What is Urea Cycle Disorders?
Urea Cycle Disorders (UCDs) are a type of health issue that a person is born with, where problems occur in the body’s process of removing waste materials. More specifically, these disorders arise from defects in any one of six enzymes or two transporters that help the liver remove ammonia from the bloodstream. This ammonia is converted into a substance called urea, which is then disposed of by the kidneys.
These types of disorders fit under a larger umbrella of health conditions known as inborn errors of metabolism (IEMs). IEMs can be split into two main types: those caused by a lack of certain enzymes needed to convert fats or carbohydrates into energy, and those caused by a lack of specific enzymes needed to break down substances like amino acids. When these enzymes are lacking, these substances can pile up and become toxic if not treated. UCDs belong in this second category.
When the body breaks down proteins, it releases amino acids. The breaking down (or deamination) of these amino acids produces ammonia. Here’s a simple way to visualize this process:
+H3N-CHR-COO- –> O=CR-COO- + NH4+
Ammonia, however, is very harmful, especially to our brains. Newborns with severe mutations in any one of the first four enzymes of the urea cycle can suddenly become extremely ill within one to two days after birth, despite seeming healthy at birth. This means a newborn could be sent home from the hospital before signs of UCDs appear, leading to possible unrecognized symptoms at home.
A condition called hyperammonemia, which means having too much ammonia in the blood, is critical in diagnosing UCDs. Treatment should not be delayed while trying to reach a final diagnosis.
What Causes Urea Cycle Disorders?
Urea Cycle Disorders (UCDs) happen when there’s a problem with various proteins in two parts of the cell, namely, the ‘mitochondrial matrix’ and ‘cytoplasm’. The urea cycle is a biochemical process in our body that gets rid of excess nitrogen (in form of urea) that is produced during the digestion of protein. Now let’s break it down for you.
Our body goes through several steps in the urea cycle:
Step 1 involves an enzyme called carbamoylphosphate synthetase I (CPS1), which combines ammonia and bicarbonate to create a substance called carbamoyl phosphate. If there is a defect in CPS1, certain stressful situations such as severe infection (sepsis), can cause serious UCDs and high ammonia levels. It’s also important to note that N-acetylglutamate plays a role in enhancing the action of CPS1. If there’s a problem with an enzyme that creates N-acetylglutamate, it can cause conditions similar to when CPS1 is defective, resulting again in high ammonia levels.
In step 2, the liver enzyme, ornithine transcarbamylase (OTC), reacts with carbamoyl phosphate to create citrulline. The gene for OTC lies on the X chromosome, which affects how this disorder is inherited. Defects in OTC are the most common cause of UCDs. Males with this defect tend to have a severe form of UCD. The severity in females varies widely. The ornithine needed for OTC has to be transported into the mitochondrial matrix and defects in this transport process, although rare, can later result in high levels of ammonia.
Step 3 and all the following steps happen in a part of the cell called the cytoplasm. Here, argininosuccinate synthase 1 (ASS1) helps create argininosuccinate from citrulline and aspartic acid. Problems with ASS1 can cause elevated citrulline levels and high ammonia levels.
Step 4 involves the breakdown of argininosuccinate to produce fumaric acid and arginine, guided by the enzyme argininosuccinate lyase (ASL). Defects in ASL can cause severe UCD, particularly in newborn babies, resulting in persistent high levels of ammonia if not treated.
In the final step of the urea cycle, arginine is split into urea and ornithine by the arginase enzyme. A defect in arginase can result in both argininemia (high arginine levels) and high ammonia levels. Symptoms of arginase deficiency usually appear by the age of three.
Risk Factors and Frequency for Urea Cycle Disorders
Urea Cycle Disorders (UCDs) are not common, occurring in about 1 out of every 35,000 births. Currently, most state labs can only detect 2 out of the many conditions that could cause UCDs. Around two-thirds of all UCDs are caused by mutations in a gene called OTC, one-fifth are due to ASS1, and one-tenth are due to ASL.
