Understanding Urea Cycle Disorders

Urea cycle disorders are a group of related genetic disorders that can cause serious neurological symptoms in the first few days of life. In less severe cases, symptoms appear later in childhood or adulthood. The severity varies, partly depending on the exact genetic mutation involved. These rare and life-threatening conditions often cause long-term brain damage and intellectual disability. However, the diagnosis and treatment of these conditions have improved in recent years.

The Urea Cycle

The chemistry of the urea cycle can be quite intimidating. However, the main idea is that the urea cycle is a multi-step biochemical process that the body uses to help get rid of certain waste products. The body regularly needs to break down proteins. These might come from excess protein taken in through foods, or as protein from old cells of the body that need to be replaced.

When proteins are broken down in the body, they create a waste substance called ammonia. The problem with ammonia is that it is quite toxic, and it is difficult to excrete safely. So the body has a process called the urea cycle that converts ammonia to a less toxic chemical called urea. This takes place mainly in the liver. Here, various specialized proteins catalyze a series of reactions that ultimately result in the formation of urea. From there, urea is released into the bloodstream. Eventually, it travels to the kidneys, where exits the body through the urine.

Urea Cycle Disorders

Urea cycle disorders result when one of the helper proteins needed in this process doesn’t work very well. The problem might be with an enzyme or with a special protein that transports materials in and out of smaller parts of the cell. This happens because of an inherited genetic defect.

In a urea cycle disorder, ammonia begins to build up in the body to toxic levels, because it can’t be normally disposed of through the urea cycle. This leads to the symptoms of these disorders.

Urea cycle disorders are thought to affect roughly one in 35,000 infants. However, this number is probably higher if one considers partial defects. Urea cycle disorders fall into a larger category of diseases called inborn errors of metabolism.

Types

Inherited defects in any of the following proteins can cause urea cycle disorders:

• Carbamoyl phosphate synthetase I (CPS1)
• Ornithine transcarbamylase (OTC)
• Argininosuccinic acid synthetase (ASS1)
• Argininosuccinic acid lyase (ASL)
• N-acetylglutamate synthetase (NAGS)
• Arginase (ARG1)
• Ornithine translocase (ORNT1)
• Citrin

Ornithine transcarbamylase deficiency (OTC) is the most common type.

In some cases, one of these proteins may have some activity but may be much less effective than normal. In other cases, the protein may not work at all. This makes a difference in a person’s symptom severity.

Symptoms

Urea cycle disorders mostly cause symptoms that affect the brain and nervous system. The specific symptoms and severity of urea cycle disorders vary based on the severity of the genetic defect and the specific enzyme involved. Some people have proteins that don’t work at all, or work extremely poorly. A person with one of these types of defects in the first five proteins will have more severe symptoms from their urea cycle disorder. This includes CPS1, OTC, ASS1, ASL, and NAGS.

In people with severe urea cycle defects, ammonia begins to build up in the body in the newborn period. These infants appear normal at birth, but they soon become quite sick. In the first few days of life, these infants begin to develop brain swelling (cerebral edema). This is quite dangerous, as it puts pressure on a part of the brain called the brain stem. Symptoms may become severe very quickly. These may include:

• Vomiting and failure to eat
• Low body temperature
• Greater than normal sleeping
• Breathing too slowly or too quickly
• Seizures
• Abnormal muscular rigidity (called neurological “posturing”)
• Organ failure
• Coma
• Respiratory arrest
• Death

People whose genetic defects aren’t as severe don’t usually have symptoms until months or years after birth. In these people, ammonia levels don’t get as high, so symptoms aren’t as severe. These people may first notice symptoms later in their life. Sometimes, these symptoms are subtle and chronic. For example, chronic symptoms might include:

• Migraine-like headaches
• Intellectual disability
• Liver problems
• Tremor or balance problems
• Sleep problems
• Psychiatric symptoms (like mood changes, hyperactivity, aggressiveness)
• Fragile hair (especially for ASL)

Certain kinds of stress can worsen these symptoms or trigger new ones. This happens when ammonia levels become extra elevated. For example, any of the following might trigger symptoms:

• Illness
• Surgery
• Prolonged fasting
• Extreme exercise
• Giving birth

These stressors might trigger dangerous brain swelling and additional symptoms like the following:

• Loss of appetite
• Vomiting
• Lethargy
• Delusions and hallucinations
• Seizures
• Coma and organ failure

Diagnosis

Diagnosis begins with a careful medical history and a physical exam. This will include questions about the family history, including deaths of infants and neurological or psychiatric problems in the family. Your healthcare provider will want a full understanding of the symptoms and all potential signs of the condition. However, medical testing is also needed to diagnose a urea cycle disorder.

