Arginase Deficiency

Arginase deficiency is a rare inherited disorder that affects the body’s ability to process protein, causing harmful substances to gradually build up in the blood and affecting primarily the nervous system and movement.

ARG1 deficiency, Arginase-1 deficiency, Argininemia, Hyperargininemia, Arginase deficiency disease

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Table of contents

• What is Arginase Deficiency
• How Common is This Condition
• What Causes Arginase Deficiency
• Signs and Symptoms
• Diagnosis and Testing
• Treatment and Management
• Inheritance Pattern
• Long-term Outlook

What is Arginase Deficiency

Arginase deficiency is an inherited disorder that causes the amino acid (a building block of proteins) called arginine and ammonia to accumulate gradually in the blood^[1]. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia^[1].

This condition belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys^[1].

• Liver
• Red blood cells
• Brain and spinal cord (nervous system)
• Muscles

The enzyme arginase helps our bodies get rid of nitrogen by changing it into urea, which is flushed from the body with urination. It does this by breaking down arginine. Arginine contains nitrogen and is usually broken down in the liver by the arginase enzyme^[3]. The arginase enzyme facilitates the final step of the urea cycle, which produces urea by removing nitrogen from arginine^[1].

Arginase, commonly found in the liver, red blood cells, and salivary glands, catalyzes the fifth and last reaction of the urea cycle^[2]. Its deficiency or absence causes accumulation of arginine, which can reversibly translate into ammonia overproduction^[2].

How Common is This Condition

Arginase deficiency is a very rare disorder. It has been estimated to occur once in every 300,000 to 1,000,000 individuals^[1]. The estimated incidence ranges from 0.5 to 1 per 1,000,000^[2].

Arginase deficiency is the most uncommon urea cycle disorder^[2]. As newborn screening for this condition is not common in all areas, its incidence is probably underestimated^[5]. Males and females are equally affected^[5].

What Causes Arginase Deficiency

Arginase deficiency is caused by variants, also called mutations, in the ARG1 gene. This gene provides instructions for making an enzyme called arginase^[1]. Biallelic pathogenic or likely pathogenic variants in ARG1 lead to an unstable arginase enzyme, a protein found primarily in the liver and responsible for the final step of the urea cycle^[2].

In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency^[1].

Another gene, ARG2, is responsible for arginase activity and can be found mainly in the mitochondria of tissues outside the liver, particularly in the kidney, with lower levels in the brain and gastrointestinal tract. However, it is not translated in enough quantities to compensate for the primary ARG1 defect^[2].

Elevated arginine levels and its derivatives, such as the epileptogenic guanidinoacetate, cause direct neurotoxicity^[5]. Nitrogen comes mostly from the protein we eat. In children with adequate levels of arginase, nitrogen does not cause any problems. However, when it cannot be broken down, it can build up in the blood and nervous system and become toxic to the brain and spinal cord^[4].

Signs and Symptoms

Arginase deficiency usually becomes evident by about the age of 3^[1]. Most patients are asymptomatic from birth to toddlerhood. Typically, the first symptoms are observed at age 1-3 years^[5]. The clinical course of the disease is highly variable, and some symptoms differ from those observed in other classical urea cycle defects^[5].

There is a wide spectrum of severity in this disorder^[4]. More severe arginase deficiency starts before age three and can even begin during the newborn period. Less severe arginase deficiency starts later in childhood^[4].

Most Common Symptoms

The most common symptom is spasticity, especially in the legs, caused by abnormal tensing of the muscles^[1]. Spasticity in the muscles of both the arms and legs or in the muscles of both legs is the most common symptom. It occurs in both severe and milder cases^[4]. Clinical manifestations include spasticity predominantly affecting lower extremities, which may later progress to paraplegia, reduced mobility and gait disturbances^[5].

Other symptoms may include^[1][4][5]:

• Slower than normal growth
• Developmental delays and eventual loss of developmental milestones
• Intellectual disabilities
• Seizures
• Tremors
• Difficulty with balance and coordination (ataxia)
• Complete loss of bowel and bladder control may occur

If arginase deficiency goes undetected, babies and children may have abnormal muscle tensing and stiffness, delayed growth, learning delays, tremors, or seizures^[3]. Seizures tend to involve shaking of the whole body. They generally can be managed well with antiseizure medication. Seizures occur in about 60% to 75% of patients^[4].

Attention deficit hyperactivity disorder (ADHD) and aggressive behavior are frequently observed^[5]. As extracerebral manifestation, liver dysfunction may be observed^[5].

Episodes of Illness

Occasionally, high-protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting^[1].

On rare occasions, babies and children may show signs of ammonia build-up, also called hyperammonemia, after eating a lot of protein, or after an illness or surgery. Symptoms include vomiting, refusing to eat, and being tired and irritable^[3].

The risk of metabolic decompensation with hyperammonemia, which may occur in the neonatal period and manifest as coma, central dysregulation, hyperventilation and epileptic seizures, is lower in arginase deficiency than in other urea cycle disorders^[5]. However, severe episodes of hyperammonemia can occur but are infrequent^[6].

Progressive Nature

Arginase deficiency is a progressive disease. If the symptoms are untreated, they can worsen over time. However, they can be improved with treatment^[4]. The disease is highly progressive in most patients^[5]. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability^[8].

In some affected individuals, the signs and symptoms of arginase deficiency may be less severe and may not appear until later in life^[1].

Diagnosis and Testing

The diagnosis of arginase deficiency is established through a combination of clinical findings and laboratory testing. The presentation of hyperammonemia or spasticity in a patient may prompt a blood amino acid analysis, revealing highly elevated arginine levels, which is pathognomonic for arginase deficiency^[5].

