Information about urea cycle disorders


Frequently asked questions about urea cycle disorder treatment and management

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1. My child is suspected of having a urea cycle disorder. What tests should be performed?

The basic tests used to help diagnose urea cycle disorders are blood ammonia, plasma amino acids and urine organic acids. These laboratory tests measure substances that reflect how well the urea cycle is working. When there is a deficiency (block) in one of the enzymes in the urea cycle, certain chemical compounds build up behind the block and others are not adequately formed beyond the block. It is like the effects of a dam. Ammonia builds up in all urea cycle disorders and should be measured. Certain amino acids are elevated in some urea cycle disorders and decreased in others, depending on where the block lies. So amino acids should be measured in plasma isolated from blood (this is a single test that at one time measures all the amino acids; plasma is what is left in blood after you remove all of the red and white blood cells). Finally, urine is often needed to measure certain organic acids (primarily orotic acid and other organic acids that may affect the urea cycle). These tests are available at most Academic Medical Centers and Children's Hospitals.

2. Does my child need a specialist or can my pediatrician treat this disorder?

You need both. Ideally, the initial testing and the acute treatment for a urea cycle disorder should be done by a metabolic/genetic specialist experienced in treating these disorders. This metabolic specialist is often a Pediatric Geneticist and works in a hospital-based metabolic clinic that has a metabolic nutritionist, genetic counselor and social worker. This team approach offers the best chance for a good outcome. The metabolic team can then work with your pediatrician to provide ongoing care in a collaborative fashion.

3. Is DNA testing available and/or necessary to diagnose the disorders?

DNA testing is available for some of the disorders, but is not used as a general screening test. If the plasma amino acids and urine tests do not clearly confirm the diagnosis, more specialized testing is done. This may include obtaining blood, a skin biopsy or rarely a liver biopsy to measure the suspected missing enzyme or performing a DNA analysis on blood to identify the specific mutation or error causing the enzyme defect. These specialized tests can be obtained at an academic (university-based) medical center or Children's Hospital. These tests will usually have to be sent out for analysis, usually to one of the sites that are part of the Urea Cycle Disorders Consortium. The enzyme and DNA tests are usually done if a urea cycle disorder is strongly suspected and as yet undiagnosed. The DNA testing may also be done to help in genetic counseling of other family members, family planning, or in prenatal diagnosis.

4. My child has been diagnosed with a urea cycle disorder. Are my other children at risk and should they be tested?

This issue should be taken up with you metabolic specialist who can arrange any testing that is needed for your other children or yourself. Urea cycle disorders are genetic conditions; therefore there may be a risk for other members in your family. However, if your child has the newborn-onset form (presenting within the first month of life) of the disorder and you have other older children who have not been symptomatic, it is most unlikely that they will be affected. Even in the late-onset form (presenting after the first month of life) of urea cycle disorders, children will usually exhibit protein intolerance and intermittent symptoms. So if you have other children who do not have clinical signs of hyperammonemia they are probably all right, but testing is available if you are worried. In the case of OTC deficiency, which is usually passed on from the mother, there may be risks for the mother's sisters or their families and testing should be arranged. This issue of risk should be taken up with your metabolic specialist or genetic counselor who can arrange any testing that is needed for your other children, yourself or other family members.

5. My toddler has been diagnosed with a urea cycle disorder and refuses to eat sometimes, or has a temper tantrum when we try to feed him. Why is placement of a gastric tube advised for administration of medications and in case my child gets sick and will not eat?

Many families worry about the placement of a gastrostomy tube. These tubes can be a real stress reliever for you and your child around feeding issues. It is very common for children with urea cycle disorders to have eating problems. This may include a lack of appetite, physical difficulty eating, or behavior problems. Unlike children who don't have one of these conditions, the diet of a urea cycle patient must be very carefully regulated and consistent. There are a number of reasons for the frequency of these eating problems that involve both the biology of the disease, learned behaviors, and the taste of the medicine and formula. While ideally it is best for your child to eat by mouth, this is not always possible. If he/she is not gaining weight, you find that eating issues become a negative focus of the family's life, or taking medications by mouth becomes a constant battle, the gastrostomy tube (G-tube) may be the answer. It can provide an effective alternative means of feeding and providing medication. There are certain risks in inserting and maintaining a G-tube and these should be discussed with your doctor. In general, however, children with urea cycle disorders who require G-tubes have benefited from them with improved weight gain, better metabolic contro, fewer and/or shorter hospital admissions and fewer behavior problems. These tubes are usually placed by a pediatric surgeon experienced in this procedure.

6. My child has had periodic hyperammonemic episodes sometimes characterized by lethargy and other times hyperactivity or agitation. Why does my child exhibit these contradictory symptoms?

