Introduction to Ornithine Transcarbamylase Deficiency

Ornithine Transcarbamylase  (OTC) Deficiency will occur when there is a disorder in one's urea cycle and is one of the most common hereditary disorder. Urea cycle is also known as a series of reaction which takes place in the liver cells. This is usually due to the aggregation of ammonia. OTC is a mitochondrial enzyme which is part of the urea cycle. When there is OTC Deficiency, there is usually a missing or damaged enzyme that is used to initiate a reaction in the urea cycle. This causes nitrogen, produced when there is a usage of proteins by the body, to accumulate as ammonia thus causing hyperammonemia.

 This deficiency is more commonly seen in infants and children as compared to adults as there is a frequency of OTC Deficiency occurring 1 in every 80,000 births.

Children or infants with OTC Deficiency happens usually because either insufficient OTC or nonfunctional OTC are being produced. Thus, the body will have difficulty removing ammonia by urine as the OTC are not working properly. This will cause ammonia to accumulate in the body which is dangerous as high levels of ammonia is toxic. Ammonia is a neurotoxin is known to cause damages to the patient's nervous system. Thus, OTC deficiency will bound to cause the liver to be damaged and also to bring about neurological problems.

References:
http://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency

Pictures:
http://books.google.com.sg/books?id=EnIl7KSNCrgC&pg=PA252&lpg=PA252&dq=what+is+ornithine+transcarbamylase+used+for&source=bl&ots=8N1NdTWU_V&sig=zSFjFx-Em_n7rDc_VUGxmGsv1FU&hl=en&sa=X&ei=Tg_AU-uyOoWwuATGhoCoDA&ved=0CEAQ6AEwBDgU#v=onepage&q=what%20is%20ornithine%20transcarbamylase%20used%20for&f=false

http://www.healingmatthew.com/page/2/

How to obtain Ornithine Transcarbamylase Deficiency?

Ornithine Transcarbamylase (OTC) Deficiency is a very common hereditary disorder and is an X-linked recessive disorder where the mother is a carrier of the mutated gene herself. There are two sex chromosomes in everyone, one of which is an X-chromosome. X-linked conditions happens when the mutated gene is situated on the X-chromosome. The distinctive of X-linked disorders is that the X-linked traits can only be passed on from the mother also only to their sons. Therefore, males will definitely have a higher chance of getting affected with OTC deficiency as compared to females.

In order for males to be contracted with OTC deficiency, all they need is a copy of the non-functional genes from their mothers. Females with a copy of the non-functional gene may express symptoms related to the condition. There is a possibility of having more than one child which has the condition when either one or both of the parents possess the non-functional gene.

There are cases whereby OTC deficiency do not get inherited by any of their children at all. This is due to the OTC gene either being deficient or missing.


References:
http://aidanselephants.co.uk/about-us/about-otc-deficiency/

Pictures:
http://aidanselephants.co.uk/about-us/about-otc-deficiency/

Symptoms for Ornithine Transcarbamylase Deficiency.

As mentioned in the previous post "How to obtain Ornithine Transcarbamylase Deficiency?", it is mentioned that males usually get contracted with this disease more frequently as compared to females as it is a X-linked recessive disorder. However, it does not just stops there. Hemizygote males has different symptoms as compared to heterozygote females.

Hemizygote males will appear to be normal at birth. Symptoms of OTC deficiency will only start appearing from 24 hours to 72 hours after being fed, whereby proteins is usually included as part of the meal. The symptoms will be expressed in neurological, gastronomical and others. 

Neurological symptoms are caused because of nerves being damaged in the infants mainly due to hypoammonemia which is the result of OTC deficiency.

The first neurological symptom is infantile hypotonia. Infantile hypotonia is basically hypotonia occurring at birth. Hypotonia is due to decreased muscle tone. Infants with infantile hypotonia will find difficulties in keeping their joints, knees and elbows, bent. They will appear to be limp as well. Additionally, these infants will continue to face problems when comes to being fed.

The second neurological symptom is neonatal seizures. The downside to neonatal seizures as compared to normal seizures is that neonatal seizures are very difficult to be detected as the infants will not experience convulsion. When the baby experience neonatal seizure, he/she will turn unresponsive out of sudden with his/her eyes looking at everywhere. They will also be lip smacking and there may be short periods whereby they are not breathing.

