home»conditions»urea cycle disorders

Urea Cycle Disorders (UCD)

What is Urea Cycle Disorder?

Urea cycle disorders are a group of inherited diseases characterised by incomplete ‘metabolism’ or processing of nitrogen. This metabolic fault causes ammonia to build up in the blood, which poisons the brain.

After we eat protein, our bodies break them down into amino acids. As part of this processing, nitrogen is generated as a waste product. A multi-step pathway of reactions known as the urea cycle is responsible for removing this nitrogen from the blood, turning it into urea and excreting it via the kidneys in urine. The steps of the pathway require enzymes and/or ‘co-factors’ (enzyme helpers) that perform a specific task in the overall processing of nitrogen to urea. In individuals with urea cycle disorders, one of the enzymes or an enzyme ‘co-factor’ from the pathway is absent or has reduced activity. The consequence of the deficiency is that the urea cycle produces ammonia instead of urea.

There are six different types of urea cycle disorders. Each is named after the deficient urea cycle enzyme or, in the case of NAGS, a deficient co-factor:

• arginase deficiency (ARG)
• argininosuccinate lyase deficiency (ASL)
• argininosuccinate synthetase deficiency (ASS)
• carbamyl phosphate synthetase deficiency (CPS)
• N-acetylglutamate synthase deficiency (NAGS)
• ornithine transcarbamylase deficiency (OTC)

Animal proteins are found in dairy products, meat, eggs and fish. Proteins are also found in plants including soy, legumes, grains and nuts. The body uses the amino acids from proteins to make its own proteins essential for life – for example enzymes; structural proteins in muscles, hair, skin, cells and cartilage; proteins that generate movement in muscles; or those involved in cell functioning or immune responses. Requirements are higher in childhood as proteins are needed to support growth and development. Certain amino acids must come from the diet, as the body cannot manufacture them itself. These are known as ‘essential’ amino acids. In periods of fasting or illness, the body often switches to use its own proteins, and stored fats, to generate energy.

How common are the urea cycle disorders?

Overall, urea cycle disorders are thought to occur in at least 1 in 30,000 individuals globally, although this may be an underestimation of the true prevalence. OTC is the most common condition, affecting 1 in 30,000 people. CPS and ASL are seen in 1 in 60,000 and 1 in 70,000 individuals respectively. The remaining conditions, NAGS, ASS and ARG, are much more rare.

What causes urea cycle disorders?

In CPSI, OTC, ASS and ASL, the condition is due to a defect in the gene that codes for an enzyme of the urea cycle. The enzyme has reduced activity or is missing completely as a result. A genetic defect is also responsible for NAGS, although the gene codes for an enzyme co-factor.

NAGS, CPS, ASS, ASL and ARG are recessively inherited genetic disorders, meaning that a child would only have the condition if both parents ‘carry’ the genetic mutation. Genes are arranged in structures called chromosomes that contain two strings or ‘alleles’. Offspring inherit one allele from their father and one from their mother. Carrying one copy of the mutated recessive gene does not affect health, but when two mutated copies come together, the linked enzyme is deficient either in quantity or effect and the disease is expressed. For each and every pregnancy, there is a 1 in 4 chance of two carriers of the genetic mutation having a child with the disease. 

OTC, however, is X-linked, so it is mainly male infants who are affected. In X-linked diseases, the condition is only passed to infants if the mother is a carrier with a defective X chromosome. Women have two X chromosomes so the normal X chromosome will mask a defect on the other X chromosome to a certain degree. Therefore, female offspring of a carrier mother will either be carriers of the disease and show no symptoms or will have a mild version of the disease. In males, there is one X chromosome and one Y chromosome so any defect on the X chromosome will be expressed and they will show the full features of the disease. 

What are the symptoms and signs of urea cycle disorders?

The severity of urea cycle disorders varies according to how early the symptoms appear, the degree of residual enzyme activity and the position of the affected enzyme or co-factor within the urea cycle.

