What is The Urea Cycle?
The Urea Cycle is a sequence of reactions that occur in your liver cells. The Urea Cycle processes excess nitrogen, (which is made when protein is used by the body) to make a compound called urea, which is released into the blood. Urea is then transferred from the blood into your urine by the kidneys, so that your body is able to dispose of it.
What is a Urea Cycle Disorder?
A Urea Cycle Disorder is a genetic (gene-related) disorder which is caused by a mutation in one of your genes, almost like one of the genes being ‘damaged’. Sometimes, an entire gene can be missing, rather than damaged. When a Urea Cycle Disorder occurs, a damaged or missing gene means that one of the six enzymes in the Urea Cycle does not work properly (an enzyme is a substance which is required to convert one thing into another).
These six enzymes work to remove ammonia from the blood. The purpose of the Urea Cycle is to remove nitrogen from the blood and convert it into urea, which is transferred into the urine and removed from the body. In Urea Cycle Disorders, the nitrogen cannot be removed properly, which means that ammonia stays in the body. Ammonia is highly toxic, and if it is left in the body it causes something called ‘hyperammonemia’, which means elevated blood ammonia. The ammonia reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death.
How Many Types of Urea Cycle Disorder Are There?
There are six types of Urea Cycle Disorder. If you have a Urea Cycle Disorder, it means you are deficient or missing one of the six enzymes in the Urea Cycle. The six Urea Cycle Disorders are:
– Arginase Deficiency (ARG)
– Argininosuccinate Lyase Deficiency (ASL)
– Argininosuccinate Synthetase Deficiency (ASS)
– Carbamyl Phosphate Synthetase Deficiency (CPS)
– N-Acetylglutamate Synthase Deficiency (NAGS)
– Ornithine Transcarbamylase Deficiency (OTC)
Except for OTC Deficiency, five of the Urea Cycle Disorders are ‘autosomal recessive’, which means that for a baby to be born with one of these disorders, they have to receive two damaged or missing genes, one from each parent. As being a carrier for these is rare, it is even rarer that two carriers would meet, and make a baby. That is why these conditions are not the most common UCDs. So for example, for a baby to be born with Arginase Deficiency, the baby would need to receive two chromosomes that had missing or damaged ARG genes.
OTC Deficiency is X-linked, which means that it is only found on the X chromosome, and only one damaged or missing OTC gene is enough to cause OTC Deficiency. This makes it one of the more common Urea Cycle Disorders, although it is still very rare. You can find out more about how OTC Deficiency occurs by reading below.
Rather than explain each type of Urea Cycle Disorder, we have decided to concentrate on OTC Deficiency, which is the Urea Cycle Disorder that affected Aidan. If you would like to find out more about the other five Urea Cycle Disorders, please get in touch with us, or refer to the NUCDF for further information.
What is OTC Deficiency?
Ornithine Transcarbamylase (OTC) Deficiency is one of the six Urea Cycle Disorders. It is a rare Metabolic Disorder that occurs in approximately one out of every 80,000 births. It is an X linked disorder, which means that it can be found on the X chromosome. It can be inherited from a child’s parent, or it can be a spontaneous mutation that only occurs within the child and has not been inherited.
People with OTC Deficiency are unable to break down ammonia, which is made when the body breaks down proteins. People who do not have a missing or damaged OTC gene are able to break down ammonia and it is disposed of through their urine. If the OTC gene is damaged or missing, you are unable to dispose of ammonia through urine, and it builds up in your body, causing hyperammonemia, which can result in brain damage, coma and/or death.
What is Ammonia and Where Does it Come From?
Almost everything in your body is made from proteins. These are chains that combine to make your organs, such as your heart and brain, muscles and even the substances that transport oxygen around your body, Haemoglobin.
The building blocks of these chains are called amino acids. There are many of these but the body uses 21. Our bodies can make some of these on its own, but requires some from food known as essential amino acids.
We get protein from food and it is particularly high in meats, fish, eggs, dairy and beans, pulses, seeds and nuts. The proteins we get from food are broken down by our digestive system into the amino acids – so that they are small enough to enter the bloodstream.
From the bloodstream they enter other organs and tissues, where they are used to make other chains that the body needs.
The whole point of proteins is to build tissues, such as muscles or skin, or to do a specific job, for example one protein in Haemoglobin will hold onto Oxygen to transport it in blood. However, if there were not enough carbohydrates (sugars) in the body, used to make energy, it would use proteins and amino acids instead.