Anytime a person has unexplained neurological or psychiatric symptoms, healthcare providers must consider the possibility of elevated ammonia levels (called hyperammonemia). Infants with such symptoms should be tested for this promptly. Hyperammonemia is a very important sign of a potential urea cycle disorder, though it can be caused by other problems, such as liver failure or other genetic disorders. Early on, a urea cycle disorder might be mistaken for sepsis, an overwhelming response that the body makes to some sort of infection. However, in a urea cycle disorder, no such infection is actually present. A variety of other blood tests can also be used to help diagnose a urea cycle disorder.

To confirm the diagnosis of a urea cycle disorder, genetic testing is needed. This can be used to prove that a urea cycle disorder is present and also to identify the specific type of disorder. Some of the urea cycle disorders are included in the standard newborn screening tests that all infants receive at birth, so a diagnosis might come from this. However, not all urea cycle disorders are screened in these tests.

It is critical that diagnosis happens as quickly as possible. That’s because infants who have higher and longer levels of exposure to ammonia experience more severe brain damage.

Treatment

When a urea cycle disorder is first detected, it is critical to decrease the amount of ammonia in the body. Some form of dialysis is needed to quickly reduce the amount of ammonia in the blood. The specific type of dialysis used may vary based on the patient’s age, degree of illness, availability, and other factors. An ECMO pump (extracorporeal membrane oxygenation pump) used with a hemodialysis machine may be the quickest method.

There are also several treatments that can be given to increase excretion of ammonia. These can be given at higher doses during a crisis and at lower doses as a maintenance therapy. One such potential treatment is sodium benzoate.

Depending on the specific type of cycle disorder, other therapies may also benefit. For example, carbamylglutamate can be very effective at treating the NAGS type of urea cycle disorder. The amino acid L-arginine is another example of a therapy that is beneficial in certain types of urea cycle disorder.

Treatment also often involves in-depth nutritional support. It may be necessary to dramatically reduce the amount of protein intake for a limited period of time. Over the long-term, patients will need to follow a low protein diet. They may also need specific supplementation with specific amino acids, vitamins, and minerals.

Liver transplantation is also an option for some people with urea cycle disorders. This can potentially cure the condition completely. However, any permanent brain damage that has already occurred cannot be reversed with a liver transplant.

Individuals with urea cycle disorders need to be seen by a medical expert with experience managing and treating these conditions, such as a healthcare provider specializing in genetic metabolic diseases.

Prognosis and Management

Unfortunately, some infants with severe urea cycle disorders do not survive the first few weeks of life. However, with rapid diagnosis and better treatments for urea cycle disorders, the survival of affected infants has improved dramatically.

A large percentage of infants will have developmental delays and mental retardation. Unless a liver transplant occurs, recurrent crises of elevated ammonia can continue to be triggered by illness or other stressors. It is important that a plan be put in place to deal with any possible triggers of elevated ammonia. These periods of elevated ammonia can be critically dangerous to any person with a urea cycle disorder, even if their disease is usually well-managed.

Genetics

Except for OTC, the urea cycle disorders are inherited in an autosomal recessive fashion. That means that an affected infant has to receive an affected gene from both their mother and father. If an affected child has been born to a couple, there is a 25% chance that their future child would also have a urea cycle disorder.

Unlike the forms of urea cycle disorder, OTC follows X-linked inheritance. That means that the affected gene is found on the X chromosome (of which women have two and men have one). Because of this, OTC is more common in males than in females, and males tend to have more severe symptoms.

Females with one affected copy of the OTC gene often do not have any symptoms at all or only very mild ones. However, a significant minority of these women do have an episode of elevated ammonia at some point in their lives. A woman with one affected OTC gene has a 50% chance that her potential son will have a urea cycle disorder.

Many people find it helpful to talk with a genetic counselor if they know that urea cycle disorders are a risk in their family. Prenatal testing is available for urea cycle disorders. In some cases, couples may opt to terminate a pregnancy if a child is prenatally diagnosed with a severe form of a urea cycle disorder.

A Word From Verywell

It can be overwhelming to learn that your child has a serious genetic disease. Patients are often diagnosed with urea cycle disorders when they are quite sick and in need of acute medical intervention. Know that you aren’t alone. Through social media, it is easy to connect with other families that have experienced something similar. Your medical team will help talk you through every aspect of the decision-making process.