Urea Cycle Defect: Causes, Symptoms & Treatment

If the medical profession speaks of a urea cycle defect, it uses an encroachment that predominantly affects several metabolic diseases, which on the one hand have a genetic origin and on the other hand are responsible for a disturbed nitrogen excretion. If left untreated, the urea cycle defect leads to the death of the patient. Liver transplantation represents the only form of therapy to correct the urea cycle defect.

What is urea cycle defect?

A urea cycle defect usually serves as an umbrella term for several metabolic diseases, all of which have impaired nitrogen excretion. Another common feature is said to be genetic origin; such metabolic diseases can therefore be inherited. Since a urea cycle defect leads to a pathological increase in the nerve toxin ammonia, the disease – if not treated in time – leads to brain damage and subsequently to death. It should be noted that there are six different enzyme defects. Symptoms may vary, depending on age and initial manifestation.

Causes

Urea cycle defects are inherited in an autosomal recessive manner. The only exception is OTC deficiency; OTC deficiency is inherited exclusively in an X-linked recessive manner. Occasionally, spontaneous mutations can also occur. This means that the urea cycle defect is not inherited, but the genetic defect has arisen spontaneously. Urea cycle defects are therefore congenital metabolic disorders of the liver that are potentially life-threatening. In this case, there is not only an increase in the ammonia level, but also a disturbed protein breakdown. Due to an existing deficiency of certain enzymes, the body is unable to subsequently convert the ammonia, a toxic intermediate product, into urea. This inevitably leads to an increase in ammonia levels, with the neurotoxin being deposited in the blood and other tissues. There is a risk of brain and nerve damage, and the disease can sometimes lead to the death of the patient. To date, six enzyme defects are known to be responsible for urea cycle defect:

  • Carbamyl phosphate synthetase (CPS)-1 deficiency.
  • Ornithine transcarbamylase(OTC) deficiency
  • Argininosuccinate synthetase(ASS) deficiency (citrullinemia type 1).
  • Argininosuccinate lyase(ASL) deficiency (argininosuccinic acid disease).
  • Arginase-1 deficiency (hyperargininemia).
  • N-acetylglutamate synthetase (NAGS) deficiency.

Why such deficiencies occur has not yet been elucidated.

Symptoms, complaints and signs

Symptoms vary, depending on age and initial manifestation. Therefore, they are predominantly based on the age of the affected person. In infancy, vomiting, an extremely excessive respiratory rate, seizures, and also decreased fluid intake are possible. At times, the infant may lapse into a coma. In infancy, seizures are recurrent; behavioral disturbances, growth deficits, and also decreased food as well as fluid intake could also be observed. The patient is also at risk of falling into a coma in infancy. The following symptoms are predominantly seen in adolescents and adults: Affected individuals are irritable, lethargic, often confused, suffer recurrent nausea and vomiting, and feel listless. In severe forms, patients may also fall into a coma. Depending on the clinical picture, the symptoms can vary. On the one hand, they may be particularly intense, but on the other hand, they may occur only mildly.

Diagnosis and course

If symptoms that suggest a urea cycle defect sometimes exist, laboratory tests are performed. In these tests, physicians detect an excessive level of ammonia in the blood. The diagnosis can be substantiated, for example, by a genetic test, in which the identification of the mutation is checked. Severe disease progressions result predominantly from defects in the first three enzymes. Basically, the enzyme deficiency is responsible in further consequence, which disease course has to be feared. Higher residual activities usually cause chronic courses, although these only become apparent after the neonatal phase. If the urea cycle defect is treated incorrectly or not at all, brain and/or nerve damage will inevitably result.Subsequently, an untreated urea cycle defect leads to the death of the affected person. It does not matter which enzyme defect is present. All enzyme defects, if left untreated, can lead to death.

Complications

Without treatment, urea cycle defect leads to the death of the patient in most cases. For this reason, urgent treatment of this disease is necessary for the patient. This will also prevent complications and secondary damage. The affected person usually suffers from nausea and vomiting due to the urea cycle defect. In addition, there are cramps associated with severe pain. Gasping for breath occurs and it is not uncommon for a panic attack to occur. Likewise, the affected person may lose consciousness or even fall into a coma. It is not uncommon for those affected to suffer from behavioral disorders, which can have a negative effect on the development of children in particular. Patients are usually confused and easily aggressive. Sleep disturbances also lead to mild irritability. If the defect is not treated, in most cases the patient’s life expectancy is greatly reduced and eventually death occurs. The treatment itself does not lead to further complications. However, the affected person may be dependent on dialysis for a liver transplant. In most cases, further symptoms depend on the underlying disease.

When should you see a doctor?