Your body contains amino acids, which are made up of three parts. One amine part and one carboxylic part that are common to all amino acids. These are like links in a chain that can be opened to allow them to attach to other amino acids to form bigger chains (a protein). The third group is different from one amino acid to the other but defines which amino acid it is.
The Carboxyl part of an amino acid group is re-arranged to make sugars, but to get to this the amino group must be shed. This amino group, once shed from the amino acid, forms Ammonia.
Ornithine Transcarbamylase is an enzyme (something that helps convert one thing into another) and its job is to work as part of a chain of events, to convert the poisonous ammonia into something safe that the body is able to get rid of. If the body doesn’t have enough of the Ornithine Transcarbamylase enzyme, then it struggles to break down proteins and process ammonia so that it can be passed out through the body in urine.
Ammonia is toxic in the body, particularly in the brain. Here it affects how the brain transmits signals and also causes the brain to swell. This can lead to irritability, drowsiness, vomiting, coma and death. This high level of ammonia, known as hyperammonemia, is the underlying problem of a Urea Cycle Disorder and was the first clue that Aidan may have suffered from one of these disorders, when the Consultant asked for it to be measured and it came back high.
Normally Ammonia is not allowed to get to a high enough level to do this as it is converted into safer substances and removed from the body in your urine.
How Does OTC Deficiency Occur?
Women have two X chromosomes, and Men have an X and a Y chromosome.
What determines whether a baby is male or female is which chromosome they get from their father. Boys get one X from their Mother, a Y from their father. Girls receive an X chromosome from both parents.
Girls and boys can be born with OTC Deficiency purely by chance. This is called a spontaneous or ‘de novo’ mutation, which means a new mutation that only occurs in the baby and has not come from the mother or father of the child. We have not found any consistent data that tells us how often this occurs.
Boys can only receive an OTC deficient gene from their mother, as they only get an X chromosome from their mother (and a Y chromosome from their father).
In summary, babies are born with OTC Deficiency because of one of three reasons:
1: (For Male or Female babies) as an inherited trait from the Mother’s X chromosome.
2: (For Female babies only) as an inherited trait from the father’s X-chromosome
3: (For Male and Female babies) as a spontaneous mutation, called a ‘de novo mutation’, which occurs in the foetus.
Why Does OTC Deficiency Not Cause Problems for a Baby During Pregnancy?
While babies with OTCD are in the womb, their Mother’s ‘healthy’ OTC gene takes over and works to dispose of ammonia for them. This is because they are attached to their Mother’s body by the umbilical cord. Once the umbilical cord is cut, babies are ‘on their own’, and do not have the benefit of their Mother’s body to repair the damage for them. As the benefits of the umbilical cord wear off, babies begin to show symptoms (often within 24 to 72 hours).
Does OTC Deficiency Always Affect Babies As Soon As They Are Born?
In males there are two types of OTC Deficiency:
– Neonatal Onset, where babies suffer severe hyperammonemia within the first few days of life (usually 24-78 hours), which often results in death.
– Late Onset, which can occur at any point after the neonatal period and can be aggravated by infection, eating a high amount of protein, or high levels of stress.
Aidan had the neonatal onset type of OTC Deficiency, which we will talk about below. If you are looking for information about Late Onset OTC Deficiency, please refer to the NUCDF for more information.
What Are The Symptoms of Neonatal Onset OTC Deficiency?
Babies with neonatal onset OTC Deficiency usually show symptoms within the first 24-72 hours of life. The baby may be refusing to feed, be irritable and ‘sleepy’ or ‘not very alert’ (lethargic). Typically after the first 24 hours, seizures may occur, which may be so subtle as to only affect the face or one limb and therefore easy to miss. The baby may also have poor muscle tone or be ‘floppy’ (called ‘hypotonia’, referred to as being ‘hypotonic’). These symptoms, if untreated, are followed by the baby slipping into a coma. Lethargy, irritability and poor feeding can occur for many, many reasons when a baby is unwell. Therefore doctors are likely to treat for much more common things such as infection (which would be treated with antibiotics), rather than suspect something as rare OTC Deficiency. It is worth bearing in mind that many experienced medical professionals will never come across a case of OTC Deficiency in their working lives. However Ammonia blood tests are possible and if the results show raised ammonia, then a Urea Cycle Disorder should be suspected. This can then be discussed with specialist metabolic doctors, who can give advice on what to do next.
