Urea cycle disorders are hereditary metabolic disorders in which there is a defect in the breakdown of amino acids. This results in excessive levels of ammonia in the blood. In healthy persons, the ammonia is being removed by certain enzymes who convert the ammonia into urea. The enzymes move the urea through the body via the bloodstream and kidneys where it will eventually be excreted in the person's urine. Patients with an urea cycle disorder have a deficiency in these enzymes causing an inability to remove the ammonia.  

There are different types of urea cycle disorders. The type of disorder depends on which enzyme is deficient. Below is an overview of the different types. 

NAGS, N-acetylglutamate synthase.
CPS1, carbamoyl phosphate synthetase.
OTC, ornithine carbamoyltransferase.
ASS, argininosuccinate synthetase.
ASL, argininosuccinate lyase.
AR, arginase. 

In addition, there are also certain amino acids transport disorders involved in the urea cycle. These include the following disorders:

HHH: hyperammonemia-hyperornithinemia-homocitrullinuria.
LPI: Lysinuric protein intolerance.

The incidence numbers of urea cycle disorders differ per type. Exact numbers can also be different per country. Estimates range from 1 in 35,000 to 1 in 2 million, averaging 1 in 50,000.

The cause of urea cycle disorders lies in our DNA. Flaws in the DNA cause a deficiency of enzymes or a production of enzymes who do not work properly. Urea cycle disorders are inherited disorders (exceptions are possible). In most cases, the parents are carriers of the disorder but do not have symptoms themselves.  

Symptoms of urea cycle disorders vary from patient to patient. In infants, drowsiness can be seen with rapid breathing. An infection around birth can worsen this. The disease can also sometimes manifest later in life. In older children and adults, the disorder may come to light because of a viral infection. 

In milder forms, developmental disabilities and abnormal behavior may be the first manifestation of the disease. In very mild cases, a reluctance to eat protein products and (chronic) vomiting after ingesting more protein may prompt the diagnosis. The greatest danger is the development of coma due to high ammonia. This can be life-threatening.

When an urea cycle disorder is suspected, the doctor will do a number of tests to make the diagnosis. For example, the doctor will do blood and urine and sometimes liquor tests to measure ammonia levels and amino acids. Sometimes, with arginase deficiency, a skin biopsy is done in which the enzyme activity in the skin cells is being measured. Very sporadically, the doctor will do a liver biopsy. 

Imaging may also be part of the diagnostic tests. For example, to determine whether there are abnormalities of the liver and/or kidneys. The following tests may be used: 

• Ultrasound 
• CT scan
• MRI 
• EEG (electrical activity of the brain).

Long-term treatment

Treatment of urea cycle disorders consists of following a protein-restricted diet to reduce the risk of high ammonia levels in the patient's blood. Proteins are a very important part of a healthy diet and limiting too much protein can cause harm to the body in relation to growth and development. Therefore, patients with an urea cycle disorder take supplements and extra vitamins and minerals to make up for the limited protein intake.  

Medication

Depending on the type of urea cycle disorder, patients may additionally be treated with medication. For example, you or your child may be treated with citrulline or arginine. These medications help convert ammonia to urea. Other medications include sodium benzoate and sodium phenylbutyrate. These two medications help to remove the ammonia from the patients blood. For the NAGS deficiency type of urea cycle disorder, the medicine carglumic acid is sufficient.
 
To administer these treatments properly, it may be necessary to use a gastrostomy tube or PEG-tube. This is a tube which is inserted directly in the stomach. A plastic disc under the skin secures the tube.  Another way to administer the medicine is the use of a port-a-cath (port). This is a small device implanted under your skin with continuous access to large blood vessel.

Treatment to prevent coma 

High ammonia levels in the blood are very harmfull and can put the patient in risk for coma. Patient with a risk for coma can sometimes be treated with only medications, but in the worst case dialysis is necessary. Protein intake must be stopped and is replaced by sugars and fats. In doing so, it is important to provide plenty of calories. Also, the breakdown of own body proteins during fasting increases the risk of high ammonia.

Children with an urea cycle disorder are being seen by a metabolic pediatrician until the age of 18 years. After this, the patient will be transferred to metabolic internist. Patients with an urea cylce disorder will also see other medical specialist. For example, the primary care physician works closely with the metabolic dietitian because of the low-protein diet the patient must follow. Other specialists involved in the care of urea cycle disorders are:

• Pediatric neurologist
• Pediatric physical therapist
• Pediatric psychologist
• Pediatric nephrologist
• Pediatric gastroenterologist
• Social worker
• Clinical geneticist
• Internist

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