Carbamoyl phosphate synthetase 1 deficiency

Alternate Names:

Hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency; CPS 1 deficiency; Carbamyl phosphate synthetase (CPS) deficiency

Definition

Carbamoyl phosphate synthetase I deficiency (CPS1 deficiency) is a genetic disorder that causes episodes of toxic levels of ammonia in the blood (hyperammonemia).

Summary

• Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The brain is especially sensitive to the effects of excess ammonia.
• In the first few days of life, infants with carbamoyl phosphate synthetase I deficiency typically exhibit the effects of hyperammonemia, which may include unusual sleepiness, poorly regulated breathing rate or body temperature, unwillingness to feed, vomiting after feeding, unusual body movements, seizures, or coma.
• Affected individuals who survive the newborn period may experience recurrence of these symptoms if diet is not carefully managed or if they experience infections or other stressors. They may also have delayed development and intellectual disability.
• In some people with carbamoyl phosphate synthetase I deficiency, signs and symptoms may be less severe and appear later in life.

Epidemiology

Carbamoyl phosphate synthetase I deficiency is a rare disorder; its overall incidence is unknown. Researchers in Japan have estimated that it occurs in 1 in 800,000 newborns in that country.

Cause

Mutations in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. The CPS1 gene provides instructions for making the enzyme carbamoyl phosphate synthetase I. This enzyme participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells. The urea cycle processes excess nitrogen, generated when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys. The specific role of the carbamoyl phosphate synthetase I enzyme is to control the first step of the urea cycle, a reaction in which excess nitrogen compounds are incorporated into the cycle to be processed.

Carbamoyl phosphate synthetase I deficiency belongs to a class of genetic diseases called urea cycle disorders. In this condition, the carbamoyl phosphate synthetase I enzyme is at low levels (deficient) or absent, and the urea cycle cannot proceed normally. As a result, nitrogen accumulates in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and excreted. Ammonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of carbamoyl phosphate synthetase I deficiency.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Symptoms

The symptoms of CPS1 deficiency occur very quickly in the first few days after birth. Without diagnosis and treatment, high levels of ammonia in the blood may result in breathing problems, seizures, intellectual and developmental disability, coma and even death. Children who are successfully treated are still at risk for repeated episodes of high ammonia. Some people with CPS1 deficiency have a milder form and signs and symptoms may be less severe and appear later in life. Symptoms may include:

• Poor feeding
• Vomiting
• Progressive lack of energy, irritability, listlessness
• Low body temperature (hypothermia)
• Low muscle tone (hypotonia)
• Complications of breathing (respiration deficiency)
• Seizures (convulsions)
• Coma

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Aminoaciduria (High urine amino acid levels)
• Episodic ammonia intoxication
• Hyperammonemia(High blood ammonia levels)
• Hypoargininemia (Low blood arginine levels)
• Muscular hypotonia(Low or weak muscle tone)
• Respiratory insufficiency(Respiratory impairment)
• Seizure

5%-29% of people have these symptoms

• Stroke

Diagnosis

Carbamoyl phosphate synthetase I deficiency (CPS1 deficiency) is diagnosed based on clinical examination, symptoms, biochemical and genetic testing. Some states in the United States screen for CPS1 deficiency as part of newborn screening. Tests may include:

• Arterial blood gas
• Blood ammonia
• Blood glucose
• Plasma amino acids
• Urine organic acids
• Genetic tests
• Liver biopsy
• MRI or CT scan

Treatment

Treatment for carbamoyl phosphate synthetase I deficiency (CPS1 deficiency) includes aggressive removal of excess ammonia during an episode of hyperammonemia. CPS1 deficiency is also managed by a special low protein diet that includes supplements and additional medications. Other treatment is based on the symptoms. Seizures can be treated with specific anti-seizure medications. In severe cases, liver transplant may be an option.

Initiate intravenous infusion of 10% glucose (or higher, if administered through a central line) and lipids. Intravenous sodium benzoate and sodium phenylacetate may be helpful. Arginine is usually administered with benzoate and phenylacetate. This is best administered in the setting of a major medical center where facilities for hemodialysis in infants is available. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Glycerol phenylbutyrate (Brand name: Ravicti)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 (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).