deficiency  cannot be cited because of the absence of any population screening data.


The morbidity associated with arginase deficiency is high, but the rarity of the condition makes citing statistics impossible. Death from arginase deficiency appears to be relatively infrequent, but reliable statistics are not available.


As an autosomal recessive trait, arginase deficiency equally affects both genders. [4]


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. Some cases likely go undiagnosed, with clinical symptomatology attributed to cerebral palsy. [5]

With heightened awareness of arginase deficiency, more affected individuals are surviving into adolescence and adulthood; hence, the natural history of arginase deficiency, with and without treatment, is emerging. [6, 7]



In view of the relatively subtle and progressive presentation, patient rarely escape irreversible damage to the CNS. Nonetheless, early diagnosis in the clinical course allows for improved outcome.

Even in patients who receive a late diagnosis, treatment from birth in a subsequent infant of an affected family should prevent the developmental delay and the spasticity, based on more recent experience.


Patient Education

Advise parents of an affected child of their obligate heterozygote status.

Adherence to a low-protein diet is imperative; stress the importance to long-term outcome.

Seek early medical attention for intercurrent illnesses because hyperammonemic crisis, although uncommon in this disease, can occur.

Prenatal diagnosis is possible with an enzyme assay using fetal RBCs; arginase mutations have been identified in skin fibroblasts from amniotic fluid and specimens from chorionic villus biopsies.