Blood Testing

Blood testing looks for increased arginine in blood. The ammonia level in the blood is also sometimes elevated^[4]. Affected newborns are found to have elevated levels (up to 4 times) of arginine^[2].

Genetic Testing

Molecular genetic testing typically identifies two pathogenic variants in the ARG1 gene^[5]. The diagnosis is confirmed by identification of biallelic pathogenic variants in ARG1^[8].

Enzyme Testing

In limited instances, diagnosis can be made by failure to detect arginase enzyme activity (usually less than 1% of normal) in red blood cell extracts^[8]. Enzyme analysis of arginase in red blood cells is rarely performed but may be helpful when genetic testing detects variants of uncertain significance^[5].

Newborn Screening

Often diagnosed at birth through newborn screening (NBS), affected newborns are found to have elevated levels of arginine^[2]. Newborns in some US states are now tested for arginase deficiency. If the condition is identified early and treatment is followed carefully, the most serious health problems can be avoided^[3]. However, newborn mass screening for early detection of the disease is not widely available yet^[5].

Recent experience with tandem mass spectrometric newborn screening technique has permitted early identification and treatment. Infants treated in this fashion have thus far done well and remained healthy^[10].

Treatment and Management

Treatment should involve a team coordinated by a metabolic specialist^[8]. Management should closely mirror that for urea cycle disorders, except that individuals with arginase deficiency are not as likely to have episodes of hyperammonemia; if present, such episodes respond to conservative management^[8].

Dietary Management

Protein intake is restricted in patients with arginase deficiency. A carefully monitored diet plan is necessary^[10]. Routine outpatient management includes restriction of dietary protein^[8]. Ensuring meals for the day stay under appropriate protein limits is a constant challenge for caregivers^[16].

Medical Formula and Medications

Treatment includes use of a special medical formula^[3]. Consideration of oral nitrogen-scavenging drugs is recommended in those who have chronic or recurrent hyperammonemia^[8]. Chronic treatment consists of protein restriction along with nitrogen-scavenging medications^[2].

Long-term therapy rests on provision of significantly protein restricted essential amino acid supplementation and nitrogen scavenger administration. Treatment with sodium benzoate and/or sodium phenylbutyrate is similar to other urea cycle disorders, except arginine is contraindicated^[6].

Clinical trials are ongoing using an enzyme replacement therapy as an arginine lowering approach and early results are promising^[10].

Management of Acute Illness

Because severe hyperammonemia is unusual, the need for intravenous therapy or hemodialysis is unlikely^[10]. Treatment of an acutely ill (comatose and encephalopathic) individual requires rapid reduction of plasma ammonia concentration; use of pharmacologic agents (sodium benzoate and/or sodium phenylbutyrate/phenylacetate) to promote excretion of excess nitrogen through alternative pathways; and introduction of calories supplied by carbohydrates and fat to reduce catabolism and the amount of excess nitrogen in the diet while avoiding overhydration and resulting cerebral edema^[8].

Supportive Care

Standard treatment for seizures, spasticity, developmental delay/intellectual disability, and joint contractures is recommended^[8]. Orthopedic and rehabilitative interventions to alleviate spasticity are especially useful^[10].

Some teens and young adults with arginase deficiency have anxiety or depression. Counseling and medication can help^[3].

Medications to Avoid

Patients should avoid medicines that contain valproic acid, including Depakote®^[3].

Liver Transplantation

Orthoptic liver transplantation has been advocated as a definitive cure for arginase deficiency, especially in patients who respond poorly to traditional therapy. Liver transplantation has been shown to prevent neurological damage and improve quality of life^[10]. In the rare instance of progression to hepatic fibrosis and cirrhosis, liver transplantation can be considered^[8].

Emergency Preparedness

Patients should stay in regular contact with their health care providers and health specialists and keep an Acute Illness Protocol that they can bring with them to the emergency room^[3]. If you have an illness, fever, surgery, or are pregnant, contact your health-care provider right away. Watch for signs of ammonia build-up including nausea, vomiting, sleepiness, or unusual problems with your mood or thinking. If you have any of these, get medical care right away^[3].

Inheritance Pattern

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition^[1].

Arginase deficiency is a recessive genetic disorder. This means that both copies of a child’s ARG1 gene must be abnormal for them to have arginase deficiency. Typically, children with arginase deficiency have inherited one abnormal gene from each parent. Each parent will have one normal and one abnormal copy of the ARG1 gene. However, neither of the parents themselves will have arginase deficiency^[4].

Arginase deficiency does not affect your ability to have children. Genetic counseling can help you and your partner understand the risks to your children^[3]. Prenatal diagnosis can be performed using DNA analysis^[10].

Long-term Outlook

Individuals treated from birth, either as a result of newborn screening or having an affected older sibling, appear to have minimal symptoms^[8]. Maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein and use of oral nitrogen-scavenging drugs as necessary can help prevent primary manifestations^[8].

Life expectancy is limited in most patients^[5]. Some urea cycle disorders lead to life-threatening episodes of high ammonia in the body. This is less common in arginase deficiency than in other urea cycle disorders. However, it can occur. In rare cases, it can be fatal^[4].

The disease is highly progressive in most patients if left untreated^[5]. However, treatment can help prevent severe intellectual and physical disability^[4]. You can manage arginase deficiency throughout your life with a special low-protein diet, a special medical formula, drug therapy, and ongoing health care^[3].

It is important to keep immunizations up-to-date and stay in regular contact with health care providers and health specialists^[3]. Pregnant women with arginase deficiency must follow a careful diet with guidance from a dietician^[3].