Hyperammonemia due to NAGS deficiency

Overview

Hyperammonemia due to N-Acetylglutamate synthase (NAGS) deficiency is a metabolic disturbance characterised by an excess amount of ammonia in the blood. Children with this severe urea cycle disorders typically show symptoms directly after the first 24 hours of life. Symptoms may include vomiting, lethargy, seizures, respiratory distress and coma. The basic tests to make the diagnosis are the measurement of blood ammonia, plasma amino acids and urine organic acids concentrations. Severe consequences can be avoided through direct medication in combination with a strict diet.

Symptoms

Children with severe urea cycle disorders typically show symptoms after the first 24 hours of life. The baby may be irritable at first, or refuse feedings, followed by vomiting and increasing lethargy. Soon after, seizures, hypotonia (poor muscle tone, floppiness), respiratory distress (respiratory alkalosis), and coma may occur. These symptoms are caused by rising ammonia levels in the blood (hyperammonemia). Sepsis and Reye’s syndrome are common misdiagnoses. If untreated, these severely affected infants will die.

Major characteristics of NAGS deficiency, considered the rarest urea cycle disorder, include severe hyperammonemia, deep encephalopathy despite only mild hyperammonemia, recurrent diarrhea and acidosis, movement disorder, hypoglycemia and hyperornithinemia. Hyperammonemia due to NAGS deficiency is a severe neonatal disorder with fatal consequences, if not detected immediately upon birth.

Sources: Wikipedia, National Urea Cycle Disorders Foundation, Medscape

Causes

In N-acetylglutamate synthetase (NAGS) deficiency, an important enzyme is mutated and does not fulfil its metabolic function. This leads to an accumulation of toxic ammonia in the body (hyperammonemia), which can have fatal effects on the child if it is not early detected.

The normal enzyme function of N-acetylglutamate synthetase (NAGS) is confined to the hepatic mitochondria and mediates the reaction acetyl-coenzyme A and glutamate to N-acetylglutamate (NAG) and coenzyme A. Acetyl- coenzyme A is a cofactor in many mitochondrial reactions, and glutamate is the transamination product of a-ketoglutarate and alanine; a-ketoglutarate is produced by the Krebs cycle. The normal function of N-acetylglutamate (NAG) is to act as an activator of carbamyl phosphate synthetase (CPS), which is also a mitochondrial enzyme. The activation process requires physical binding of NAG to the CPS enzyme, in turn, causing the inactive form of CPS to convert to an active state. Thus, CPS activity is regulated by the relationship of available NAG to inactive CPS enzyme protein. CPS is needed for the first enzymatic reaction of the urea cycle. This cycle involves a series of biochemical steps in which toxic ammonia, a waste product of protein metabolism, is converted to urea. The less toxic urea is then removed from the blood through the kidneys and the bladder as urine.

The biochemical effect of NAGS deficiency is an inability to form N-acetylglutamate (NAG). If NAG is not produced, it cannot activate the urea cycle, which is needed to convert ammonia to less harmful urea. If the urea cycle is not working properly, ammonia accumulates to toxic concentrations in the blood (hyperammonemia). The high concentrations of ammonia can cause irreversible brain damage, coma and/or death.

Other enzymes that can cause hyperammonemia are mutations in the other enzymes of the urea cycle like the carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (AS), argininosuccinate lyase (AL) and arginase (AG). Mutations in these genes can lead to a milder form of symptoms or a later onset of the disease.

Sources: Wikipedia, National Urea Cycle Disorders Foundation, Medscape

Prevention

N-Acetylglutamate synthase (NAGS) deficiency is an autosomal recessive urea cycle disorder. If you know of a case of hyperammonemia in your family, prenatal testing is advised. Since urea cycle disorders are genetic disorders, there is often a risk for future children having the disorder. Prenatal testing is available for all of the urea cycle disorders. Working with a metabolic specialist, a genetic counsellor or your obstetrician can help you determine what type of testing is best, and when it should be done. It is recommended that you contact a counsellor either before you are pregnant or as soon as you know so that testing can be more easily arranged.

Diagnosis

The basic tests to make the diagnosis are the measurement of blood ammonia, plasma amino acids and urine organic acids concentrations. DNA testing is available for some of the disorders, but is not used as a general screening test.

These laboratory tests measure substances that reflect how well the urea cycle is working. When there is a block in one of the enzymes in the urea cycle, certain chemical compounds build up behind the block and others are not adequately formed beyond the block. It is like the effects of a dam. Ammonia builds up in all urea cycle disorders and should be measured. Certain amino acids are elevated in some urea cycle disorders and decreased in others, depending on where the block lies. So amino acids should be measured in plasma isolated from blood (this is a single test that at one time measures all the amino acids). Finally, urine is often needed to measure certain organic acids (primarily orotic acid and other organic acids that may affect the urea cycle). These tests are available at most Academic Medical Centers and Children's Hospitals, including the 8 UCDC sites. If the plasma amino acids and urine tests do not make the diagnosis, more specialized testing is done. This may include obtaining blood, a skin biopsy or rarely a liver biopsy to measure the suspected missing enzyme or performing a DNA analysis on blood to identify the specific mutation or error causing the enzyme defect. These specialized tests can be obtained at an academic (university based) medical center or Children's Hospital but will need to be sent out for analysis, usually to one of the sites that are part of the Urea Cycle Disorders Consortium. The enzyme and DNA tests are usually done if a urea cycle disorder is strongly suspected and as yet undiagnosed. The DNA testing may also be done to help in genetic counseling of other family members or in prenatal diagnosis.

