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Urea Cycle disorders

Background

In humans, protein rich foods are broken down to make energy for our bodies. After the energy is used up, waste substances like nitrogen are created. In the body, excess nitrogen in the form of ammonia (which is toxic in high levels) is converted to urea via the urea cycle. Urea is then simply cleared in the urine. The urea cycle disorders (UCDs) are a group of metabolic diseases where the urea cycle is unable to operate correctly. Ammonia levels can then build up, which causes certain symptoms. They are usually noticed in the first month of life, but symptoms may start at almost any age.

Credits

Last updated June 2014 by Dr M Champion, Consultant in Paediatric Inherited Metabolic Disease, Evelina London Children's Hospital, London, UK.

What are the symptoms?

High ammonia levels in the blood and brain cause irritability, poor feeding, vomiting, drowsiness and, in severe cases, coma.

The most common symptom of arginase deficiency is the neurological disorder spastic diplegia, where there is an abnormal increase in muscle tension and the muscles are tight and stiff. Developmental delay may also occur.

What are the causes?

The urea cycle has several steps, each catalysed (driven) by a different enzyme. UCDs occur when there is a deficiency (low levels or complete absence) of one of these enzymes:

  • N-acetyl glutamate synthase (NAGS) deficiency
  • carbamyl phosphate synthase (CPS) deficiency
  • ornithine transcarbamylase (OTC) deficiency
  • citrullinaemia (argininosuccinate synthase deficiency)
  • argininosuccinic aciduria (argininosuccinate lyase deficiency)
  • arginase deficiency

The most common UCD is OTC deficiency.

Each condition results from a fault (mutation) in the gene that codes for the enzyme involved.

N-acetyl glutamate synthase (NAGS) deficiency

NAGS gene

carbamyl phosphate synthase (CPS) deficiency

CPS1 gene

ornithine transcarbamylase (OTC) deficiency

OTC gene

citrullinaemia (argininosuccinate synthase deficiency)          

ASS1 gene

argininosuccinic aciduria (argininosuccinate lyase deficiency)

ASL gene

arginase deficiency           

ARG1 gene

How is it diagnosed?

The diagnosis of a UCD requires tests on blood to look at ammonia levels, the pattern of the building blocks of protein (amino acids) and a urine test (organic acids) to look for substances found in UCDs.

The diagnosis is then confirmed on either an enzyme test to prove that the enzyme is not fully working or a gene test to identify where the fault in the gene has occurred.

How is it treated?

The main aim of treatment is to keep the level of ammonia in the blood at a safe level. UCDs are usually treated with a low protein diet and medicines such as sodium phenylbutyrate, sodium benzoate or carbamylglutamate. Arginine or citrulline may be supplemented to help the urea cycle work harder in removing the ammonia.

Infections or a sudden increase in the amount of protein eaten can cause blood ammonia levels to rise. During periods of infection, protein intake is stopped, and special high energy drinks are given (glucose polymer) or glucose is given intravenously (in a vein). If levels of ammonia are very high, dialysis may be used to control and bring down levels down more quickly.

Inheritance patterns and prenatal diagnosis

Inheritance patterns
Mutation in CPS1, ASS1, ASL, NAGS, and ARG are inherited in an autosomal recessive manner. OTC deficiency is inherited in an X-linked manner.

Prenatal diagnosis
Prenatal diagnosis is available for all the conditions, if the mutation in the family is known. Affected families should seek genetic advice.

Is there support?

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