Arginase Deficiency

Etiology

Biallelic 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. [2] 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, the kidney being a significantly affected location with lower levels in the brain and gastrointestinal tract. However, it is not translated in enough quantities to compensate for the primary ARG1 defect.[3]

Epidemiology

Arginase deficiency is the most uncommon urea cycle disorder. The estimated incidence ranges from 0.5 to 1 per 1,000,000.[4] No particular genotype-phenotype correlations have been postulated to date, meaning there is no accurate method to indicate a particularly affected population.[1][5]

Pathophysiology

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

Its deficiency 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 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.[6][5]

Histopathology

Brain lesions (cortical atrophy, ischemic changes, and edema) have been found on neuroimaging and histopathology of patients with arginase deficiency, similar to those (patients) affected by hypoxic-ischemic events.[7]

Late manifestations of the liver include fibrosis, cirrhosis, and hepatocellular carcinoma.[8]

Toxicokinetics

The substantial toxic effect of ammonia accumulation causes brain damage through cerebral edema. Affected regions include the parietal, occipital, and frontal lobes.[8] Another proposed mechanism suggests ammonia (in a minor role) along with guanidino compounds (polyamines, nitrous oxide, agmatine) through the enzyme arginine-glycine amidinotransferase could be the reason for neurotoxicity and spasticity.[9]

History and Physical

Arginase deficiency (argininemia) rarely presents in the newborn/infant period. Hyperammonemia may still be 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 when the patient presents with an acute, precipitating incident.[10]

While developing, patients progressively present a reduction of linear growth (100%) and spastic diplegia (the most obvious sign of the condition) while cognitive development stagnates or regresses.[2] 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 is rare. These included mild to severe liver dysfunction and bone involvement.[2]

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.[11][8]

Evaluation

Newborn screening programs around the nation can successfully detect high arginine levels. However, it is not universal 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.[10]

Initial steps to be performed after a positive newborn screen are plasma ammonia levels, plasma amino acids, and urine organic acids (with a focus on orotic acid). 

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 molecular analysis of ARG1 confirm the diagnosis; however, the latter is considered the first confirmatory step due to the difficulty of performing enzyme analysis.[4]

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, hyperammonemia usually requires no more than conservative treatment, i.e., intravenous (IV) fluids. 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. When using carbohydrates with intravenous fluids, use dextrose 10% and appropriate electrolytes (sodium and/or potassium) for age. Avoid overhydration, as cerebral edema can occur. Abstinence from protein should not last more than 24 to 48 hours, as further catabolism can occur. In some cases, particularly in the presence of severe hyperammonemia refractory to medical interventions, clinicians could consider reduction by dialysis, either through CRRT (continuous renal replacement therapy) or hemodialysis. Dialysis should be stopped once ammonia levels reach 250 micrograms/dL or lower. Should seizures present, use phenobarbital or carbamazepine. Valproate is contraindicated since it induces hyperammonemia.[10](B3)

For maintenance, protein restriction should be in the minimal protein intake range to help with 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 at 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.[12][13] (B3)

Liver transplantation can be considered the 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. Various trials have used approaches like enzyme replacement therapy, adeno-associated viral vectors, CRISPR-associated protein nine genome editing, and induced pluripotent stem cells. Some have shown a successful response to their target goal. However, these results have not all been translated into a clinical setting due to their early stages.[6][4]

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.[6][4]

Prognosis

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, leading to poor quality of life if completely affected. 

Complications

Untreated children may present with seizures, spasticity, short stature, and intellectual disability. Most infants affected with this condition are now identified at birth through newborn screening, although this is not the norm everywhere.