The basic tests to make the diagnosis 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 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 is. A blood test called quantitative plasma amino acids can be obtained to determine these levels. A urine test for organic acids is often needed to measure levels, 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, including the 8 UCDC centers. DNA testing may be obtained from specialized labs to identify the specific genetic change responsible for the disorder.
DNA testing is available for all of these disorders, but is not used as a general screening test. DNA testing does not identify the responsible genetic changes in all patients. If the plasma amino acids and urine tests do not 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 to identify the specific mutation or error causing the defect. These specialized tests can be obtained at an academic (university-based) medical center or children's hospital but will need to be sent out for expert analysis, frequently 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. DNA testing may also be done to help in counseling of other family members about genetic risk or in prenatal diagnosis.
Urea cycle disorders are genetic conditions; therefore there may be a risk for other members in your family. In the case of OTC deficiency, which is usually passed on from the mother to a son, there may be risks for the mother's sisters or their children and testing should be arranged. You should discuss this issue of risk with your metabolic specialist or genetic counselor who can arrange any testing that is needed for your other children, yourself or other family members.
Because urea cycle disorders are inherited disorders, there is often a risk for future children inheriting the disorder. Prenatal testing is available for all of the urea cycle disorders. Your metabolic specialist, a genetic counselor and your obstetrician can help you determine what type of testing is best, and when it should be done. It is recommended that you contact a genetic counselor either before you are pregnant or as soon as you know so that testing can be arranged in the most optimal time in the pregnancy.
Many families worry about the placement of a gastrostomy tube. The positive side is that these tubes can be a stress reliever for you and your child around feeding issues. It is not uncommon for children with urea cycle disorders to have eating problems. This may include a lack of appetite, physical difficulty eating, or behavioral problems. Unlike in healthy children the diet of a urea cycle patient need to be carefully regulated. 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 becomes the focus of family's life, or taking medications by mouth becomes a constant battle, a gastrostomy tube (G-tube) may be useful. It can provide an effective alternative means of feeding and providing beneficial medications. In general, children with urea cycle disorders who receive G-tubes have benefited from them with improved weight gain, better metabolic control and less instability from ammonia elevations, and less behavioral problems. These tubes are usually placed by a pediatric surgeon experienced in this procedure.
The interaction between ammonia and the brain is not well understood. The elevations in ammonia and 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 depends on which part of the brain and which chemicals are affected first. In general, in some children agitation, unusual irritabiity or hyperactivity tend to be first symptoms of an impending hyperammonemic episode. In other children, lethargy is one of the first symptoms or may follow a period of unusual irritability or hyperactivity.
This is a difficult issue, and we don't really have a good answer. There appears to be a lot of individual variation in the types of early signs or symptoms a child or adult with UCD may exhibit as their ammonia level rises. Very often the early signs are recognized. Some urea cycle patients have recognized symptoms at moderate ammonia levels (over 50-60 micromoles/liter) while others may not have symptoms that are recognized until much higher levels (in the 100's or more). In general, the better ammmonia levels are controlled, and the fewer hperammonemic episodes, the better the developmental outcome. Also, the better the long-term metabolic control of a urea cycle disorder the better the outcome. Careful monitoring of your child's overall mental state is sometimes a more reliable measure of how he/she is doing. The response to a blood level of ammonia can change with age. Whenever your child becomes symptomatic or you think he or she may be at risk (such as during a viral illness), the metabolic team should be consulted and usually an ammonia level checked. If you cannot get in touch with your metabolic specialist or if the symptoms are progressing, take your child to the emergency room. 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 samples for this test. The ammonia level should be evaluated by a metabolic specialist 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 obtain the name of a metabolic physician or hospital that can treat your child if he or she becomes sick.
Your child with a urea cycle disorder will face many challenges in life. The outcome and the effect on their life will depend a great deal on how sick they were when they were diagnosed and how deficient their urea cycle is. Most patients presenting with a hyperammonemic coma have some degree of delay in their development (developmental delay is defined as a measurable delay in the normal development of skills and intellect). Patients with complete defects in their urea cycle require treatment with many drugs and strict dietary controls and may need liver transplantation. 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 loved members of their family.
