Collated and co-written by Rachael Sharman, Vice President MDDA.
Co-written and edited by Dr Jim McGill, Director Metabolic Medicine, Royal Children's Hospital, Brisbane, Queensland, Australia.Urea cycle disorders come in six different forms, each named after the missing or deficient enzyme.
CPS - Carbamyl Phosphate Synthetase
NAGS- N-Acetylglutamate Synthetase
OTC - Ornithine Transcarbamylase
ASD - Argininosuccinic Acid Synthetase (Citrullinemia)
ALD - Argininosuccinase Acid Lyase (Argininosuccinic Aciduria)
AG - Arginase
In normal protein metabolism, nitrogen (a waste product of protein metabolism) is converted to urea and removed from the body via urine. In these disorders, the deficiency of one of the above enzymes leads to a build up of nitrogen in the body, in the form of ammonia. High ammonia levels can cause brain damage or death.
All except OTC are inherited as autosomal recessive traits (that is, both parents are carriers of the faulty gene and all their children have a one in four, or 25% chance of inheriting the condition). OTC is referred to as a sex-linked or X-linked trait, meaning the mothers are carriers. In this case, male offspring have a 50% chance of inheriting the disorder, female offspring will have a 50% chance of becoming carriers. Some female carriers may exhibit characteristics of the disorder, and can have problems after childbirth as there is so much protein breakdown as the uterus shrinks.
Like other inborn errors of metabolism (IEM), symptoms can range in severity according to the level of deficiency of the particular enzyme. Babies with the worst deficiencies usually become unwell within the first few days of life due to vomiting and lethargy. Seizures, hypotonia (floppy baby), respiratory problems and coma may also occur.
Arginase deficiency presents with progressive spasticity and is often mistaken for cerebral palsy.
Children and adults with mild to moderate deficiencies have also been diagnosed. Clinical presentations have included individuals who exhibit an aversion to high protein foods (meat), mild to severe behavioural problems, frequent vomiting, increasing lethargy and some may have their symptoms misdiagnosed as psychiatric in nature. Hyperammonaemia may be also triggered by events such as viral infections, high-level activity or the intake of high levels of protein.
Treatment is similar to all IEproteinM and involves the usual balancing act of ingesting just enough amino acids required for normal growth and development whilst restricting excess protein that will trigger the build up of ammonia. Babies and children with severe forms also require medications/supplements (such as sodium phenylbutyrate and sodium benzoate)to provide alternate ways of removing nitrogen waste and therefore minimising the amount of ammonia in the blood. The amino acids, citrulline or arginine, which are both part of the urea cycle, are supplemented in CPS and OTC deficiencies. Arginine supplements are the basis of treatment in argininosuccinic aciduria. These children commonly require tube feeding by gastrostomy (a tube that is surgically implanted in the stomach) as there appetites are often poor and the medication not very palatable. Essential amino acid supplementation (these have less nitrogen than natural protein) and vitamin supplements may also be necessary for these children.
Main issues for families revolve around diet and the constant monitoring of ammonia and amino acid levels that is required. The diet for severe cases is very restrictive. Most feeds for severe cases are formula based and via the g-tube. Monitoring of ammonia levels is via blood test and the child can become rapidly ill if ammonia levels are too high. This means parents may be required to "drop everything" at a moments notice to get to hospital for immediate treatment. Some parents have chosen to have a portacath implanted (an intravenous line inserted under the skin) so treatment is as swift and painless as possible.
General prognosis if diet and treatment are maintained is very variable and depends on the type of urea cycle defect and the severity. Even with the best available treatment, those with severe disease who present in the neonatal period have a high chance of having some disability. Some do not survive infancy. Liver transplants have been tried with some success but there can be difficulties keeping the child stable and without damage while waiting for a suitable donor.
Children or adults who present for the first time at an older age, often do reasonably well, but this depends on the status of their nervous system at the age the diagnosis is reached.
With all forms, there is a risk of further episodes of decompensation and a diet plan for when the child is sick is essential (usually called an unwell regime) and early presentation to hospital, before symptoms progress, is essential to minimise the risk of further problems.