Arginase Deficiency (Argininemia)

Article Author:
Jose Morales
Article Editor:
Kristin Sticco
2/6/2019 10:36:55 AM
PubMed Link:
Arginase Deficiency (Argininemia)


Arginase deficiency (Arginininemia) is an autosomal recessive metabolic disorder characterized by hyperammonemia secondary to arginine accumulation. Ammonia levels can vary according to patient’s current age and status, presenting initially with reduction of growth, and moving to milestone development and cognition. Sometimes when not treated the disorder leads to regression. 

Often diagnosed at birth through newborn screening (NBS), affected newborns are found to have elevated levels (up to 4 times) of arginine. Its management corresponds classically as another urea cycle defect, with mild or absent hyperammonemia and, if present, responds adequately to reductive ammonia actions. Chronic treatment consists of protein restriction along with nitrogen-scavenging medications.[1]


Mutations in ARG1 lead to an unstable arginase enzyme, a protein found in the cytosol and responsible for the final step of the urea cycle. This results in the hydrolysis of arginine to urea and ornithine.

Another gene responsible for arginase can be found (ARG2); however, it is not translated in enough quantities to compensate the primary defect.[2]


Arginase deficiency is the most uncommon urea cycle disorder. The estimated incidence is around 1 per 1,000,000. No particular genotype-phenotype correlations have been postulated to date, meaning there is no accurate method to indicate a particularly affected population.[1][3]


Arginase, commonly found in liver, erythrocytes, and salivary glands, catalyzes the fifth and last reaction of the urea cycle, hydrolyzing L-arginine into ornithine and urea. 

Its inactivation or absence, causes accumulation of arginine, reversibly translating into ammonia overproduction at different levels and expressions after 1 to 3 years of life; although, a few cases have been reported in early infancy. 

Orotic acid accumulation can often be found, given that reduction of ornithine impairs ornithine transcarbamylase activity, creating a backup or overflow of carbamyl phosphate which is subsequently shunted to the pyrimidine synthetic path.[4][3]


Brain lesions found on the histopathology of patients with chronic hyperammonemia on infancy have often been correlated to those of hypoxic-ischemic events.

Late manifestations of the liver include fibrosis, cirrhosis, and hepatocellular carcinoma.[5]


The substantial toxic effect of ammonia accumulation causes brain damage through cerebral edema. Affected regions include parietal, occipital, and frontal.[5]

History and Physical

Arginase deficiency (arginininemia) rarely presents in the newborn/infant period. Hyperammonemia may still present, but it is not life endangering. After 1 to 3 years of life, patients develop intermittent episodic hyperammonemia which can be induced by catabolic states (infections), high dietary protein intake, or medications (valproate). This status can only be recognized while the patient is presenting the acute injury.[6]

While developing, patients progressively present reduction of linear growth (100%) and spastic diplegia while cognitive development stagnates or regresses. Particular long-term cognitive manifestations evidenced on recent studies include intellectual disability, ADHD, aggressive behaviors, pervasive development disorder, memory recollection, and fine motor skills impairment. The last 2 are remarkable in the adult population.

If no treatment is provided, patients will develop severe complications of the abnormalities stated above. Objective neurologic findings discovered through brain imaging studies consist of seizures, microcephaly, and cortical atrophy.[7][5]


Newborn screening programs around the nation can successfully detect high arginine levels. However, it is not universal as of yet, around 12 states do not include it in their analysis, therefore, in individuals with no such opportunity, a high index of suspicion should rise if they present with regression of development milestones. [6]

Following elevated arginine levels (which can rise 4-fold), ammonia levels in acute states (if present, above 200 micrograms/dL). Subsequent arginase enzyme analysis on red blood cells (less than 1%) or sequence analysis of ARG1 confirm the diagnosis; however, the latter is considered the first confirmatory step due to feasibility to perform.[8]

Treatment / Management

Initial workup after diagnosis consists of plasma ammonia concentration, plasma arginine levels, and cognitive and neurologic evaluation. This stage is critical, as there are particular managements for other types of urea cycle disorders, where arginine administration is provided to reduce ammonia levels by being catalyzed and indirectly increasing citrulline levels.

For acute states, most of the time, hyperammonemia requires no more than conservative treatment, for example, intravenous (IV) fluids. If severe hyperammonemia, clinicians should consider reduction by dialysis, either through ECMO or hemodialysis. These should be stopped once ammonia levels reach 250 micrograms/dL or lower. The use of nitrogen scavengers like sodium phenylacetate or sodium benzoate for severe or moderate cases, along with restriction of protein intake, and the introduction of non-protein calorie sources like fats and carbohydrates should be considered. When using carbohydrates with intravenous fluids, use dextrose 10% and one-quarter normal saline. Avoid overhydration as cerebral edema can show up. Abstinence from protein should not last more than 48 hours, as further catabolism can present from essential amino acids. Should seizures present, use phenobarbital or carbamazepine. Valproate is contraindicated since it induces hyperammonemia.[6]

For maintenance, protein restriction should be on the minimal protein intake range to help basic functions and development. With half of the dietary protein free of arginine, a total absence of this amino acid cannot be accepted given its essential role for T cell and endothelial function. Ideal protein intake in infants ranges from 1 to 1.5 gm/kg. As the child grows, the restriction can be tolerated on lower levels. Daily administration of nitrogen scavengers on maintenance dosing is sodium phenylbutyrate 350 to 600 mg/kg per day.

Liver transplantation can be considered as an ultimate treatment to reduce recurrent hyperammonemia.

Monthly visits during infancy, with progressively increased intervals between visits as the patient grows. Monitor liver function, arginine levels, spasticity, and development.

Preference should be given to medications that bypass liver metabolism over other medications. Examples are ibuprofen over acetaminophen or another antiepileptic over valproate.

Research has been implemented to provide a better response or an ultimate cure for this pathology. Approaches like adeno-associated viral vectors, CRISPR-associated protein nine genome editing, and induced pluripotent stem cells have shown a successful response to their target goal. However, these results have not been translated to a clinical setting due to their early stages.[4][8]

Differential Diagnosis

Despite elevated levels of arginine in comparison to other amino acids that may even be encountered as normal on newborn screening or amino acid profile, suggest a strong diagnosis of arginase deficiency. Other urea cycle disorders should be considered, particularly in the event of hyperammonemia without a strong amino acid profile.[4][8]

Pearls and Other Issues

[9]Given the broad phenotype and variable presentation, an initial, thorough investigation of proband can later expand to siblings or other relatives should they present with similar symptomatology.

For prenatal testing, gene sequencing should be the first diagnostic step, as chorionic villus sampling and amniocytes lack arginase become unsuitable procedures.[10]