Because urea cycle defect can lead to death in the worst case, it must be treated by a physician. Self-cure does not occur with this condition. Urea cycle defect can occur even in children or infants. It leads to vomiting or a high respiratory rate. If parents notice these symptoms, a doctor should be consulted. Complaints and irregularities in growth also indicate the disease. Furthermore, the disease leads to seizures or difficulty drinking. Those affected suffer from behavioral disorders and are often aggressive or irritable. Confusion also frequently indicates urea cycle defect. The severity of the symptoms can vary greatly, so they do not always have to be a symptom of the defect. However, since the disease can only be cured by transplantation of the liver, an examination should always take place as a precaution if said symptoms are noticeable. As a rule, the urea cycle defect can be diagnosed by an internist. The treatment then takes place with the help of a surgical intervention in a hospital. Whether there will be a positive course of the disease cannot generally be predicted.

Treatment and therapy

Several therapies are available for treatment options. In the case of a neonatal manifestation of disease in which there is a risk to the life of the infant, intensive medical treatment is initiated. Such treatments, also known as acute therapies, take place primarily in metabolic centers. The goal of such therapies is for toxic ammonia levels to be lowered. The ammonia level is lowered, for example, by dialysis, whereby “blood washing” is only carried out when the ammonia concentration exceeds 400 µmol/l. The infants are not given any proteins. Infants are not given proteins; sometimes medications to help reduce blood ammonia levels are given. Sometimes hepatocellular therapy can also be successful. Such therapies are recommended primarily for infants; although liver transplantation would be more effective, the procedure is extremely stressful for the newborn, so many physicians refrain from it. The risk that the child will not survive the procedure is too high in almost all cases. In liver cell therapy, adult hepatocytes are obtained from the donor liver and then cryopreserved – free of bacteria – in a suspension. In the long term, physicians opt for dietary and drug treatment. It must be taken into account that that treatment must be carried out for the whole life. The only truly curative therapy, which sometimes corrects the urea cycle defect, is liver transplantation. Only when liver transplantation is performed can the urea cycle defect be corrected.

Prospect and prognosis

In many cases, the diagnosis of urea cycle defect does not lead to a normal life. The disease establishes limitations in everyday life.Only a long-term treatment can ensure the greatest possible freedom from symptoms. Affected persons have to reckon with restrictions in their diet when the hereditary disease arises. Blood washing and medication accompany life. A cure is impossible. If the defect is not recognized in time, brain damage usually sets in. Ultimately, the urea cycle defect then leads to death. Statistically, the disease occurs more frequently in certain phases of life. This is where the greatest risk prevails; however, in relation to all persons of one age group, the urea cycle defect represents a marginal phenomenon. Boys and girls in infancy and childhood are particularly affected. About 50 percent of all cases are attributable to this age group, which corresponds to just 80 newborns per year in Germany. Women also fall ill sporadically during pregnancy. In principle, cases in persons of full age have a marginal character. The long-term therapy aims at keeping the ammonia and glutamine concentrations of the blood in the normal range. This is achieved by maintaining a constant low-protein diet. If this procedure is followed, it is possible to lead a symptom-free life. Patients must demonstrate a high degree of discipline to achieve this.

Prevention

Because urea cycle defect is a genetic disorder whose origin is unknown and is usually inherited or results from spontaneous mutation, the metabolic disorder cannot be prevented.

Follow-up

Because self-healing cannot occur with a urea cycle defect and the disease is genetic, the options for aftercare for this disease are severely limited in most cases. The affected person is primarily dependent on a rapid diagnosis with subsequent treatment, so that there is no further worsening of the symptoms. In the worst case, this can lead to the death of the patient if the disease remains untreated. Patients are often dependent on the measures of dialysis. They also need the care and support of their own family and friends. This can also alleviate or completely prevent psychological upset or depression. When taking medication, patients should ensure that they take it regularly and also take the correct dosage to alleviate their symptoms. A healthy lifestyle with a balanced diet can also have a positive effect on the course of this disease. Should the affected person wish to have children, genetic counseling is advisable to prevent the recurrence of the disease in the children. Possibly, the life expectancy of the patient is reduced due to the disease.

What you can do yourself

A urea cycle defect is a serious disease that often takes a negative course. The most important self-help measure is to inform the responsible physician immediately of any unusual symptoms or to take the child to the nearest hospital. If a metabolic disease is actually present, treatment must be initiated immediately to avoid consequential damage. The individual symptoms can be treated with the known remedies and measures. Dietary measures as well as bed rest and rest are helpful against nausea and vomiting. Cramps can be relieved by sedation and the use of medicinal preparations. If the child shows signs of a panic attack or even becomes unconscious, the emergency physician must be called. In the case of behavioral disorders, behavioral therapy is useful, in which the parents should also participate. Through comprehensive training, irritability, aggressiveness and other conspicuities can be responded to in the best possible way, which at least reduces the risk of developmental disorders. In the long term, therapeutic counseling is also useful. In many cases, the disease leads to the death of the patient – a circumstance that represents an enormous burden for the affected child, but also for the relatives.