Urea Cycle Disorders

Introduction

The urea cycle is a filtering process that removes harmful substances from the body while keeping substances that help the body move around.

The liver produces the substance urea (carbamide). After eating, the urea cycle starts. Protein in the diet is broken down (metabolized) by the body and converted into amino acids, which are the building blocks of proteins. The body uses amino acids to maintain organ health, move nutrients, and build muscle. Protein digestion produces waste materials that decompose into ammonia. Ammonia is toxic to the human body. Enzymes, proteins that cause chemical reactions, change ammonia into urea to eliminate it. Urea contains arginine, ornithine, and citrulline, along with ammonia. Enzymes move urea through the kidneys and blood. The last phase in the urea process is to excrete urea from the body through the urine.

What Are Urea Cycle Disorders?

Urea cycle disorders are disorders in which the human body's normal mechanism for moving urea through it is defective. It usually happens when an enzyme or protein is lacking. Urea cycle disorder (UCD) is a genetic condition called an inborn error of metabolism (IEM). IEMs are classified into two types: deficiencies in specific enzymes required to convert fat or carbohydrates into energy and deficiencies in specific enzymes required to break down amino acids or other metabolites, allowing them to accumulate and become toxic if not treated. UCDs belong to the second type. It produces ammonia buildup in the blood (hyperammonemia), which is hazardous to the body. Hyperammonemia is important in diagnosing urea cycle disorder, and treatment should be completed on time until a definite diagnosis is determined. The brain and organ function are the primary targets of these symptoms.

What Are the Types of Urea Cycle Disorders?

Eight different forms of urea cycle disorders can be identified by the absence or improper function of specific proteins and enzymes in the metabolism that play key roles in the cycle.

• N-Acetylglutamate Synthase (NAGS) Deficiency: NAGS is required for the activity of carbamoyl phosphate synthetase I (CPS1), the first enzyme in the urea cycle. Due to CPS1's inactivation in the absence of NAGS, hyperammonemia has symptoms resembling CPS1 deficiency. It is the only urea cycle defect that allows for the complete treatment of hyperammonemia.

• Carbamoyl Phosphate Synthetase I (CPS1) Deficiency: Newborns lacking in CPS1 have hyperammonemia. The urea cycle abnormality is extremely severe, and even after therapy and recovery, there is a chronic risk of episodes of hyperammonemia. A partial or minor CPS1 deficiency can produce symptoms at any age, especially due to stress or infection.

• Ornithine Transcarbamylase (OTC) Deficiency: OTC deficiency is more common in men than in women since there is only one X chromosome on which the gene for OTC is found. It can be as severe as CPS1 deficiency. Females have a lower risk of OTC deficiency since they have two X chromosomes and are more likely to have one functional OTC gene.

• Argininosuccinate Synthase 1 (ASS1) Deficiency or Citrullinemia Type I: People with this condition experience severe hyperammonemia. Additionally, the blood levels of citrulline in them are excessively high. However, directing some waste nitrogen into the urea cycle is still possible, making treatment quite simple.

• Citrin Deficiency or Citrullinemia Type II: Citrin is a transporter protein that transports aspartate into the urea cycle. This protein deficiency causes hyperammonemia, which leads to seizures and coma. It is more common in Asian populations where Citrin gene mutations are common.

• Argininosuccinate Lyase (ASL) Deficiency: Rapid hyperammonemia in infants is a characteristic of this disorder. It results in an increase in transaminases and persistent hepatic hypertrophy. In addition, Hepatocyte enlargement may result in fibrosis.

• Arginase (ARG) Deficiency: This abnormality does not cause rapid-onset hyperammonemia. However, some children have severe symptoms, such as increased stiffness and stunted growth.

• Ornithine Translocase Deficiency: Ornithine translocase is another transport protein that transports ornithine and citrulline molecules within the urea cycle. Lack of this protein delays the cycle and results in an accumulation of ammonia. Coma, vomiting, and hyperammonemia are common symptoms.

What Are the Symptoms of Urea Cycle Disorder?

Indications of urea cycle disorders typically appear shortly after birth, though they can appear at any age. The following are symptoms of urea cycle disorders:

• Fatigue or lethargy.

• Babies' fussiness.

• Nausea or vomiting.

• Need help to feed or eat.

• Breathing too quickly or slowly.

• Confusion.

Too much ammonia in the blood (hyperammonemia) causes symptoms of urea cycle disorders. The following symptoms can be mild to severe:

• Cognitive development issues.

• Intellectual difficulties.

• Changes in behavior.