Moving on to gastrointestinal symptoms. The first symptom is persistent vomiting and poor feeding. This may lead to dehydration in the baby.

The next symptom is hepatomegaly. Hepatomegaly is a liver disease and usually due to the unusual increasing in size of the baby's liver. Livers usually will only increase with one's age and weight. The abnormal liver will be very tender to touch if it enlarges too rapidly. Additionally, hepatomegaly will cause pain to the baby. This is due to pain in the abdominal area or fullness.









Lastly, OTC deficiency in hemizygote males will have symptoms such as hyperventilation, hypothermia and lethargy.

In 10% of the heterozygote females, the symptoms for OTC deficiency will only start appearing in their childhood unlike the hemizygote males. However, heterozygote females has too, both neurological and gastrointestinal symptoms.

For the first neurological symptom is acute ataxia. When ataxia is being diagnosed in a child, the child will find it unable to coordinate his/her own muscle activities. The child will be unable to control the direction, intensity and rate of the movements they wish to do. This will end up having the child to be unable to complete the particular movement properly also they may lose their balance.







Another neurological symptom is hyperactivity. Hyperactivity is one of the early symptoms. Hyperactivity in children usually brings about  screaming for no particular reasons and they will cause harm to their own body. On top of that, they are unwilling to consume meat or any related food that are high in protein.

Lastly is migraine - headaches. This is due to too much protein being consumed.

Heterozygote females do experience gastrointestinal symptoms. However, these symptoms are similar to those gastrointestinal symptoms occurring in hemizygote males. These gastrointestinal symptoms are also known as persistent vomiting and hepatomegaly.




References:
http://www.pedbase.org/o/ornithine-transcarbamylas-deficiency/
http://learnpediatrics.com/body-systems/nervous-syste/approach-to-the-ataxic-child/
http://www.healthline.com/symptom/liver-enlarged
http://www.healthcaremagic.com/articles/Enlarged-liver-or-Hepatomegaly-in-children/7246
http://www.emedicinehealth.com/seizures_in_children/article_em.htm
http://www.aim4health.com/family/otc.htm
https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/309/printFullReport

Pictures:
http://www.carbaglu.net/hcp/clinical-presentation.php
http://en.wikipedia.org/wiki/Hepatomegaly
http://www.medindia.net/patients/patientinfo/ataxia.htm
http://www.rayur.com/hypotonic-infant.html

Diagnosis methods for OTC deficiency

When a person expresses all the symptoms of OTC deficiency, he is first put through a initial test where the test is specific to OTC deficiency and several other conditions, therefore we do not say that it is a specific test. If the test results come back positive, a confirmatory test is then given to the patient to confirm that he has OTC deficiency. This test is far more specific than the initial test, however may require more sample from the patient.

One of this confirmatory test methods is the test for blood gases. The patient would be tested for respiratory alkalosis due to hyperammonemia, this would clearly distinguish that the patient has a urea cycle disorder compared to an organic acidemia.

An initial test that can be done to confirm OTC deficiency is the plasma ammonia concentration test. When a patient’s blood ammonia concentration is above 100 micromol/L. If this initial test comes back positive, the confirmatory test would be carried out.

This confirmatory test varies depending on the age group of the patient testes. In newborns, samples would be taken from the baby and run through plasma amino acid analysis to test the results of amino acid testing, the result expected would be high concentrations of glutamine and a low concentration of citrulline.

When the testing is done on anyone else except newborn babies, the same test can be repeated and the results of the test should be the same, which would conclude that this person has OTC deficiency. However there is another test that can be done to confirm that this person has OTC deficiency. This is the urine organic acid analysis, the results of the test for a OTC deficient patient should be that the orotic acid concentration would likely to be elevated. This method is more specific to OTC deficiency because it is one fo the few diseases that would cause this to happen.

When the patient has tests that come back as all positives, the doctors would put the patient through a final diagnosis which would confirm that he has OTC deficiency. This is a genetic test, and therefore would be very specific towards OTC deficiency. The first test is the identification of the pathogenic mutation in OTC, which is the only mutation which can cause OTC deficiency.

