What are the other Names for this Condition? (Also known as/Synonyms)

• UCD (Urea Cycle Disorder)

What is Urea Cycle Disorders? (Definition/Background Information)

• A Urea Cycle Disorder (UCD) is a genetic disorder that results in a deficiency of one of the six enzymes in the urea cycle. These enzymes are responsible for removing ammonia from the blood stream
• The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is changed to a compound called urea and removed from blood. Normally, the urea is removed from the body through the urine
• In urea cycle disorders, nitrogen builds up in blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death
• The onset and severity of urea cycle disorders is highly variable. The severity correlates with the amount of urea cycle enzyme function

(Source: Urea Cycle Disorders; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Urea Cycle Disorders? (Age and Sex Distribution)

• Urea Cycle Disorders are rare congenital disorders. The presentation of symptoms may occur at birth or later in life
• The estimated frequency of occurrence of these disorders is 1 in 8,500 births. However, it is believed that many cases remain undiagnosed
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Urea Cycle Disorders? (Predisposing Factors)

• A positive family history may be an important risk factor, since Urea Cycle Disorders can be inherited

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Urea Cycle Disorders? (Etiology)

Urea Cycle Disorders (UCDs) are categorized under inborn errors of metabolism.

• UCDs are caused by gene mutation(s) that lead to a deficiency in one of 6 enzymes that is part of the urea cycle. The urea cycle is a group of reactions that result in the conversion of ammonia to urea
• The 6 enzymes include the following:
  • Carbamoyl phosphate synthase, coded by CPS1 gene
  • Ornithine transcarbamylase, coded by the OTC gene 
  • Argininosuccinate synthetase, coded by ASS1 gene
  • Argininosuccinate lyase, coded by ASL gene
  • Arginase, coded by ARG1 gene
  • N-acetylglutamate synthetase, coded by NAGS gene
• A deficiency in any of the 6 enzymes, caused by mutation(s) in their respective genes, can cause the accumulation of ammonia in the body, which gives rise to the characteristic symptoms of the disorder
• Mutation(s) in CPS1, ASS1, ASL, ARG1 and NAGS genes are inherited in an autosomal recessive manner
• Mutation(s) in the OTC gene that causes Urea Cycle Disorder is inherited in an X-linked manner

Autosomal recessive pattern of inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

X-linked recessive pattern of inheritance: Occurs when a gene associated with a condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What are the Signs and Symptoms of Urea Cycle Disorders?

The signs and symptoms of Urea Cycle Disorders arise due to accumulation of ammonia in the body, and may differ among affected individuals in severity, depending on the gene mutation that caused the condition.

The gene mutation(s) leading to signs and symptoms are listed below, in the order of least to most severe:

• ARG1 (causes arginemia)
• ASL (causes arginosuccinic aciduria)
• ASS1 (causes citrullinemia)
• OTC
• CPS1
• NAGS

Mild signs and symptoms of Urea Cycle Disorders:

• Failure to thrive
• Intellectual deficiency
• Episodes of increased hyperammonemia interspersed with normal ammonia levels in blood

Severe signs and symptoms of Urea Cycle Disorders:

• Confusion
• Swelling in brain

Signs and symptoms in females, particularly those individuals with OTC gene mutation(s):

• Growth abnormalities
• Psychiatric problems
• Episodes of elevated and normal blood ammonia levels (during stressful times and post-partum)
• Vomiting
• Weakness
• Brain damage (swelling in brain)
• Seizures

Signs and symptoms in males with OTC gene mutation(s):

• Recurrent vomiting episodes
• Irritability
• Weakness
• Tiredness
• Intellectual deficiency
• Stiff muscles

How is Urea Cycle Disorders Diagnosed?

Urea Cycle Disorders is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests, including tests to:
  • Check for levels of ammonia in blood
  • Serum amino acid profiles to understand possible gene mutation and specific enzyme deficiency
• Imaging studies
• Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Urea Cycle Disorders?

The complications of Urea Cycle Disorders may include:

• Risk of falls due to seizures
• Irreversible brain damage
• Coma and death

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Urea Cycle Disorders Treated?

The medications listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of Urea Cycle Disorders:

• Benzoate and phenylacetate - FDA-approved indication: Adjunctive therapy in the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle
• Sodium phenylbutyrate - FDA-approved indication: Adjunctive therapy in the chronic managment of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase
• Glycerol phenylbutyrate - FDA-approved indication: Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients at least 2 months of age with Urea Cycle Disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone
• RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements)
• Benzoate and phenylacetate - FDA-approved indication: For adjunctive therapy in the prevention and treatment of hyperammonemia in patients with urea cycle enzymopathy due to carbamylphosphate synthetase, ornithine, transcarbamylase, or argininosuccinate synthetase deficiency

(Source: Urea Cycle Disorders; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Urea Cycle Disorders be Prevented?

Urea Cycle Disorders may not be preventable, since they are inherited metabolic disorders.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Urea Cycle Disorders? (Outcomes/Resolutions)

• The prognosis of Urea Cycle Disorders is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Severe symptoms can lead to serious complications that can lead to fatality
• Typically, the prognosis may be assessed on a case-by-case basis
• Urea Cycle Disorders can be difficult to treat, and in many cases, liver transplantation may be necessary

Additional and Relevant Useful Information for Urea Cycle Disorders:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/