The interaction between ammonia and the brain is not well understood. The elevations in ammonia and the other urea cycle-related amino acids (like glutamine) can affect different parts of the brain in different ways. Sometimes this makes a child sleepy and sometimes it makes them agitated. Both can be signs of an onset of hyperammonemia. It really depends on which part of the brain and which chemicals are affected first. In general, however, agitation and hyperactivity tend to occur prior to lethargy in a hyperammonemic episode.

7. How high does the ammonia level have to be to cause damage to my child? At what level should my child receive treatment to lower the level?

This is a difficult issue, and we don't really have a good answer. There appears to be a lot of individual variation. Some urea cycle patients get symptomatic at moderate ammonia levels (over 50-60 micromoles/liter) while others only become symptomatic at much higher levels (in the 100's or more). In general, the fewer the symptomatic hyperammonemic episodes, the better the developmental outcome. Also, the better the long-term metabolic control of the urea cycle disorder the better the outcome. Careful monitoring of your child's overall mental state is sometimes a more reliable measure of how they are doing. The response to a blood level of ammonia can change with the age of the child and that can also be confusing. Whenever your child becomes symptomatic or you think he may be at risk (such as during a viral illness), the metabolic team should be consulted and usually an ammonia level checked. If you can't get in touch with your metabolic specialist, take your child to the Emergency Department of the hospital that treats your child. The blood test for ammonia is difficult to perform properly and should only be done in a medical setting and laboratory experienced in the processing and handling of these samples. The ammonia level should be evaluated by a metabolic physician experienced in your child's case and urea cycle disorders. Working with you, the metabolic team can determine what treatment is best for your child. Remember that changes should only be made in close consultation with your metabolic treatment team. When you are traveling it is always useful to get the name of a metabolic physician or hospital that can treat your child if he/she gets sick.

8. How often should my child’s ammonia levels and amino acid levels be monitored?

This should be determined by your metabolic specialist. Depending on the severity of the disease and the age of your child, this can vary from weekly to several times a year.

9. Will my child ever grow out of this disorder or will he always have to take medications and be on a special diet?

Your child was born with a genetic change that caused deficient or absent activity of one of the urea cycle enzymes. This absence/deficiency will remain throughout your child's life. Y our child will not "grow out" of the disease. The severity of his clinical condition , however, may change with age. We hope someday to provide a "genetic fix" for these patients but the technology is not ready yet.

10. If protein can make my child ill, wouldn’t it be better to not give him any protein at all?

We all need some protein for our bodies to grow and repair our tissues. The restriction of protein in a urea cycle patient is a delicate clinical issue. There are many amino acids (subunits of protein) that the body cannot make on its own and must get from protein in the diet. Without these outside sources of protein and amino acids the body will break down its own protein. This break down of body protein releases ammonia which can cause hyperammonemia as bad as or worse than too much protein in the diet. Proper management of a urea cycle disorder patient involves tailoring the diet to give enough protein for growth but not more than can be handled by the broken urea cycle. This balance is difficult to achieve and changes in protein intake should be made in close consultation with the metabolic treatment team.

11. How can you determine the difference between a hyperammonemic episode from too much protein intake as opposed to insufficient protein intake?

This is best done by examination of the amino acid levels in the blood stream. If certain amino acids levels are low or high, your metabolic doctor can determine if the patient is breaking down protein from the body or taking too much in. Surprisingly, more patients probably become hyperammonemic from breaking down their own protein than from overdosing in their diet. This is particularly common during infections or times of stress (such as fever or decreased food intake) when the body's metabolic needs are greatest. You should discuss plans for these stressful times with your doctor before they occur.

12. What can trigger hyperammonemic episodes?

Anything which places increased stress on the patient can trigger an episode. Viral infections are probably the most common cause, but episodes can be triggered by physical or emotional stress, dehydration, trauma, broken bones, the menstrual cycle, certain medications (like valproic acid), and changes in the diet.

13. My 1-year-old has just been diagnosed with a UCD. Will my child be retarded? Will my child be able to live a normal life?

Your child with a urea cycle disorder will face many challenges in life. The outcome and the affect on their life will depend a great deal on how sick they were when they were diagnosed and how severe their defect in the cycle is. Most patients presenting with a hyperammonemic coma have some degree of delay in their development (mental retardation is defined as a measurable delay in the normal development of skills and intellect). Some of these children have delayed speech -- they start talking later than unaffected children -- or learning disabilities. Patients with severe defects in their urea cycle require treatment with many drugs and strict dietary controls. While this will complicate their daily routine, they can grow up and participate in school, play, and work. This disease does not prevent them from being loving and beloved members of their family.

