Arginase deficiency

December 31, 2014

Synonyms

Overview

Arginase deficiency is an inherited metabolic condition in which the body is unable to process arginine (a building block of protein). As a result, people affected by the condition have high levels of arginine in the blood and may also experience episodes of hyperammonemia (a buildup of ammonia in the blood). The features of arginase deficiency generally develop between ages one and three years.

A very rare urea cycle disorder caused by a deficiency of the enzyme (arginase) needed to convert ammonia to the urea which can then be removed in the urine. The condition leads to excess build-up of ammonia in the body which is toxic to the nervous system.

Symptoms

The signs and symptoms of arginase deficiency and the age at which they develop can vary from person to person. Most affected people appear to be healthy with normal development at birth and during early childhood. The first features of the condition often become apparent between the ages of one and three years, although cases of earlier and later onset have been reported.

Signs and symptoms may include:

Poor growth
Spasticity (abnormal tensing of the muscles)
Developmental delay
Loss of previously acquired developmental milestones
Intellectual disability
Seizures
Microcephaly
Problems with balance and coordination
Progressive mental retardation
Hyperactivity
Growth failure

Occasionally, people with arginase deficiency may have episodes of severe hyperammonemia (a buildup of ammonia in the blood). Although rare, these episodes are more likely to occur following a high-protein meal or during periods of stress caused by illness or fasting. Hyperammonemia can be associated with irritability, lethargy, refusal to eat, and vomiting.

If arginase deficiency is undiagnosed or if an affected person is unable to follow the strict diet, the prognosis is poor and may include severe intellectual disability and muscle stiffness; loss of the ability to walk; and loss of bladder and bowel control. However, even with treatment, the outcome can vary.

Causes

Arginase deficiency is caused by changes (mutations) in the ARG1 gene, which provides instructions for making an enzyme called arginase. This enzyme plays a key role in the urea cycle, a sequence of reactions that process the excess nitrogen released when the body uses protein. Arginase controls the final step of the urea cycle, which removes nitrogen from arginine and makes a compound called urea. Urea is released by the kidneys in urine.

Mutations in ARG1 cause absent or reduced levels of functional arginase. As a result, arginine is not broken down properly, urea cannot be produced, and excess nitrogen builds up in the blood (ammonia). Increased levels of ammonia and arginine are thought to cause the many signs and symptoms associated with arginase deficiency.

Arginase deficiency is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Diagnosis

A diagnosis of arginase deficiency is often suspected based on the presence of characteristic signs and symptoms. Special blood tests to measure plasma levels of arginine and ammonia may then be ordered to further investigate the concerning symptoms. A diagnosis of arginase deficiency is confirmed when genetic testing identifies a disease-causing change (mutation) in each copy of the ARG1 gene or a blood test demonstrates reduced arginase enzyme activity in the red blood cells.

In some cases, arginase deficiency in a newborn may be suspected if elevated levels of arginine are found through newborn screening. For more information on newborn screening, including which conditions are screened for in each state, please visit Baby's First Test.

Prognosis

The long-term outlook (prognosis) for people with arginase deficiency varies from person to person and depends on many factors, including the severity of the condition, the affected person's ability to follow the strict diet recommendations and the response to treatment. For example, some children appear to have more severe intellectual disability while others are more physically affected (i.e. severe spasticity with joint contractures). It is thought that approximately 75% of affected people survive the condition and live long lives.

If the condition is undiagnosed or if an affected person is unable to follow the strict diet, the prognosis is poor and may include severe intellectual disability and muscle stiffness; loss of the ability to walk; and loss of bladder and bowel control. However, even with treatment, the outcome can vary. In some cases, treatment has been shown to lower arginine levels in both the blood and the cerebrospinal fluid significantly, with some affected people even having near normal levels. With this response, continued treatment would be expected to improve long-term outlook and prevent progression of neurological symptoms. However, some affected people who follow the recommended treatment regimen may continue to have high levels of arginine in their blood, which can be associated with symptoms that worsen overtime. In fact, one study found that 50% of people with arginase deficiency who are compliant with treatment see an improvement in symptoms, 25% have symptoms that remain the same, and 25% experience a progression of the condition.

Treatment

The main goals in the treatment of arginase deficiency are lowering arginine levels and preventing hyperammonemia (a buildup of ammonia in the blood). People with arginase deficiency must be closely supervised by a medical team with experience treating metabolic conditions and often require frequent blood tests to check their arginine levels. Because arginine is a building block of protein, affected people must follow a diet that is very low in protein. In fact, it is often recommended that people with arginase deficiency eat the minimal amount of protein needed to maintain good health, which varies based on many factors including age and weight. Protein is found in high amounts in meat, fish, beans, dairy products, eggs and nuts; however, it also occurs in foods like pasta, fruit and vegetables. Under the guidance of a metabolic dietician, people with arginase deficiency must closely monitor all the protein they eat. They are often advised to drink special formulas and/or buy medical foods in which the protein levels are tailored to fit their needs. Affected people may also need to take certain medications (called nitrogen-scavenging drugs) to reduce levels of arginine.

During an episode of severe hyperammonemia, people with arginase deficiency are generally treated in the hospital. They may require dialysis, nitrogen-scavenging medications, intravenous (IV) fluids/feeds or other treatments. These treatments are given to quickly reduce blood ammonia levels and prevent brain damage.