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Urea cycle disorders

Urea cycle defect, UCD

Overview

Urea cycle disorder 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 the blood. Normally, the urea is removed from the body through the urine. In urea cycle disorders, nitrogen builds up in the 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.

Symptoms - Urea cycle disorders

Neonatal:
Babies with very severe urea cycle disorders typically show symptoms after the first 24 hours of life. Some signs may include:

  • Irritation
  • Vomiting
  • Increased lethargy
  • Seizures
  • Hypotonia (poor muscle tone)
  • Respiratory distress
  • Coma and death, if untreated. 

Childhood:
Children with mild or moderate urea cycle enzyme deficiencies may not show symptoms until early childhood, or may be diagnosed subsequent to identification of the disorder in a more severely affected relative or through newborn screening. Early symptoms may include:

  • Hyperactive behavior sometimes accompanied by screaming and self-injurious behavio
  • Refusal to eat meat or other high-protein foods.
  • Later symptoms may include:
  • Frequent episodes of vomiting, especially following high-protein meals
  • Lethargy and delirium
  • Coma and death, if untreated 

Children with this disorder may be referred to child psychologists because of their behavior and eating problems. Childhood episodes of hyperammonemia (high ammonia levels in the blood) may be brought on by viral illnesses including chicken pox, high-protein meals, or even exhaustion. The condition is sometimes misdiagnosed as Reye’s Syndrome. 

Adulthood:

  • Stroke-like symptoms
  • Episodes of lethargy
  • Delirium

These adults are likely to be referred to neurologists or psychiatrists because of their psychiatric symptoms. However, without proper diagnosis and treatment, these individuals are at risk for permanent brain damage, coma, and death.

Causes - Urea cycle disorders

Urea cycle disorders are included in the category of inborn errors of metabolism and represent a substantial cause of brain damage and death among newborns and infants.

Prevention - Urea cycle disorders

Prenatal testing is available for all of the urea cycle disorders. Working with a metabolic specialist, a genetic counselor or your obstetrician can help you determine what type of testing is best, and when it should be done.

Diagnosis - Urea cycle disorders

 Disorders may vary on an individual basis for each patient. Only your doctor can provide adequate diagnosis of any signs or symptoms and whether they are indeed Urea Cycle Disorders symptoms.

Prognosis - Urea cycle disorders

The survival for the late onset cases seems to be quite good if diagnosed and treated early, but there is still a significant risk of a life-threatening or debilitating hyperammonemic episode, so symptoms should always be taken seriously.

Treatment - Urea cycle disorders

The treatment of urea cycle disorders consists of balancing dietary protein intake in order that the body receive the essential amino acids responsible for cell growth and development, but not so much protein that excessive ammonia is formed. This protein restriction is used in conjunction with medications which provide alternative pathways for the removal of ammonia from the blood. These medications are usually given by way of tube feedings, either via gastrostomy tube (a tube surgically implanted in the stomach) or nasogastric tube through the nose into the stomach. The treatment may also include supplementation with special amino acid formulas developed specifically for urea cycle disorders, multiple vitamins and calcium supplements. Frequent blood tests are required to monitor the disorders and optimize treatment, and frequently hospitalizations are necessary to control the disorder.

If diet alone cannot manage the disorder, medications may be used in the management of the condition.

Approved therapies:

  • Benzoate and phenylacetate (Ammonul) - 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 (Buphenyl) - 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 (Ravicti) - FDA-approved indication: Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients > or = to 2 years 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 (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements). 
  • Benzoate and phenylacetate (Ucephan) - 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.

Resources - Urea cycle disorders

Refer to research Publications.

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