In Aidan’s case, he rapidly declined after the first 24 hours. His new-born check was done when he was 32 hours old, which is when a doctor notice very slight irregular movements in one of his legs – consistent with the slight seizures that often occur as a symptom of OTC Deficiency. He was lethargic and irritable, and had struggled to feed since birth. At 48 hours old, a blood test revealed ammonia in Aidan’s blood, leading his pediatric consultant to suspect a Urea Cycle Disorder and liase with a metabolic specialist who suspected that Aidan had OTC Deficiency and wanted him to be brought to a specialist unit for treatment.
How Rare is OTC Deficiency?
Approximately 1 in every 80,000 babies is born with OTC Deficiency. However, it is worth bearing in mind that some cases may have been undetected and put down to Sudden Infant Death Syndrome (SIDS), as babies are often born healthy and rapidly decline after the first 24 hours of life.
Is OTC Deficiency Treatable?
If picked up early enough, medications need to be given into one of the baby’s veins, which will help the body get rid of the ammonia. However by the time it is picked up the levels in the blood are likely to be so high that dialysis is required and these medications will be used as a stand-in until dialysis can start. Dialysis is a process where the baby’s blood is fed into a machine, which draws the ammonia out of it, before transfusing the blood back into the baby’s body.
However, this is just a measure to bring down the ammonia levels temporarily as they will start to rise again once the dialysis stops. Occasionally medications can be used, once the ammonia levels have been reduced, to try keep them low, but it is unlikely that they will be kept at low enough levels 100% of the time.
Currently the only hope of a “cure” of neonatal onset OTC Deficiency is a liver transplant, which is itself a very risky procedure that can cause death or may not work. Even if a liver transplant is planned, the baby will still need immediate and continuous dialysis prior to the transplant, to remove any ammonia from the blood stream, in order to prevent permanent brain damage occurring as a result of hyperammonemia.
In milder cases of OTC Deficiency, the disorder can be treated by drugs such as Buphenyl and L-citrulline. Buphenyl is usually taken 4 times a day for a lifetime; to make sure that ammonia does not get chance to build up in the body. It helps the body to remove ammonia from the blood stream and prevent hyperammonemia. L-citrulline is also taken over a lifetime and helps to speed up the urea cycle enzymes so they can remove ammonia faster. Antacids are often also prescribed to minimise the side effects of drug treatment. Protein intake also needs to be restricted. Protein (found in meat/fish, eggs, dairy, etc.) is required in your diet as it used to build tissues in the body, such as muscles and skin (for more information about protein, please refer back to the ‘What Is Ammonia and Where Does It Come from?’ section). However, too much protein for someone who has OTC Deficiency can cause ammonia levels to rise rapidly, which is why management of diet is an important part of OTC Deficiency treatment. Overall, treatment of milder cases of OTC Deficiency is a lifelong commitment to dietary management and drug treatment. If these treatments fail, a liver transplant may be an option.
Children who are treated for and live with OTC Deficiency often experience developmental delays, especially those who have experienced periods of hyperammonemia (which causes damage to the brain).
In Aidan’s case, once OTC Deficiency was suspected, he was going to be sent to a specialist Children’s Hospital to have dialysis which would remove the ammonia from his blood. We knew that there was a very high risk that if Aidan survived, the damage to his brain would have left him severely disabled. We loved our son and would have loved him whatever the outcome. However, Aidan’s heart stopped before he was put in the ambulance to go to Sheffield, and we learnt that the damage to his brain was so severe that there was no chance he would live. At this point, Aidan’s ammonia levels were over 40 times higher than what is normal for a baby. We were told that Aidan would die, even if he was sent for the aggressive dialysis treatment. With the knowledge that our son would die whatever path we chose, we decided that to put him through any more pain just so we could feel we had done everything we could, would be incredibly selfish. We did not want to have him to suffer anymore and risk him dying in the ambulance on the way to the Children’s Hospital, without both his parents beside him. We spent precious time with our baby boy before and after his life support machines were removed. He lived for one hour after the machines were turned off. We will never know whether Aidan would have lived if his OTC Deficiency had been diagnosed and treated as soon as he was born.
How Do You Test for OTC Deficiency?
High levels of ammonia in the blood indicate that a person may have a Urea Cycle Disorder. OTC Deficiency can be diagnosed by doing enzyme analysis on a liver biopsy, or by finding high levels of orotic acid in the blood, using biochemical analysis. In order to fully confirm a diagnosis of OTC Deficiency, the OTC gene needs to be screened in a genetics lab, using blood samples, skin samples or liver samples. Here, a geneticist will look at all the DNA (almost like a ‘code’) that makes up the OTC gene, and pinpoint where there is a damaged part of the DNA. Screening can also show that a gene is entirely deleted. This testing process usually takes around 8 weeks to complete.