OTC in boys and CPS present very early, perhaps in the first few days of life, as do cases of ASS, ASL and NAGS with complete loss of enzyme or co-factor activity. Individuals with such early-onset variants typically have severe disease features and a poor prognosis. They seem healthy at birth but protein intake triggers symptoms due severe accumulation of ammonia in the blood. Early signs are vomiting, problems with feeding and extreme tiredness. Progressive brain damage manifests as poor muscle tone, seizures and abnormally fast breathing (hyperventilation). The liver may also become enlarged. Untreated, there is a high risk for these infants to fall into a coma and die. 

Alternatively, symptoms may not develop until later in childhood in some individuals with CPS, ASS, ASL or NAGS. In these cases, there is usually some remaining enzyme activity, ammonia levels are not as high as in the early-onset variant and the disease manifestations are not immediately life-threatening. These children normally have a history of nausea after eating high-protein foods, or of periods of irritability, hyperactivity, frequent vomiting and extreme tiredness.

In some, for example those with relatively mild disease or females with OTC, the disease remains hidden until adulthood. A history of disliking protein-rich foods, vomiting, periodic unusual behaviour and symptoms of mental illness may be the only clues that a problem exists.

For both categories of late-onset urea cycle disorders, illness, fever, accidents, surgery or certain medications can trigger a ‘crisis’ in which ammonia levels in the blood rapidly increase, bringing the risk of brain damage and coma. The crises are due to the body breaking down stored proteins, causing toxic ammonia to accumulate in the blood. Symptoms of high ammonia levels include hallucinations, sleep disorders, delusions and vomiting.

ARG is different from the other urea cycle disorders as its symptoms develop much more slowly. Individuals rarely have raised ammonia levels and the main disease features are delayed development, reduced growth, abnormal muscle tone (spasticity) and tremor.

How are the urea cycle disorders diagnosed?

Diagnosis of urea cycle disorders can be difficult and infants with the early-onset form are frequently misdiagnosed as suffering from severe infection. The characteristic finding in those with urea cycle disorders is that of high ammonia levels in the blood plus a normal blood glucose level and normal anion gap. An anion gap is simply a measure of various biochemical substances in the blood.

Amino acid analysis of the blood helps pinpoint the precise disorder, as can measuring the level of an acid called orotic acid. Additionally, liver samples may be taken to assess the activity of specific enzymes from the urea cycle. DNA tests confirm the diagnosis by identifying the genetic mutation at fault. Finally, magnetic resonance imaging (MRI) and computed tomography (CT) can help determine the degree and type of brain damage.

How are urea cycle disorders treated?

Management of urea cycle disorders comprises dietary manipulation to reduce the protein load, and therefore the burden on the urea cycle, and treatment to reduce the levels of ammonia in the blood.

A diet is prescribed that is sufficiently low in protein to avoid excessive ammonia production but high enough to sustain proper growth and development in children. Several low-protein products are available to help achieve this goal. The balance of protein, carbohydrates and fat must ensure that adequate calories are ingested, to protect against the body breaking down its own sources and therefore creating more ammonia. The balance must be adjusted over time to reflect children’s changing nutritional needs. This reduced-protein diet needs to be continued indefinitely and must be closely monitored by a dietician. Alongside the diet, specially formulated powders containing a balanced mix of essential amino acids are given, to avoid malnutrition of these important elements. In some cases, amino acids such as arginine or citrulline are supplemented, depending on the urea cycle disorder.

Multiple vitamin and calcium supplements are also recommended.

During periods of illness, fasting and infection, aggressive treatment is initiated to prevent the body breaking down its own energy stores. This comprises limiting protein intake and giving glucose and additional fluids. Sufferers are advised to avoid long periods of fasting; for example, by eating a snack at bedtime to reduce the period of overnight fasting.

Ammonia-reducing treatments include arginine chloride, which blocks the production of ammonia, and nitrogen-scavenging drugs (sodium phenylacetate, sodium phenylbutyrate and sodium benzoate), which ‘mop up’ the nitrogen and prevent it from being turned into ammonia. Dialysis is useful particularly where ammonia levels are significantly elevated. In some patients, liver transplantation may be required.

There is no cure for the urea cycle disorders. Early diagnosis and appropriate treatment of urea cycle disorders are often critical as even individuals with milder disease are at risk of permanent brain damage, coma and death if left untreated.