The next test that the doctors can use to confirm that this person has OTC deficiency is looking for decreased OTC enzyme activity in the liver, the exact numbers are <20% of control in severe cases of OTC deficiency and up to 30% of control in a milder case of OTC deficiency.

When a patient has all these tests turn up positive, there is a very high chance that he suffers from OTC deficiency, and the doctors can conclusively say that the patient is OTC deficient and should start medical care for the disease.

Sources: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=664

Treatment of OTC deficiency

The treatment of OTC deficiency can be split into 3 ways of treatment.

The first way, is dietary plans for the patient given by the doctor. This includes immediate temporary discontinuation of specific protein intake, and an increase of carbohydrate and lipids intake to compensate for the lack of those proteins. These foods has to provide the patient with essential amino acids while limiting the intake of non essential amino acids. 

Essential amino acids include Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan and Valine. Some examples of diets of OTC deficient patients, especially babies, include breast milk from a mother or cow’s milk formulate which is an essential amino acid formula.

For adults who suffer from OTC deficiency can take in essential amino acids from foods such as eggs, meat, soybeans and quinoa. More information can be found at this link http://www.livestrong.com/article/249606-foods-high-in-essential-amino-acids/ .

The second way is to have medical care administered to the patient. This includes the first step of temporarily stopping intake of specific proteins and compensating with more carbohydrates and lipids.

Patients with extremely high levels of ammonia in their system due to the OTC deficiency would also require hemodialysis to remove them. On top of that, IV drips of sodium benzoate, arginine and sodium phenylacetate would also be given to the patient to aid with the OTC deficiency.

Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The main aim of the medical treatment is to prevent this from happening or reducing the amount.

The final way of dealing with OTC deficiency is to have a liver transplant, this is the last resort of the treatment for OTC because of the apparent dangers that it poses to both the patient and the donor. However if done successfully, would cure the patient of OTC deficiency. However due to the nature of the surgery, it can be quite dangerous, especially for children. Therefore this method is only considered as the last resort and a specialist should be consulted before making any decisions.

sources

http://www.nucdf.org/ucd_treatment.htm

http://emedicine.medscape.com/article/950672-treatment#a1129

https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/309/printFullReport

http://www.livestrong.com/article/249606-foods-high-in-essential-amino-acids/

Case study of patients who has gone through surgery for their OTC deficiency

Ornithine Transcarbamylase Deficiency can be a very deadly disease if not detected and treated carefully. There are several children who were born with OTC deficiency and subsequently cured with a liver transplant. Today we are going to take a look at 3 of such cases.

The first case is about a boy named Billy Corfield, he was diagnosed with OTC deficency when his mother was 8 months pregnant with him. Even though the doctors had advised her to abort the baby, she refused, convinced that she would be able to take care of him perfectly.

Billy was born into a world where most of his days as an infant was spent in the hospital getting treated by doctors with experimental treatments, which even though did not cure him, gave him more time. Eventually, he was treated with a full liver transplant at the age of 11 and had been fully cured of OTC deficiency.

The next case study is about Ava Taylor, a six year old that under went surgery for a liver transplant from her mom. Similar to Billy, Ava also suffers from the same condition, OTC deficiency and is unable to lead a normal life due to this. Her mom, was given the good news that an anonymous donor had tested as a match to Ava’s body and they could begin the surgery immediately. As suggested by Ava’s doctors, surgery was the best course of action that they could take, seeing that this was Ava’s best hope in having a long and fruitful life.

Fast forward 10 months from the surgery, Ava is set to take part in the Transplant Games, an international event where all athletes that have had organ transplants take part in. This means that Ava’s surgery was more than a success, it shows that she was able to get back to full health and get back to having an active life in just 10 months.

Both of these case studies show that OTC deficency is an extremely common disease, however it is also very treatable with the right kind of medical treatment, people who suffer from OTC deficency should seek help from experts and specialist, and consider having liver transplant surgery.

Sources:

http://www.liverpoolecho.co.uk/news/liverpool-news/anfield-schoolboys-miracle-recovery-rare-7382404

http://www.examiner.co.uk/news/west-yorkshire-news/golcars-ava-taylor-6-take-7371456