In general, children who are diagnosed after the newborn period and don't have a severe hyperammonemic crisis are less severely affected. It means that their enzyme deficiency is not a complete deficiency, and they have some capacity to get rid of ammonia. This offers some protection to the brain. These "late-onset" cases can have normal intelligence and may live a fairly normal life. They will, however, need to practice protein restriction and take medications throughout their life. While most children with late-onset urea cycle disorder are not severely mentally disabled, many have milder disabilities such as attention deficit hyperactivity disorder or learning disabilities. All patients with urea cycle disorders should probably receive some form of periodic evaluation of developmental and mental function and may greatly benefit from early interventional therapies, such as speech and occupational therapy. The Urea Cycle Disorders Consortium is conducting a long-term study to find out how well urea cycle disorder patients do with current treatment and therapies.

14. My child has developmental delay. Will my child ever catch up to his peers?

With developmental intervention programs and careful medical management, urea cycle patients can catch up with their peers. However, most patients who experience a severe hyperammonemic episode will have some degree of developmental delay. The duration of the hyperammonemic episode (particularly coma) does affect the outcome, with longer episodes causing worse damage to the brain. In addition to developmental delay, urea cycle patients are also at risk for milder disabilities such as attention deficit disorder or learning disabilities. If your child has a urea cycle disorder, your metabolic treatment team should arrange periodic assessment by a developmental specialist. Your child should be enrolled in an appropriate developmental intervention program at an early age based on their medical condition or developmental assessment. In some states, the therapists will come to your home and some state/federal/private insurance programs will cover these costs. These programs can really make a difference and are an important part of your child's overall treatment plan. Your metabolic treatment team will be familiar with the resources available in your area.

15. What is the life expectancy of a child with UCD?

We don't know the complete answer to this question. While the life expectancy of many of our most severely affected patients is shortened, new improvements in diagnosis and treatment may improve their outcome. We are currently engaged in a study to answer that question. The last study occurred almost 20 years ago when modern therapy was just being developed. The results then were not encouraging. About half of children with newborn onset disease did not survive to age 5 years. Neonatal-onset OTC and CPS1 deficiencies seemed to have a worse prognosis than the other urea cycle disorders. Many of these children are now being treated with liver transplantation (a procedure with its own serious risks and complications). Others are surviving because of improved medical management, so we believe the survival rate is much better now. The survival for the late-onset cases (presenting outside the newborn period) seems to be quite good, but there is still a significant risk of a life-threatening or debilitating hyperammonemic episode, so symptoms should always be taken seriously.

Expanded newborn screening has helped identify urea cycle children with ASA-lyase, citrullinemia and arginase deficiency before they become seriously ill. We are seeing the outcomes for these patients in most cases being better than that of children diagnosed after they become ill.  A newborn screen for OTC deficiency is being tested and, once approved, we believe will make a significant difference in saving the lives and improving the outcomes of children with OTC deficiency.

16. We have had a child with a urea cycle disorder and want to have more children. Will subsequent pregnancies be affected? Is prenatal testing available?

Because urea cycle disorders are genetic disorders, there is often a risk for future children having the disorder. Prenatal testing is available for all of the urea cycle disorders. Working with a metabolic specialist, a genetic counselor and your obstetrician can help you determine what type of testing is best, and when it should be done. Preimplantation Genetic Diagnosis (PGD) is available to families with identified mutations who wish to plan for more children. This involves implanting pre-selected embryos which do not have the mutation.  We recommend that you contact a counselor either before you are pregnant or as soon as you know so that testing can be more easily arranged.

17. Why isn’t liver transplant recommended for all children with urea cycle disorders?

Liver transplantation is sometimes the best therapeutic option for urea cycle patients. However, there are substantial risks to the procedure and long-term serious medical issues. The decision to transplant a urea cycle disorder patient is best made working closely with your metabolic specialist.


18. We live in a community where we only have access to a small community hospital. Will they be able to care for my child if he has a crisis? What should we do?

Most small community hospitals cannot deal with a major hyperammonemic episode. However, with the advent of regional patient transport systems most patients can be moved to a large hospital with the proper facilities and personnel very rapidly. With careful coordination between your metabolic specialist and local healthcare providers, many of the treatments for milder episodes and routine care can be done near your home. It is important that the hospital that treats your child has intravenous benzoate/phenylacetate (Ammonul) available in the case of a hyperammonemic crisis.

19. Why isn’t there a cure or better treatment for urea cycle disorders?

Since urea cycle disorders are genetic diseases affecting one of the most basic pathways in the body, a cure is very difficult. The cells in the body do not have the proper instructions to make a urea cycle that works. Researchers are working on new methods to deliver healthy urea cycle genes to replace the defective ones. This may cure some patients with urea cycle diseases. Liver transplantation fixes many of the problems with urea cycle diseases but has its own side effects and consequences. We have drugs that work to help patients with urea cycle disorders but do not cure the underlying causes. Part of the work of the NUCDF is to stimulate and support research to develop and test new treatments and therapies.