Continuing Education Activity
Argininemia is an autosomal recessive disorder causing hyperammonemia secondary to arginine accumulation. It is a disorder first noticed in children with growth reduction, slowing cognition, and milestone development. This activity describes the evaluation and management of argininemia and explains the role of the interprofessional team in improving care for patients with this condition.
- Describe the etiology of patients with argininemia.
- Identify the presentation of patients with argininemia.
- Summarize the use of ammonia reduction strategies in the management of patients with argininemia.
- Explain the importance of collaboration and communication among the interprofessional team members to enhance the delivery of care for patients affected by argininemia.
Arginase deficiency (argininemia) is an autosomal recessive metabolic disorder characterized by hyperammonemia secondary to arginine accumulation. Ammonia levels can vary according to the 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.
Pathogenic or likely pathogenic variants in ARG1 lead to an unstable arginase enzyme, a protein found primarily in hepatic cytosol, and responsible for the final step of the urea cycle. This results in the hydrolysis of arginine to urea and ornithine.
Another gene, ARG2, responsible for arginase activity, can be found mainly in the mitochondria of extrahepatic tissues, being the kidney a major location with lower levels in the brain and gastrointestinal tract. However, it is not translated in enough quantities to compensate for the primary defect.
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.
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.
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.
The substantial toxic effect of ammonia accumulation causes brain damage through cerebral edema. Affected regions include parietal, occipital, and frontal. Another proposed mechanism suggests ammonia (in a minor role) along with guanidino compounds, polyamines, NO, agmatine) through the enzyme arginine: glycine amidinotransferase could be the reason for neurotoxicity and spasticity. 
History and Physical
Arginase deficiency (argininemia) 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.
While developing, patients progressively present reduction of linear growth (100%) and spastic diplegia (the most obvious sign of the condition) while cognitive development stagnates or regresses. Particular long-term cognitive manifestations evidenced in recent studies include intellectual disability, attention deficit hyperactivity disorder (ADHD), aggressive behaviors, pervasive development disorder, memory recollection, and fine motor skills impairment. The last two are remarkable in the adult population. Extraneurological manifestations can present, but prevalence rare. These included mild to severe liver dysfunction and bone involvement. 
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.
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. 
Initial steps to be performed after a positive newborn screen are plasma ammonia levels, plasma amino acids, and urine organic acids.
Elevated arginine levels (which can rise 4-fold), and ammonia levels (if present, above 200 micrograms/dL) along with increased orotic acid are suggestive. 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 enzyme analysis.
This initial stage is critical, as there are other types of urea cycle disorders that benefit from arginine administration to reduce ammonia levels by indirectly increasing citrulline levels at the same time it attaches ammonia molecules for excretion.
Treatment / Management
For acute states, most of the time, hyperammonemia requires no more than conservative treatment, i.e., 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 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 appropriate electrolytes (sodium and/or potassium). Avoid overhydration as cerebral edema can occur. Abstinence from protein should not last more than 24-48 hours, as further catabolism can occur. Should seizures present, use phenobarbital or carbamazepine. Valproate is contraindicated since it induces hyperammonemia.
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.
Other authors advocate for ornithine supplementation, which could replenish hepatic ornithine and prevent hyperammonemia, while also inhibiting the formation of neurotoxic guanidino compounds.
Liver transplantation can be considered as an ultimate treatment to reduce recurrent hyperammonemia.
There should be 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 into a clinical setting due to their early stages.
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.
The prognosis for most patients remains a mystery. The disorder is rare and follow-up has been poor. However, most patients develop moderate to severe neurological damage and lead a very poor quality of life.
Pearls and Other Issues
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, like chorionic villus sampling, and amniocytes lack arginase become unsuitable procedures.
Enhancing Healthcare Team Outcomes
Arginase deficiency (argininemia) is an autosomal recessive metabolic disorder characterized by hyperammonemia secondary to arginine accumulation. The disorder is rare and is best managed by a pediatrician, geneticist, endocrinologist, and a dietitian. The disorder is sometimes identified during the screening of the newborn. The ammonia levels can vary according to the patient’s 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. Genetics nurses and nurse practitioners are involved in patient care, education, and follow up. The pharmacist should educate the caregiver on the need for compliance with medication and assist in the acute treatment of neurologic events. [Level 5]