How Can You Test to See if Someone is a Carrier of OTC Deficiency?
To test a carrier from OTC Deficiency, it is possible to screen the suspected carrier’s OTC gene to search for abnormalities. Or the test results from the affected baby can be used to form a ‘probe’ that allows the suspected carrier’s gene to be pinpointed, to look for the exact same deletion. Obviously, waiting for the affected baby’s test results to come back means that there is a much longer wait involved, which may cause health risks for the suspected carrier.
What Does it Mean to be a Carrier of OTC Deficiency?
Carrier females have an OTC gene that is either completely missing, or has deletions. Females have two X chromosomes, and the working OTC gene on their other X chromosome takes over and usually means that the body is still able to process ammonia and dispose of it through urine.
Depending on how severe the deletion in the carrier’s OTC gene is (or if it is missing completely), the carrier may or may not show symptoms of OTC Deficiency. Symptoms of OTC Deficiency may range from unknowingly not liking foods because they are high in protein, which is a common trait of carriers. It is likely that as small children, carriers stop eating foods with higher amounts of protein because it makes them feel unwell and they and they subconsciously learn to avoid it in future. During pregnancy and during and after the labour, there is a heightened risk of ammonia levels rising in carriers, which will mean they need to have their blood screened regularly. They will also need to give birth at a hospital supported by specialist metabolic doctors. It is probably a good sign if someone has been well their whole lives or has uneventful pregnancies/deliveries. Unfortunately this does not remove the risk during future pregnancies/deliveries.
How Are Carriers Affected?
Most female carriers (reported to be around 80%) do not have any symptoms. Because females have two X chromosomes, they have one that works like a ‘backup copy’ for the other one, taking over the process that the damaged (or missing) X chromosome is unable to complete (disposing of ammonia). However, some female carriers may show symptoms later in life, particularly following physically stressful events such as childbirth, extreme dieting or gastric bypass. Carrier women who do have symptoms (reported to be around 20%) will experience headaches, trouble concentrating, an intolerance to protein, vomiting and episodes of mild hyperammonemia (which can cause irritability, lethargy, reluctance to eat, hypotonia – and eventually, if left untreated, coma and death). Females who have OTC Deficiency that is symptomatic will require medication and monitoring of their blood ammonia levels to ensure that the risk of them experiencing hyperammonemia is lowered. Repeated elevation of ammonia can cause brain damage, leading to developmental delays, coma and eventually death. OTC Deficiency can usually be managed in females, providing medical staff treat it seriously and provide prompt, accurate monitoring and have a plan of care in place to treat raised ammonia levels if/when they occur. OTC Deficiency can be fatal in girls if it is not managed correctly. Very rarely, females with OTC deficiency can not be treated and the disorder is fatal for them. For further information about females with OTC Deficiency, please contact the NUCDF who will be able to explain the complexities better than we are able to.
Can Babies Be Tested for OTC Deficiency Before They Are Born?
Babies can be tested for OTC Deficiency by pre-natal testing, which is done while the baby is still in the womb. This can be done by Chorionic Villus Sampling (CVS) from 11 weeks, or amniocentesis from 15 weeks. These tests can increase the risk of miscarriage and do not 100% guarantee an accurate diagnosis of whether the unborn baby does or does not have OTC Deficiency.
Tests for OTC Deficiency are not offered as standard, and are usually only offered if the mother or father or a child has been diagnosed as a carrier of OTC Deficiency, or if the couple have already lost a child to OTC Deficiency (bearing in mind that carrier tests are not always accurate, and just because someone has been identified as not being a carrier – it doesn’t give a 100% guarantee that they are not).
There is no way of knowing which carriers will get symptoms and which will not, therefore monitoring of ammonia levels and protein in the diet is the safest way of trying to avoid symptoms or knowing who to treat.
Are Tests for OTC Deficiency Carriers and Pre-Natal Tests Accurate?
We cannot find any consistent statistics that tell us how accurate tests for OTC Deficiency (or for carriers of OTC Deficiency) are. What we do know, is that tests do not guarantee to find where the mutation in the OTC gene is. Sometimes, the mutation cannot be found at all – usually because it is a new mutation that has never been seen before.
There are no guarantees that any testing for OTC Deficiency will be 100% accurate. It is a rare disorder and testing for it is not something that is done frequently. Undergoing any type of testing for OTC deficiency is a long wait and there is a chance it may not reveal a definitive answer.
