Introduction
The incidence of ARG1 deficiency has been reported to range somewhere between approximately 1:300,000–1:2,000,000. Arginase deficiency is a condition in which there is a collection of amino acid arginine (protein building block) and ammonia in the blood. When there is a formation of ammonia in high amounts in the body, it becomes toxic. It affects the function of the nervous system. There is stiffness in the legs, and it causes abnormal tensing of the muscles. It also causes abnormal development as well as slower normal growth. It is a disorder first noticed in children with growth reduction. It is characterized by episodic hyperammonemia (elevated levels of ammonia) of variable degrees. Acute cases can be managed by conservative treatment, such as an intravenous fluid with ten percent dextrose. On the other hand, chronic cases can be treated by reducing the amount of protein along with some medications. It can be life-threatening or cause death if left untreated.
What Is Arginase Deficiency?
Arginase was discovered in mammalian liver tissue in 1904. Arginase deficiency is also called argininemia. It is an autosomal recessive metabolic disorder (a hereditary disorder that only manifests in people who have acquired two copies of an autosomal gene) that can be characterized by the accumulation of ammonia and arginine. It affects liver-based urea cycle, which impairs ureagenesis (synthesis of urea in the body). It is caused due to mutation (alteration in the gene) in the gene. These mutations result in partial or complete loss of enzymes, breaking arginine into ornithine and urea. This loss of enzyme results in the accumulation of arginine in the body.
The urea cycle disorder affects the liver metabolism, which in turn results in the detoxification of ammonia. The liver is the main site of urea cycle activity where the proximal three enzymes are in the mitochondria [N-acetyl-glutamate synthase (NAGS), carbamoyl phosphate synthetase 1 (CPS1), and ornithine transcarboxylase (OTC). The mechanism of arginase is as follows;
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The enzyme catalyzes the hydrolysis of arginine to ornithine and urea.
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Ornithine and urea are transported in the blood to the kidneys.
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Urea is excreted in the urine.
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Ornithine is recycled to continue the cycle for further rounds of urea production.
What Causes Arginase Deficiency?
The exact cause of arginase deficiency is not known. Some genes are responsible for arginase deficiency, such as ARG1 and ARG2. ARG1 leads to an unstable arginase enzyme that results in the hydrolysis of arginine to urea and ornithine. ARG2 is responsible for the activity of arginase. It will affect sites such as the kidney, lower levels of the brain, and GIT (gastrointestinal tract). ARG2 deficiency does not affect the phenotype (characters) of ARG1. Arginase gene (ARG1)-encoding ARG1 sits on chromosome 6 (6q23), comprised of eight exons. There are at least 43 potentially disease-causing variations in ARG1. Arginase deficiency is caused by mutation of different types. ARG1 mutations may alter the structure, function, and stability of the enzyme by compromising active site residues, introducing packing defects, or causing incorrect gene transformation. Thus, these various mutations can affect the central nervous system by depriving the function of the brain.
What Are the Symptoms of Arginase Deficiency?
A genetic metabolic disorder called arginase deficiency causes the body to be unable to metabolize arginine. So, there is an accumulation of arginine in the body.
Individuals will suffer from the following symptoms:
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Seizures (which are sudden, uncontrollable electrical abnormalities of the brain).
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Spasticity (abnormal increase in muscle tone or stiffness of muscle).
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Joint contractures.
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Feeding problems.
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Vomiting.
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Poor growth.
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Intellectual disability (a neurodevelopmental condition) can be seen.
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Laziness and clumsiness.
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Irritation.
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Recurrent vomiting.
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Anorexia (loss of appetite).
How Arginase Deficiency Is Diagnosed?
Arginase deficiency can be diagnosed at birth through NBS (newborn screening). In some conditions, arginase deficiency is present with hyperammonemia; in others, there is mild or absent hyperammonemia. The management of arginase deficiency is dependent upon the presence of hyperammonemia.
The following are the investigation to diagnose arginase deficiency;
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Electroencephalograms - This is the imaging technique that shows the function of the brain. Electroencephalograms also help in diagnosing seizures.
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Electromyography (EMG) - EMG shows all motor and normal nerve conduction velocities.
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Brain Imaging - Brain Imaging may reveal cerebral atrophy (degeneration of the brain cells and small brain size) in a few patients.
What Are the Treatment Options for Arginase Deficiency?
Untreated individuals have a slowing linear growth at ages one to three years. For maintenance, a person should avoid proteins or reduce the intake of protein.
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Acute conditions (which occur suddenly) can be managed by IV fluids (intravenous fluids).
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In critical conditions, sodium phenylacetate or sodium benzoate should be given.
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The replacement of the deficient enzyme by administration of packed red blood cells (which contain ARG1) can be delivered to the patients.
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Diet plays a key role in the treatment of hyperargininemia since it has been shown that strict restriction of dietary protein in combination with the supplementation of an essential amino acid mixture that is free of arginine can decrease arginine levels in plasma and cerebrospinal fluid (CSF). However, the response to dietary restriction is relatively poor, and improvement of the clinical picture is unsatisfactory.
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The use of nitrogen scavengers, such as benzoate, phenylbutyrate, and phenylacetate, is an alternative pathway therapy for the excretion of waste nitrogen via the formation and excretion of hippuric acid and phenylacetylglutamine and can be used to lower plasma ammonia levels in ARG1 deficiency.
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Patients should not allow over-hydration as it may cause cerebral edema (brain swelling).
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Fresh frozen plasma should be provided to those with persistent liver synthetic function abnormalities (the liver is not functioning properly).
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In a few cases, dialysis is done through CRRT(continuous renal replacement therapy) or hemodialysis.
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If seizures are present, there should be the use of phenobarbital or carbamazepine.
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Liver transplantation is considered to treat recurrent (appearing again and again) hyperammonemia.
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Treatment with the amino acid ornithine may help to replenish hepatocellular ornithine to prevent hyperammonemia.
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Injections with Botulinum toxin and orthopedic surgery are suggested in case of symptomatic treatment of spasticity progression.
Conclusion
Researchers have provided a better response with an ultimate cure for this disorder. Enzyme replacement therapy, adeno-associated viral vectors, CRISPR (clustered regularly interspaced short palindromic repeats), and induced pluripotent stem cells are various trials to target these disorders. There should be monthly visits during infancy to monitor liver functions, arginine levels, spasticity, and development.