Sources: Wikipedia, National Urea Cycle Disorders Foundation, Medscape

Prognosis

NAGS deficiency is associated with significant morbidity and mortality. Patients with hyperammonemia are at risk for cerebral edema and death if treatment is not immediately begun. Survivors of hyperammonemic coma are likely to suffer brain damage and resulting developmental delays, learning disabilities, and/or mental retardation. The outcome and the affect on the life of the patient will depend a great deal on how sick they were when they were diagnosed. Patients with severe defects in their urea cycle require treatment with many drugs and strict dietary controls.

Treatment

Treatment of severe hyperammonemia is a true emergency. Immediate cessation of protein intake is mandatory in the face of high blood ammonia levels with provision of supplementary nonprotein energy to close the caloric gap. A strict diet together with medication can help to regulate the amount of ammonia in the blood.

Although there is currently no cure, treatment includes injections of a structurally similar compound, N-Carbamoyl-L-glutamate, an analogue of N-Acetyl Glutamate. This analogue likewise activates the urea cycle. This treatment mitigates the intensity of the disorder. If symptoms are detected early enough and the patient is injected with this compound, levels of severe mental retardation can be slightly lessened, but brain damage is irreversible.

The general treatment of urea cycle disorders consists of dietary management to limit ammonia production in conjunction with medications and/or supplements which provide alternative pathways for the removal of ammonia from the bloodstream. A careful balance of dietary protein, carbohydrates and fats is necessary to insure that the body receives adequate calories for energy needs, as well as adequate essential amino acids (for cell growth and development). Dietary protein must be carefully monitored and some restriction is necessary; too much dietary protein causes excessive ammonia production. However, if protein intake is too restrictive or insufficient calories are provided, the body will break down lean muscle mass (called catabolism) to obtain the amino acids or energy it requires; this catabolism creates excessive ammonia. Therefore, the correct nutritional balance for each individual in each stage of growth is critical in avoiding hyperammonemic crises. Frequent blood tests (serum ammonia, plasma quantitative amino acids) are required to monitor the disorders and are an important tool for optimizing treatment. 

NAGS deficiency is an extremely rare disorder with complex treatment, so consultation with a metabolic disease or medical genetic specialist is usually necessary for assistance with laboratory diagnosis and clinical care. Optimal treatment of urea cycle disorders requires a medical team consisting minimally of a geneticist/metabolic specialist and nutritionist specifically experienced in successful management of the disorders. These teams are usually found at university hospitals. Specialty consultation and second opinions from experts in the field of urea cycle disorders can be obtained by families who live in areas where optimal medical care is not available.

Specific therapy of N- acetylglutamate synthetase (NAGS) deficiency following diagnosis depends on dietary protein restriction and provision of arginine to enhance availability of ornithine and administration of carbamylglutamate (which is not widely available), a functional analogue of NAG. Treatment may include supplementation with special amino acid formulas (Cyclinex, UCD I&II), developed specifically for urea cycle disorders, which can be prescribed to provide approximately 50% of the daily dietary protein allowance. Some patients may require individual branched chain amino acid supplementation. Metabolic nutritionists routinely prescribe calorie modules such as Prophree, Polycose and ModuCal to be used combination with the amino acid formulas. Multiple vitamins and calcium supplements are also recommended. 

Reduction of blood ammonia can usually be achieved with intravenous sodium benzoate (Ammonul, approved in the United States in February, 2005), sodium phenylbutyrate (trade name Buphenyl) and phenylacetate. Sodium phenylbutyrate and sodium benzoate are “ammonia scavengers” that provide alternative pathways for removal of ammonia from the bloodstream and help to prevent hyperammonemia. Phenylacetate conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate reduces ammonia content in the blood by conjugating with glycine to form hippuric acid, which is rapidly excreted by the kidneys. These medications are administered three to four times per day in order to insure continual removal of toxic ammonia from the bloodstream.

Alternatively, hemodialysis is usually effective in bringing down the ammonia level, especially with the initial presentation. Exchange transfusion is ineffective and is not generally recommended. Intravenous fluids with glucose and sometimes arginine hydrochloride (HCl) added may be indicated.

Children with urea cycle disorders often lack appetite (due to excess serotonin in the brain suppressing appetite) and some may benefit from receiving medications and some feedings either via gastrostomy tube (a tube surgically implanted in the stomach) or nasogastric tube (manually inserted through the nose into the stomach).  The access these tubes provide often makes a critical difference in metabolic stability and in averting hyperammonemic crises; medications and formulas can still be administered when children have flu or colds.  Some centers have reported as much as 70% reduction in hospital admissions after placement of G-tubes or parents were trained to use NG-tubes.

When optimal treatment fails, liver transplant becomes an option. The transplant alternative must be carefully considered and evaluated with medical professionals to determine the potential of success compared to the serious risks and potential for new medical concerns, including the possibility of fatal viruses (Epstein-Barr, CMV), risk of developmental delay or lymphoproliferative disease as a side effect of immunosuppression.

Sources: Wikipedia, National Urea Cycle Disorders Foundation, Medscape