A More Detailed Explanation of Genetics and How OTC Deficiency Occurs.
In order to understand where OTC Deficiency comes from, it is important to have a basic understanding of genetics.
Humans are supposed to have 23 pairs of chromosomes. One of each pair comes from each parent. 1 of these pairs is called the sex chromosomes. That is because they determine what sex we are. If the baby gets an X chromosome from both parents it will be a girl. If it gets an X chromosome from the mother (because she only has X’s) and a Y from the father (who has one X and one Y) the baby will be a boy.
These pairs of chromosomes both hold genes that do a certain job, for example a gene to make the pigments in your eyes or a gene to make insulin. We have two copies of all these genes so that if one is faulty or missing often the other works so that our body can still do that job.
We may pass on affected genes to our children or are unable to pass on certain genes because they are missing in us. Alternatively when our bodies make sperm or eggs, the information can get altered and genes can change or not be made. Also it is possible that once the embryo starts to replicate itself to get bigger, that genes do not get copied exactly or that they get missed in the replication process, though this is less likely.
Ornithine Transcarbamylase Deficiency is an X-linked disorder. Any condition is considered X-linked if the mutated or missing gene that causes the disorder is on the X chromosome, one of the two sex chromosomes. This means that OTC Deficiency only occurs on X Chromosomes. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons, because their sons will inherit their Father’s Y chromosome, and their Mother’s X chromosome.
In males (who have only one X chromosome), one altered copy of the gene in each cell is enough to cause the OTC Deficiency. Males only have one X chromosome, and the Y chromosome is unable to take over and act as a ‘backup copy’.
In females (who have two X Chromosomes), the disorder will only be severe if both X Chromosomes are affected. That means, if a female inherit two X Chromosomes that have missing or damaged OTC genes (one X chromosome from her father, one X chromosome from her mother), she will have OTC Deficiency. Females who inherit one Chromosome with a damaged OTC gene (from either their mother or father), are described as ‘carriers’ (although carriers do not always inherit the gene, it can also be spontaneous in them). This means that they do not usually show symptoms of OTC Deficiency, because they have one working OTC gene in one chromosome, which takes over from the Chromosome that has a damaged OTC gene. However, some females with only one altered copy of the OTC gene also show signs and symptoms of OTC Deficiency, depending on how severely damaged the OTC gene is, or whether it is completely missing. 10% of people with OTC Deficiency have their whole OTC gene missing. 90% of people with OTC Deficiency have a damaged OTC gene.
In some cases, OTC Deficiency is not inherited at all, and is a spontaneous mutation within a child. This means that purely by chance, the child’s OTC gene had a defect in it or was completely missing. The geneticist we have spoken to has stated that around one third of cases of OTC Deficiency are caused by a spontaneous mutation, and two thirds of cases are inherited. We have read many online journals and medical articles, but have yet to find a consistent answer as to how often spontaneous and inherited cases occur, but it may be that OTC Deficiency is inherited somewhere around 90% of the time.
The image below shows how OTC Deficiency can occur in a family where a mother is a carrier of the disorder.
If the parents have a boy, there is a 50% chance that he will receive the OTC deficient gene from his mother, and a 50% chance that he will inherit her healthy gene. In most cases, the level of severity will be the same in families. So, for example, if one son born to a carrier mother had neo-natal onset OTCD, there is a very high chance that if she has another son with OTCD, that he will have neo-natal onset OTCD of the same severity.
If the parents have a girl, there is a 50% chance that she will inherit her Mother’s OTC deficient gene, and become a carrier of OTC Deficiency herself. There is a 50% chance that she will receive her Mother’s healthy gene and will not be a carrier.
So overall, if the mother is a carrier of OTC deficiency, there is a 25% chance that she will have a boy who has OTC Deficiency and whose life may be seriously at risk.
Please note that the above text has been written by us, based on our own experience and our own reading of medical journals and articles. We have not yet had time to include references to the journals and articles we have used, and will update this information later. Because OTC Deficiency is so rare, it is not easy to research accurate information online. We have been provided with very little information at all and have had to rely on personal medical knowledge and research skills in order to find out about OTC Deficiency. We have given our web address to relevant organisations, charities and medical professionals so that it can be given to people who are dealing with OTC Deficiency, either as a bereaved parent, a parent of an OTC Deficient child, or a carrier – in the hope that they will be able to find easily accessible information in one place.
We will keep this page updated as new information is released. Please keep checking back.
The information above is all original content, written by us. Please do not copy or reproduce this text without our permission.