• Developmental delays.

• Coma.

• Seizures.

• Cerebral edema (the accumulation of fluid in the brain).

• Tensed muscles (spasticity).

What Causes Urea Cycle Disorder?

A genetic mutation causes urea cycle dysfunction. Each variety results from a distinct genetic mutation, such as:

• A NAGS gene mutation that results in N-acetyl glutamate synthase.

• A CPS1 gene mutation is the cause of carbamoyl phosphate synthetase I.

• OTC gene mutation leading to ornithine transcarbamylase.

• An ASS1 gene mutation results in the protein argininosuccinate synthase 1.

• A mutation in the SLC25A13 gene causes citrin deficiency.

• An ASL gene mutation results in argininosuccinic lyase.

• ARG gene mutations lead to arginase.

• An SLC25A15 gene mutation results in ornithine translocase.

These genes create proteins and enzymes that transport urea through the body. A genetic mutation causes the body to create insufficient proteins or enzymes. When a person has a urea cycle disorder, the body cannot eliminate toxic ammonia, which builds up in the blood and causes symptoms.

How Is Urea Cycle Disorder Diagnosed?

After reviewing the symptoms and taking a complete medical history, the healthcare expert will diagnose urea cycle disorder. They may request a urine or blood test to confirm a diagnosis. Tests to identify disorders of the urea cycle include:

• Amino Acid Profile or Analysis: A doctor will examine a small amount of urine or blood to determine which amino acids the body metabolizes.

• Liver Biopsy: A small piece of the liver will be removed and examined under a microscope to test for enzymes associated with the disease. Since it may indicate low enzyme activity levels, it can be performed to confirm the diagnosis.

• Genetic Test: Genetic tests can also determine the specific type of urea cycle disorder by determining whether one of the genes required to degrade urea cycle proteins is malfunctioning.

• Imaging Tests: An Magnetic resonance imaging (MRI) or Computed Tomography (CT) scan may be performed to determine whether brain enlargement is caused by ammonia in the blood.

How Is Urea Cycle Disorder Treated?

The goal of urea cycle disorder treatment is to reduce blood ammonia levels. Possible treatments include:

• Eating a low-protein diet.

• Dialysis to remove poisons from the blood (hemodialysis).

• Taking sodium phenylacetate and sodium benzoate-based medicines to eliminate ammonia in the blood.

• Taking amino acid supplements like citrulline or arginine helps the body complete the urea cycle.

• Liver transplantation: Because urea cycle enzymes are produced in the liver, a liver transplant can effectively treat urea cycle dysfunction.

Before beginning therapy, ask the healthcare professional about any potential adverse effects of new medications or treatments. In addition, tell the clinician about any vitamins or medications you are taking to avoid drug interactions.

What Foods Should Be Avoided When Suffering From Urea Cycle Disorder?

It is preferable to follow a low-protein diet when treating urea cycle disease. A low-protein diet lowers the possibility of blood ammonia levels rising. Common protein-containing foods that should be limited in the diet include the following:

• Fish.

• Chicken.

• Eggs.

• Beef.

• Beans.

• Tofu or soy-based foods.

Since protein is a vital diet component, eliminating all proteins may have negative effects, such as limiting growth. Therefore, the doctor may advise collaborating with a nutritionist or dietitian to manage the diet and reduce the amount of protein. Sometimes a doctor will advise taking vitamins, minerals, or amino acids supplements to make up for low protein consumption.

What Is the Prognosis (Outcome) of Urea Cycle Disorders?

There is presently no cure for urea cycle diseases. The type of urea cycle disorder, how severe it is, how early it is detected, and how well the treatment plan and diet are followed all influence the outcome. Early detection and treatment are necessary for the child to have a favorable outcome. Infants who receive a diagnosis within the first week of life and are immediately put on a diet may fare well. Normal brain function is possible for the child if they stick to the diet correctly. If the child does not follow the diet or has stress-related symptoms, this might result in repeated brain swelling and irreversible brain damage. The signs of urea cycle disorders can be reversed with transplants.

Conclusion

Urea cycle disorder cannot be prevented because it is a genetic condition. If a person wants to get pregnant and knows the potential dangers of passing down a genetic problem to the unborn child, ask a healthcare provider about genetic testing. Consult the doctor if anyone experiences signs of the disease, especially if they are severely exhausted or unable to eat. It is essential to monitor the child's developmental milestones as they grow to ensure they are reaching age-appropriate expectations. Consult the healthcare practitioner if the child fails to reach the expected developmental milestones.