Signs and Symptoms of Urea Cycle Disorders
Newborns with Urea Cycle Disorders (UCDs) usually seem normal at birth but may soon exhibit nonspecific symptoms that are similar to those of many inherited metabolic disorders (IEMs) or even an infection. These include fatigue or lethargy, lack of appetite, vomiting and being overly irritable. When viewing any infant presenting with these symptoms, it’s important to consider the possibility of IEMs in the diagnostic process. Apart from arginase deficiency, most babies with severe UCDs quickly develop brain swelling and subsequent neurological issues due to elevated levels of ammonia in the blood, a condition known as acute hyperammonemia. If not treated timely, severe UCDs can cause this hyperammonemia to progress into coma and even death. Mild UCDs can trigger hyperammonemia due to various stress factors such as illness and surgery.
- Fatigue or lethargy
- Lack of appetite
- Vomiting
- Overly irritable
- Possible development of brain swelling
- Subsequent neurological issues
- Potential progression to coma or even death
Testing for Urea Cycle Disorders
In testing for Urea Cycle Disorders (UCDs), a primary indicator, or “biomarker,” is hyperammonemia. This means higher than normal levels of ammonia in the blood. Specifically, anything over 150 micromolar (a unit for measuring the amount of a chemical substance in a solution) for a newborn, or over 100 micromolar for an infant, could signify a UCD. Additionally, this must be in the absence of a high anion gap (meaning, the difference between measured cations (positively charged ions) and anions (negatively charged ions) is normal range) and there should be normal blood sugar levels.
Supplemental to testing the blood ammonia level, it’s also beneficial to check the levels of plasma amino acids and plasma lactic acid, especially if the metabolic acidosis (a condition that occurs when your body produces more acid than it can neutralize) is present.
Certain characteristic symptoms of UCDs that could show up in lab results include elevated levels of plasma glutamine (an amino acid used in the biosynthesis of proteins) and alanine (another type of amino acid), reduced plasma arginine (except in cases of arginase deficiency, which is a rare inherited disorder that’s usually marked by stiffness or tightness in the legs), and either high or low plasma citrulline levels (citrulline is an amino acid that helps the body eliminate ammonia, a toxic waste product).
Treatment Options for Urea Cycle Disorders
If you’re diagnosed with UCDs, or any inherited metabolic disorder (IEM), it’s essential that your treatment is overseen by a genetics or metabolic health expert. These specialists will know how best to manage your unique condition.
If a newborn baby has high levels of ammonia in their blood (hyperammonemia), the immediate goal of treatment is to lower these levels quickly and limit the amount of protein they consume. High ammonia levels can cause harm, so it’s really important that they are decreased as soon as possible.
Hemodialysis, a process where a machine filters wastes and water from your blood, is very effective at reducing plasma ammonia (a type of ammonia in the blood) and so it should be started without delay if a baby’s blood shows high ammonia levels.
There are also certain medications that help get rid of excess ammonia. An example is a drug called Ammonul IV. This medicine works by removing substances known as glycine and glutamate from the blood, which helps to reduce the formation of ammonia.
A medication called N-carbamylglutamate (Carbaglu) is being studied for its potential in treating UCDs. Carbaglu is similar to a substance in the body called N-acetylglutamate. Preliminary studies suggest Carbaglu may help improve the body’s ability to get rid of excess nitrogen (a waste product from protein breakdown) in certain types of UCDs. However, more detailed clinical trials are currently underway to confirm these benefits.
What else can Urea Cycle Disorders be?
These are the symptoms, which could indicate a range of conditions:
- Loss of appetite
- Blurred vision
- Swelling in the brain
- Unconsciousness
- Abnormal breathing (either too fast or too slow)
- Unusually low body temperature
- Drowsiness or slugginess
- Seizures
- Slurred speech
