The urea cycle is a metabolic pathway for the disposal of excess nitrogen (ammonia), which is life-threatening when it accumulates in the blood. Urea Cycle Disorders (UCDs) result from inherited defects in one of the enzymes or transporters involved in the urea cycle, including carbamoylphosphate synthase 1, ornithine transcarbamylase, argininosuccinate lyase, and N-acetylglutamate synthase.
What is a Urea Cycle Disorder?
The urea cycle is the system in your body that removes ammonia, a waste product of protein metabolism, from your bloodstream. In a normal urea cycle, protein is broken down into amino acids that your body uses and the excess is converted to urea (a compound that leaves your body in urine). In Urea Cycle Disorders, mutations in genes cause enzyme deficiencies that prevent the urea cycle from working properly and result in elevated ammonia in the bloodstream.
Newborns with urea cycle disorders are often diagnosed a few days after birth by universal newborn screening blood tests. However, sometimes symptoms don’t appear until later in life. In these cases, the disease can be diagnosed by genetic testing, which involves analyzing DNA extracted from cells in the sample of blood.
Some urea cycle disorders can be passed down from parent to child through autosomal recessive inheritance. Others can be inherited in an X-linked manner.
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The most severe urea cycle disorders are associated with deficiency of the carbamoylphosphate synthetase (CPS) enzyme or with transporter proteins. CPS deficiency and OTC deficiency are called primary urea cycle disorders, while argininosuccinate lyase, citrulline, and arginase deficiencies are considered secondary urea cycle disorders.
While a diagnosis of urea cycle disorder is very serious, most children who are diagnosed after the newborn period do not experience a hyperammonemic crisis and will have a good outcome. However, the longer an episode of hyperammonemia lasts, the more damage is done to your child’s brain. As a result, developmental delay is common for children with urea cycle disorders.
Those with late-onset urea cycle disorders usually have less severe symptoms and can live fairly normal lives, though they may require periodic monitoring for episodes of high ammonia and will need to practice a diet low in protein. They are also at increased risk for developing milder disabilities, such as attention deficit hyperactivity disorder and learning disabilities. Your metabolic treatment team should arrange periodic assessments by a developmental specialist and enroll your child in a developmental intervention program, based on the results of these assessments.
Symptoms
The body’s urea cycle disposes of nitrogenous waste products resulting from the breakdown of protein. People with urea cycle disorders have trouble disposing of these waste products, and too much ammonia builds up in the blood. The result is a condition called hyperammonemia. When high levels of ammonia build up for too long, they can cause brain damage and coma. Newborns with severe urea cycle disorders typically develop the first symptoms, called hyperammonemic crisis, soon after birth. They appear normal at birth but then develop symptoms of cerebral edema (swelling of the brain) including lethargy, anorexia, vomiting, hypo- or hyperventilation, respiratory failure, abnormal posturing and encephalopathy (difficulty thinking).
Babies with less severe defects may show more subtle signs in early infancy, which may go unrecognized and be mistaken for irritability, feeding problems, allergies or infections. These babies may have episodes of increased plasma ammonia concentration, but the level never reaches the point where brain function is compromised. Later on in life, these children may experience a “flare-up” of symptoms (hyperammonemic attacks) when they have illness or a stressful event such as surgery, excessive exercise or dieting, viral illnesses or the peripartum period. The attacks usually last a few days, but repeated crises can result in permanent brain damage.
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Most of the urea cycle disorders are autosomal recessive, which means they can only be passed on to kids if both parents have the gene mutation for the disorder. However, some urea cycle disorders occur in people of unknown genetic origin and are known as “sporadic”; they do not run in families. Ornithine transcarbamylase deficiency is one of these.
Adults who have mild urea cycle disorders may also experience the same symptoms as newborns, but their onset is later in life (late-onset urea cycle disorder or UCD). These adults may present to emergency rooms with staggering, confusion, combativeness and disorientation that can be mistaken for alcohol or drug intoxication. This is a warning sign that the urea cycle enzymes are not functioning normally and that they are at risk for hyperammonemic attack when exposed to stressors.
Diagnosis
Urea Cycle Disorders are genetic diseases that cause a defect in the way the body produces one of its most basic enzymes. Sadly, we have very few treatments that cure these disorders. However, the NUCDF supports research to develop and test new methods of delivering healthy urea cycle genes to the cells so they can function properly.
For newborns with severe mutations, the first symptoms appear within days after birth and usually involve loss of appetite and vomiting. Eventually, these symptoms lead to hyperammonemia (elevated blood ammonia). If left untreated, this toxic substance moves from the blood into the brain, where it causes irreversible brain damage and death. Newborn screening has not been successful in detecting these disorders early, as the severity of the mutation determines whether or when the patient will experience hyperammonemia.
Most children with urea cycle disorders that are diagnosed after the neonatal period have a less severe genetic mutation. They may experience a hyperammonemic episode during childhood, but it is not as serious as in the newborn period. In these patients, protein restriction reduces the frequency and severity of the episodes.
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If a child is experiencing a severe hyperammonemic crisis, he or she needs to be moved to a hospital that can treat this problem with intravenous medications. These include benzoate and phenylacetate (Ammonul), which are used to lower blood ammonia rapidly. Other measures to prevent these crises are a low-protein diet and regular blood ammonia measurements.
The diagnosis of a urea cycle disorder is generally made by analyzing the levels of certain amino acids in the blood or urine. For example, elevated levels of ornithine indicate CPS deficiency and elevated citrulline indicates OTC deficiency. A small sample of the liver can also be tested using a procedure called a liver biopsy, which examines the tissue under a microscope to look for the missing enzymes.
Other diagnostic tests for urea cycle disorders include an amino acid profile or analysis, a urinalysis, and a genetic test. The provider may also order an MRI or CT scan to check for brain damage.
Treatment
The symptoms of urea cycle disorders are caused by problems with enzymes that help detoxify ammonia. These enzymes are produced in the liver. If too little of these enzymes are produced, the blood levels of ammonia rise to toxic levels. The symptoms can be severe and may cause brain damage. The good news is that if the disorder is diagnosed and treated early, it can often be corrected.
The treatments for UCDs focus on keeping ammonia levels low in the blood. They include eating a very low-protein diet, dialysis to clean the blood (hemodialysis), and medicine that includes sodium phenylbutyrate and sodium benzoate (Ammonul).
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These medicines provide alternative ammonia scavenging pathways to prevent hyperammonemia. In addition, your child will take a prescription for amino acid supplements. These help your child make the proteins that are important for growth and tissue repair.
In a long-term natural history study, most children with urea cycle disorders who were treated with medical management with a diet and medicine had poor cognitive outcomes. This is likely due to repeated episodes of high ammonia levels that can lead to brain swelling and irreversible brain damage.
Most patients with urea cycle disorders will have some degree of mental retardation or developmental delay. This is related to how sick the patient was when they were symptomatic and the severity of their defect in the urea cycle.
Because urea cycle defects are genetic, they can also be passed on to future children. The best way to help ensure that these disorders don’t occur in a family is by prenatal testing. The metabolic specialists and a genetic counselor can help determine what tests are needed and when they should be done.
If a parent has a mutation in the urea cycle genes, there is a 50% chance that their children will have the same mutation. This means that a pregnancy should be planned carefully. It is recommended that you talk with a genetic counselor before you are pregnant and that you work with your obstetrician to plan a pregnancy with a genetically healthy embryo.