In general, children who are identified with UCDs on newborn screening, or are diagnosed after the newborn period and don't have a severe hyperammonemic crisis are less severely affected. This means that their enzyme deficiency is not severe and they have some capacity to get rid of ammonia. This offers some protection to the brain. These "late onset" patients can have normal intelligence and may live a fairly normal life. They may, however, need to practice protein restriction and take medications throughout their life. While most children with late onset urea cycle disorder do not have severe developmental delays, many have milder disabilities such as attention deficit hyperactivity disorder or learning disabilities. All patients with urea cycle disorders should receive some form of periodic evaluation of developmental and neurocognitive function. The UCDC is conducting a long term study to find out how well UCDC patients do with modern treatment and therapies (5101- Longitudinal Study of Urea Cycle Disorders).
We are currently engaged in a study to answer that question. There are many factors that can affect life expectancy. While the life expectancy of many of our most severely affected patients is shortened, new improvements in diagnosis and treatment has improved their outcome. Newborn screening and early indentification and treatment has significantly improved outcome for less severely affected patients with ASA, cirtullinemia and arginase deficiency. Although studies conducted 20 years ago before current treatments and newborn screening were available were not encouraging, survival and life expectency for children with UCD has increased in the last 10 years. Many children are now being treated with liver transplantation. Others are surviving with better outcomes with UCD becuase of improvements in treatments and medical management. While survival rates for our late onset patients are quite good, there is still a significant risk of a life-threatening or debilitating hyperammonemic episode, so symptoms should always be taken seriously.
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.
Every child is defferent, so this is a difficult question to answer. 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 his/her 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 team will be familiar with the resources available in your area.
Liver transplantation is sometimes the best therapeutic option for urea cycle patients. However, there are substantial risks to the procedure and long-term medical issues. The decision to transplant a urea cycle disorder patient is best made working closely with your metabolic specialist.
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 and will require life-long treatment. Your child will not "grow out" of this disease. The severity of the clinical condition may change with age. We hope to find a cure for UCD patients soon.
No. We all need protein for our bodies to grow and repair our tissues. The restriction of protein in a urea cycle patient is a delicate balancing act. There are many amino acids (subunits of protein) that the body cannot make on its own and must obtain 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 too much protein in the diet. Proper management of a urea cycle disorder patient involves tailoring the diet to give just enough protein for growth and development but not more than can be handled by the deficient urea cycle. This balance is difficult to achieve and changes in protein intake should be made in close consultation with the metabolic team.
This is best done by expert intrepretation of the amino acid levels and some specific proteins in the bloodstream. If certain amino acids levels are low or high, your metabolic doctor can determine if the patient is breaking down too much protein from the body or taking too much dietary protein in. Surprisingly, more patients probably become hyperammonemic from breaking down their own body protein than from overdosing protein 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.
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), pregnancy and delivery, and changes in the diet.
Most small community hospitals are not set to deal with a major hyperammonemic episode. However, with the advent of regional patient transport systems, most patients can be moved rapidly to a large hospital with the proper facilities and personnel. With careful coordination between your metabolic specialist and local healthcare providers, some treatments for milder episodes and routine care can be carried out near your home. In general, it is critically important to have access to a metabolic specialist and hospital that can administer the intravenous "rescue" treatment called Ammonul (IV sodium benzoate / phenylacetate) in cses of a hyperammonemic crisis.
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 tha works.Researchers are working on new methods to deliver healthy urea cycle genes to replace the defective ones or to correct the gene itself. In the future, this may cure some patients with urea cycle disorders. Liver transplantation is considered a cure for CPS1 and OTC deficiencies. In ASA, citrullinemia and arginase deficiency, live transplant corrects the "ammonia problem" but not all the problems associated with these UDCs. The benefits and risks of liver transplant must be carefully weighed against the risks of the UCD. We have drugs that work to help patinets with urea cycle disorders maintain relatively normal ammonia levels, but do not cure the underlying causes or complications. Our UCDC research teams are working to develop new traeatments for UCD.
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