Carbamyl Phosphate Synthetase and N-Acetylglutamate Synthetase Deficiencies - An Overview

Introduction

N-Acetylglutamate synthetase (NAGS) is a liver enzyme that produces N-Acetylglutamate (NAG) essential for mammal liver ureagenesis in the urea cycle. Carbamyl phosphate synthetase 1 (CPS1) is the rate-limiting enzyme that catalyzes the first step of ureagenesis. N-Acetylglutamate is necessary for the activation of carbamyl phosphate synthetase. Therefore, patients with a deficiency of these enzymes have severe complications in the early infantile period or later.

Because N-Acetylglutamate is an activator of carbamyl phosphate synthetase, deficiency of either enzyme leads to similar biochemical phenotypes and complications. It is essential to differentiate the NAG and CPS deficiencies.

What Is Urea Cycle?

The urea cycle, also called the ornithine cycle, is a cycle of biochemical reactions producing urea from ammonia. This cycle converts the toxic ammonia, the product of excess nitrogen in the body, into urea for excretion. The disorders of the urea cycle due to the deficiency of enzymes cause hyperammonemia.

What Is Carbamyl Phosphate Synthetase Deficiency?

Carbamyl phosphate synthetase 1 deficiency is a rare inherited disorder causing episodes of toxic levels of ammonia in the blood (hyperammonemia) due to complete or partial deficiency of the carbamyl phosphate synthetase (CPSI1) enzyme. The brain is sensitive to the excess effects of ammonia.

The following are the other names for this condition.

• Carbamyl phosphate synthetase I deficiency disease.

• Congenital hyperammonemia, type 1.

What Is N-Acetylglutamate Synthetase Deficiency?

N-Acetylglutamate synthetase deficiency is a rare inherited disorder causing hyperammonemia due to complete or partial deficiency of the N-Acetylglutamate synthetase enzyme, which plays an essential role in the removal of nitrogen from the body in the urea cycle.

The following are the other names for this condition.

• Hyperammonemia type 3.

• NAGS deficiency.

What Causes Carbamyl Phosphate Synthetase Deficiency?

Carbamyl phosphate synthetase deficiency is caused due to mutations in the CPS1 gene, which provides instructions for making the carbamyl phosphate synthetase enzyme. Mutations in the CPS1 gene produce abnormal carbamyl phosphate synthetase enzymes.

This disease also occurs as an autosomal recessive disorder. Recessive genetic disorders occur when individuals inherit two copies of an abnormal gene from each parent.

What Causes N-Acetylglutamate Synthetase Deficiency?

N-Acetylglutamate synthetase deficiency is caused due to mutations in the NAGS gene, which provides instructions for producing N-Acetylglutamate synthetase. Therefore, the mutated NAGS gene causes an enzyme deficiency. It is an autosomal recessive disorder in which individuals inherit two copies of an abnormal gene from each parent.

What Are the Signs and Symptoms of Carbmayl phosphate Synthetase and N-Acetylglutamate Synthetase Deficiency?

The signs and symptoms of carbamyl phosphate and N-Acetylglutamate synthetase deficiency are similar because both enzyme deficiencies result in hyperammonemia.

Severe deficiency diseases occur within 24 to 72 hours after birth. The symptoms include the following.

• Lethargy.

• Refusal to eat.

• Loss of appetite.

• Vomiting.

• Irritability.

• Hepatomegaly (abnormal enlargement of the liver).

• Seizures.

• Abnormal movements.

• Respiratory distress.

• Cerebral edema.

• Coma or death if left untreated.

Milder deficiency disorders occur later during childhood or adulthood when triggered by virus infection or stress. The symptoms include the following.

• Development disorders or failure to grow.

• Failure to gain weight.

• Ataxia (inability to coordinate voluntary movements).

• Lethargy.

• Hypotonia (reduced muscle tone).

• Vomiting.

• Learning disabilities.

• Intellectual disability.

How to Diagnose Carbamyl Phosphate and N-Acetylglutamate Synthetase Deficiency?

The diagnosis of carbamyl phosphate synthetase and N-Acetylglutamate synthetase deficiency diseases are similar, which include the following.

• The diagnosis of enzyme deficiency includes patient and family history, identification of characteristic features, and blood tests.

• A blood test detects an excess amount of ammonia in the blood.

• Urine examination to detect elevated and abnormal levels of organic acids.

• Genetic sequencing of the CPS1 gene and NAGS gene is essential for diagnosing.

• NAGS and CPS are distinguished by molecular genetic testing, an assay of the enzyme activities in liver biopsy or gene sequencing.

What Are the Differential Diagnosis of NAGS and CPS Deficiency Diseases?

The following are the other urea cycle disorders causing the accumulation of ammonia in the blood and tissues.

• Citrullinemia type 1- Arginosuccinic acid synthetase deficiency.

• Ornithine transcarbamylase (OTC) deficiency.

• Arginase deficiency.

• Citrullinemia type 2.

• Ornithine transport disorders.

• Organic acidemias due to the deficiency of enzymes responsible for breaking amino acids.

• Reye syndrome - Rare childhood disorder characterized by liver failure, encephalopathy, hyperammonemia, and hypoglycemia.

What Is the Treatment for Carbamyl Phosphate Synthetase Deficiency Disease?

The treatment aims to reduce plasma ammonia, prevent excess ammonia formation, and reduce the amount of ammonia in the diet. The treatment options include the following.

• Dialysis reduces the plasma concentration of ammonia.

• Nitrogen scavenger drugs, such as sodium phenylacetate and sodium benzoate, remove the excess nitrogen through oral or intravenous administration.

• Citrulline or arginine maintains the average rate of protein synthesis.

• Dietary restrictions include a low-protein, high-calorie diet supplemented by essential amino acids.

• Liver transplantation is the solution for patients with severe hyperammonemia or complete enzyme deficiency.

• Seizures are treated with Carbamazepine or Phenobarbital.

• Affected individuals should receive regular blood tests to detect ammonia levels.

• Genetic counseling helps the affected individuals and their families.

What Is the Treatment for N-Acetylglutamate Synthetase Deficiency Disease?

The treatment of N-Acetylglutamate synthetase deficiency disease is almost similar to the other urea cycle disorders. It includes pediatricians, neurologists, dieticians, physiologists, occupational therapists, speech therapists, and physiotherapists to treat the disabilities. The treatment options include the following.

• Carbaglu tablets reduce the ammonia levels in the blood.

• Recommended maintenance dose of carbamyl glutamate, an analog of N-Acetyleglutamate, is 10 to 100 milligrams per kilogram of body weight daily.

• In addition to carbamyl glutamate, nitrogen-scavenging agents are sometimes provided for patients with NAGS deficiency to prevent hyperammonemia and maintain normal cognition.

• Aggressive treatment includes hospitalization with intravenous administration of arginine or sodium phenylacetate.

What Is the Preventive Care for the Deficiency Diseases?

After diagnosing NAGS and CPS deficiency, steps should be taken to anticipate the onset of hyperammonemia. Periodic blood tests are vital to evaluate ammonia in the blood. The elevated levels of glutamine (an amino acid) in the blood indicate the development of hyperammonemia. So the amount of amino acids in the blood is also tested.

Conclusion

Further research and studies are required to identify risk factors for carbamyl phosphate and N-Acetylglutamate synthetase deficiencies and their management. In addition, more information is necessary to learn more about the triggers of hyperammonemia which would be helpful for the management of affected individuals.