Arginase-1 deficiency is a rare inherited autosomal recessive disorder causing hyperammonemia secondary to arginine accumulation characterized by a complete or partial lack of the enzyme arginase in the liver and red blood cells growth reduction, slowing cognition, and milestone development. Arginase is one of six enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the arginase enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood and arginine (hyperuricemia) in the blood and cerebrospinal fluid. Untreated children may exhibit seizures, spasticity, short stature, and intellectual disability. Most affected infants are now identified at birth through newborn screening. Arginase-1 deficiency is inherited as an autosomal recessive genetic disorder.
The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. In arginase-1 deficiency, the accumulation of arginine in the body and not excess ammonia is the predominant biochemical and pathological abnormality.
Symptoms
Symptoms associated with arginase-1 deficiency differ from those associated with other disorders of the urea cycle. Most infants with an arginase-1 deficiency do not exhibit any symptoms during the first few months to a year of life. Infants with arginase-1 deficiency infrequently experience severe hyperammonemia or hyperammonemia coma, which are characteristic of the other urea cycle disorders.
Affected children may experience a lag in growth between one and three years and may walk on their toes and develop progressive stiffness and lack of control of voluntary movements of the legs (spastic diplegia). Cognitive development slows or stops and if untreated, children develop severe spasticity, an inability to walk, loss of bowel and bladder control, and severe intellectual disability.
Growth and feeding. Most commonly, growth at birth and through early childhood is normal.
- At age one to three years, linear growth slows and eventually the majority of affected children demonstrate growth deficiency, which persists if arginase deficiency goes untreated.
- Microcephaly is common and is congenital in some cases.
- Feeding issues may develop, leading to inadequate nutrition. Some require a supplemental feeding tube.
Cognitive development. Initially, cognitive development in infancy and early childhood is normal.
- Starting at age one to three years, previously normal cognitive development slows or stops and the child begins to lose developmental milestones.
- If untreated, arginase deficiency usually progresses to the severe intellectual disability with accompanying neurologic findings (see Neurologic features below).
- Full-scale IQ in adults is in the 70s, and about half can live independently, though they experience significant memory and fine motor deficits. Mildly affected individuals and those treated early in life may be able to hold a job.
- Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures.
Neurologic features. In untreated individuals, progressive neurologic signs typically include the development of severe spasticity with loss of ambulation and complete loss of bowel and bladder control.
- Spasticity. Between 80% and 90% of affected individuals develop spasticity of the lower extremities.
- Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy.
- Severe spasticity can lead to joint contractures and lordosis.
- Seizures occur in 60%-75% of affected individuals and are usually controlled easily by anti-seizure medication. Generalized tonic-clonic seizures are the most common seizure type.
- Brain imaging often reveals cortical atrophy. Other parts of the nervous system including basal ganglia, cerebellum, medulla, and spinal cord are largely spared [De Deyn et al 1997].
Hyperammonemia. Unlike the other eight primary urea cycle disorders, arginase deficiency rarely results in elevated plasma ammonia concentration in the newborn period.
- Episodic hyperammonemia of variable degree may occur during illness but is rarely severe enough to be life-threatening, although death has been reported.
- Hyperammonemia presents with vomiting, lethargy, and altered mental status but in some cases is asymptomatic and only recognized if blood ammonia is obtained during an acute illness.
- Older individuals may present with postoperative encephalopathy.
Liver disease. Hepatic dysfunction, if present, is usually mild, manifesting as transaminitis, prolonged coagulation time, and in some cases hepatomegaly. Affected individuals typically do not have bleeding problems from prolonged coagulation time. Rarely, neonatal cholestatic jaundice has been reported [Braga et al 1997, Gomes Martins et al 2010], and cirrhosis can occur. Some adults have developed hepatocellular carcinoma.
Almost all affected children have growth deficiency and many also experience seizures.
Causes
Arginase-1 deficiency is inherited as an autosomal recessive genetic disorder and is caused by mutations in the ARG1 gene. Mutations in the ARG1 gene result in the production of an abnormal arginase enzyme.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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[rx]. 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.[rx]
Diagnosis
Most affected infants are now identified at birth through newborn screening. Arginase enzyme activity is usually not detectable in the red blood cells of affected individuals. Molecular genetic testing is available to confirm the diagnosis. If two mutations are not found, red blood cell enzyme testing is used to confirm the diagnosis.
History and Physical
Arginase deficiency (arginine mix) 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 while the patient is presenting the acute injury.[rx]
While developing, patients progressively present a reduction of linear growth (100%) and spastic diplegia (the most obvious sign of the condition)[rx] 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 is rare. These included mild to severe liver dysfunction and bone involvement. [rx]
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.[rx][rx]
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. [rx]
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 the feasibility to perform enzyme analysis.[rx]
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.
Preliminary laboratory findings
- Plasma quantitative amino acid analysis – Elevation of plasma arginine concentration three- to fourfold the upper limit of normal is highly suggestive of the diagnosis. Plasma arginine elevation is the primary means of ascertainment.Note: Up to twofold the upper limit of normal may be seen in infants who do not have arginase deficiency and who are otherwise normal.
- Plasma ammonia concentration – Elevation of plasma ammonia concentration may be intermittent. Acute hyperammonemia (plasma ammonia concentration >150 µmol/L) is uncommon.
- Urinary orotic acid concentration – Although urinary orotic acid concentration is often elevated, it is not a primary screen for this disorder.
- Single-gene testing – Sequence analysis of ARG1 detects small intragenic deletions/insertions and missense, nonsense, and splice-site variants; depending on the method used, exon or whole-gene deletions/duplications may not be detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: In individuals of French Canadian ancestry, the c.57+1G>A founder variant may be tested first.
- A multigene panel – that includes ARG1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting the identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.
Treatment
Treatment should be coordinated by a metabolic specialist and is based on reducing plasma ammonia and arginine concentration, preventing excess ammonia from being formed, and reducing the amount of nitrogen in the diet.
Reduction of plasma ammonia concentration is accomplished by dialysis and several different methods are available. This should be used only when the high levels are producing severe symptoms.
The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous and oral forms of these medications are available (Ammon). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only. Ravicti is a form of phenylbutyrate that is less irritating to the gastrointestinal tract and easier to take.
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 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.[rx]
For maintenance, protein restriction should be in 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[rx], while also inhibiting the formation of neurotoxic guanidino compounds.[rx]
Liver transplantation can be considered 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.
Dietary restrictions in individuals with arginase-1 deficiency are aimed at limiting the amount of arginine and protein intake. Children with arginase-1 deficiency are placed on a low-protein, arginine-restricted diet supplemented by essential amino acids.
Seizures are treated with phenobarbital or carbamazepine. Valproic acid should be avoided, as it can increase blood ammonia levels.
Affected individuals should receive periodic blood tests to determine the levels of ammonia and arginine in the blood and to be sure that liver function is not impaired. Excessive levels of ammonia or arginine should be promptly treated.
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.[rx][rx]
Genetic counseling is recommended for affected individuals and their families.
References
