Urea Cycle Disorders
The urea cycle is a body chemistry process. It allows the liver to remove nitrogen from the blood and turn it into urea. Nitrogen comes from the breakdown of proteins we eat. Once nitrogen is turned into urea, it can be flushed out of the body in the urine. If the urea cycle is not working properly, the body cannot turn nitrogen into urea. Instead, it turns the nitrogen into ammonia. Unlike urea, ammonia cannot be flushed out in the urine. Instead it stays inside the body and the ammonia levels in the blood go up. Since blood travels all over the body, the high levels of ammonia travel all over too. High ammonia levels cause damage to nearly every organ, including the brain. If left untreated, these high ammonia levels can cause developmental delays, mental retardation, and, most seriously, irreversible brain damage and/or death.
Urea cycle disorders (UCDs) occur when there is a defect in one of several different enzymes needed to make the urea cycle work. If an enzyme is missing, the urea cycle can’t move on to the next step. There are also urea cycle disorders caused by non-working transport molecules. Transport molecules are important to help to organize certain steps in the urea cycle. If they aren’t working, the whole process slows or stops, even if all the enzymes are present.
Urea cycle disorders can vary greatly. Some children die early in infancy, whereas others are not diagnosed until adulthood. These differences are usually related to which enzyme is not functioning. This determines how much nitrogen can be turned into urea. In some cases the enzyme is missing entirely, and in others the enzyme may be partially functioning. In one type of enzyme dysfunction, males have the more severe forms of UCDs, whereas females are often less affected.
There are several different urea cycle disorders (UCDs), but all are inherited conditions. In each case, one genetic instruction is not working properly, so the entire urea cycle slows down or stops.
The following six conditions are named after the specific missing enzyme:
Carbamyl Phosphate Synthetase (CPS)
N-Acetylglutamate Synthetase (NAGS)
Argininosuccinic Acid Synthetase (Citrullinemia, Type I or AS)
Argininosuccinate Lyase (Argininosuccinic Aciduria or AL/ASA)
Ornithine Transcarbamylase (OTC)
These three conditions affect the transport molecules:
Mitochondrial ornithine carrier (Hyperornithinemia-Hyperammonemia-Homocitrullinemia or HHH syndrome)
Mitochondrial aspartate/glutamate carrier (Citrullinemia Type II)
Dibasic amino acid carrier (Hyperdibasic Amino Aciduria or Lysinuric Protein Intolerance)
Infants, children, and even adults that exhibit symptoms of UCDs can be diagnosed with a simple blood test that measures the amount of ammonia in the blood. Further testing measuring the amount and type of enzyme activity is done to confirm the specific diagnosis. Through early detection and prompt treatment, many serious effects of UCDs can be prevented.
The goal of UCD treatment is to keep the amount of ammonia in the blood from rising to dangerous levels. The treatment itself consists of four main parts: diet, formula, supplements, and monitoring.
Diet: Please keep in mind that when we refer to "eating" that this includes any eating, drinking, swallowing, and chewing. When we refer to "foods," this includes all foods, drinks, medications, and even gum.
In the body, ammonia is made from nitrogen and nitrogen comes from protein. So in order to keep ammonia levels low, people with UCDs must cut down on the amount of protein they eat. This means that people with UCDs must learn what types of foods are highest in protein and limit these foods. Some examples of foods high in protein include all types of meat (e.g., chicken, pork, beef, seafood), all types of dairy (e.g., milk, yogurt, cheese, whipped cream, ice cream, etc.), all types of beans and nuts (e.g., soybeans, pinto beans, peanuts, etc.), and eggs.
People with UCDs must also learn what foods have some amount of protein and ways to measure how much. Each individual, depending on the severity of their disorder, is given a daily limit of the protein they can eat. It is okay for people with UCDs to eat some protein because, unlike an allergy, the protein will not cause them to have an "allergic" reaction. In fact, people with UCDs must eat some protein every day for growth, development, and health maintenance. The trick is not to eat too much. This is done by learning to count protein in grams and keep track of the amount they consume throughout the day.
One of the main problems in following the UCD diet is nutritional balance. Foods that are low in protein tend to be high in either fat or sugar or both. While some low-protein foods can be very nutritious, such as low-protein vegetables and fruit, others offer mostly "empty" calories. Foods that are high in empty calories supply a person with calories, but little nutrition. These calories are often needed for energy and growth but, when consumed in large amounts, can lead to obesity.
Another problem is creating enough variety in the diet, especially for picky eaters. One way to increase variety is to eat low-protein specialty products. For instance, instead of avoiding all breads, pastas, and rice (which often have too much protein), people with UCDs can try some of the special low-protein versions of these foods. There are also many other types of low protein foods available, such as cheese, peanut butter, pizza, etc. As of July 2000, California State law (Senate Bill #148) requires all health insurance companies to provide low-protein specialty foods free of charge to all patients with a condition called PKU. Kaiser Permanente has expanded this requirement to include patients with any metabolic condition requiring a low-protein diet. The Regional Metabolic Clinic has contracted with several different specialty food companies to provide these products. In order not to be charged for these products, patients must fill out RMC order forms and return them to the clinic for review and approval. The coordinators will then forward these forms on to the company(ies) and the food will be delivered directly to the patient's home. Limit: $2500 per patient per year.
Note: Although most of the emphasis is on not eating too much protein, eating too little can also cause high ammonia levels. This is because the body senses that it is not getting enough protein through food, so it begins breaking down its own muscles to get the protein it needs to function. This has the same effect of the person eating too much protein and can cause dangerously high ammonia levels.
Formula: The second part of the treatment for UCDs requires a special protein formula. UCD formulas are special because they contain all the essential amino acids that a person needs. It is often difficult to get enough protein to stay healthy on a UCD diet alone. Therefore, people with UCDs who follow very low protein diets need to drink formula in order to get enough high quality protein. The protein from the formulas tends to be used for making new body proteins. However, if the person drinks too much formula, it, too, is broken down into ammonia. Therefore these individuals need to work closely with their metabolic nutritionist in order to determine how much formula they need. UCD formulas are also fortified with essential vitamins and minerals.
Supplements and Medications: Another way to help prevent ammonia from building up in the body is to find a different way to get rid of nitrogen. There are supplements and medications (e.g., sodium benzoate, sodium phenyl butyrate, and sodium phenyl acetate) that can combine with nitrogen to form non-toxic compounds. This allows the body to safely get rid of nitrogen before it turns into ammonia.
Monitoring: The final part of the treatment for UCD is monitoring in order to know whether the other three parts of the treatment (diet, formula, supplements/medications) are actually working to keep the ammonia levels down. It is best to find this out before the person with UCD experiences any of the possible bad effects of high levels (as discussed above).
Blood tests - UCDs are monitored by several different types of blood tests. The most common blood test is, of course, to test for ammonia. Another regular test is for "plasma amino acids". Amino acids are what make up protein and is important to have enough of each of the essential amino acids to make high-quality proteins for the body to use. Since people with UCDs must restrict the amount of protein they eat, they sometimes do not get enough of all the amino acids, and this can affect their nutritional status. The plasma amino acids test measures the levels of all the different amino acids so that any deficiencies can be identified. For this test, the blood sample must be sent down to the Metabolic Lab at Kaiser, South in Los Angeles. It can take several days to a week to receive these results.
There are other blood tests that can be used to measure a person's nutritional status, but not all of them are used with every blood draw. Which tests are ordered depends on what type of nutritional deficiency is suspected.
There are also tests to measure the functioning of the body, especially the liver. Since the urea cycle takes place in the liver, we already know that the liver is not functioning properly in people with UCDs and it needs to be monitored for that reason. The liver is also the place where nitrogen is converted to ammonia. Since too much ammonia is toxic to the liver, it is important to make sure that the liver is not being damaged over time. For both of these reasons the liver is monitored by two other blood tests called "liver function tests" or "ALT and AST".
For all blood tests, a 3-day diet record is recommended. To complete a diet record, all the food eaten over the period of three days must be written down along with the amount eaten. The blood test(s) should be taken on the 4th day, right after the diet record is completed. The diet record is an important part of interpreting the test results. For instance, if the ammonia level is high, is it because the person is eating too much protein or too little? It is hard to get an accurate picture of what is happening inside the body without having the information provided by the diet record.
Other tests - Patients are regularly weighed and measured at clinic and regular doctor visits in order to monitor their growth and development. School reports can also help identify any learning disabilities.
Some UCDs are also monitored using urine tests. The most common is urine orotic acid, but a urine organic acids test may also be ordered. Both these tests require a urine sample that must be frozen immediately and sent down to metabolic lab at Kaiser, South in Los Angeles. It can take several days to a week to receive the results. Just like the blood tests, a 3-day diet record is required for urine testing.
National Urea cycle Disorders Foundation - Provides information about urea cycle disorders and support resources for families.
Low Protein Cookery for PKU (Please note: this book is helpful for all low-pro diets.)
by Virginia Schuett
Published by the University of Wisconsin Press, Madison, WN, 1997
Available through Kaiser's Regional Metabolic Clinic
The Complete IEP Guide published by Nolo Press
This book explains every nuance of the IEP process in lay terms. It provides clear concise explanations, definitions, and descriptions backed by legal codes (code reference numbers are included after every section). It also includes practical suggestions on how to deal with any problems that may arise.
How to Teach Nutrition to Kids
by Connie Liakos Evers, MS, RD
Published by 24 Carrot Press, Tigard, OR, 1995
By Jane Nelson, EdD
Published by Ballantine Books, New York, NY
Positive Discipline: The First Three Years
By Jane Nelson, EdD
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Positive Discipline for PreSchoolers
By Jane Nelsen, EdD, Cheryl Erwin, & Roslyn Duffy
Positive Discipline for Teenagers
By Jane Nelson, EdD, and Lynn Lott, MA
Published by Prima Publishing, Roseville, CA, 2000
Positive Time Out and 50 Other Ways to Avoid Power Struggles in Homes and Classrooms
By Jane Nelsen, EdD
Social Security Disability: Getting & Keeping Your Benefits published by Nolo Press
A legal guidebook to navigating the Social Security system written in plain-English. Helps the layperson to understand Supplemental Security Income (SSI) and Social Security Disability Insurance (SSDI) and the laws behind them (includes legal reference codes after each section).
Temperament Tools: Working with Your Child’s Inborn Traits
By Helen Neville and Diane Clark Johnson
Published by Parenting Press, Inc., Seattle, WA, 1998
We're Different, We're the Same by Bobbi J. Kates. Illustrated by Joe Mathieu.
Published in 1992 by Random House. Suggested ages: 4-8
Sesame Street characters learn to appreciate their differences and discover that they still have many things in common.
Why Can't I Eat That!: Helping Kids Obey Medical Diets
By John F. Taylor, PhD, and R. Sharon Latta
Published by R & E Publishers, Saratoga, CA, 1987