Ornithine Transcarbamylase Deficiency

What is Ornithine Transcarbamylase Deficiency?

Ornithine transcarbamylase deficiency (OTCD) is a hereditary condition that affects how the body breaks down and disposes of protein. It is passed down through families and is the most common problem found in a group of medical conditions called urea cycle disorders. Symptoms of OTCD vary and can exhibit differently in different people. Males fully affected by OTCD from birth often show signs such as excess ammonia in the blood, increased alkalinity in the body due to rapid breathing, and low body temperature. Also, symptoms can appear later in life in males with a partial lack of the necessary enzyme and females who carry the gene of the disease.

In people suspected to have OTCD, genetic testing usually confirms the diagnosis. Nevertheless, there are cases where standard testing of the gene responsible for OTCD doesn’t reveal any changes that would cause the disease. Even more advanced genetic testing methods and investigation of many urea cycle disorder-related genes have not been helpful in diagnosing these cases. This highlights the need for doctors to suspect the disease based on a patient’s symptoms and basic body chemistry levels, as OTCD, while rare, can have severe consequences if not diagnosed.

The understanding of how OTCD develops, its symptoms, and how it is diagnosed has been thoroughly examined. It’s essential to have a team of healthcare professionals who can work together to manage OTCD. By working together, they can ensure the best possible health outcomes and minimize the risk of complications related to the disease.

What Causes Ornithine Transcarbamylase Deficiency?

OTCD, short for Ornithine Transcarbamylase Deficiency is a genetic disorder linked to the X chromosome that interrupts the process by which the body breaks down and removes waste. This disorder is the most common form of what’s called a ‘urea cycle disorder’ worldwide. There’s a specific gene on the X chromosome responsible for creating the enzyme that facilitates this waste removal process. However, this gene has been found to have multiple variants that can cause OTCD. Notably, not all people diagnosed have a clearly identifiable variant of the gene, and about one in five diagnosed patients falls into this category. It’s thought that these patients may have alterations in areas of the gene that control or deeply affect its function.

What’s interesting about this disorder is that it can vary significantly from person to person, depending on the specific type of mutation, their genetic makeup, and their environment, among other factors. In a recent study conducted in Japan, 523 genetic variants that cause OTCD were identified, which include various forms of substitutions, deletions, duplications, and even mutations that couldn’t be categorized. It was also found that different types of alterations in the same position could lead to the onset of the disorder at different stages of life, and these variations were found to depend significantly on environmental factors.

Some of these environmental factors include long periods of fasting, a high-protein diet, pregnancy, and surgery. However, people with OTCD may also face repeated spikes in their ammonia levels (hyperammonemic crises) due to various other conditions such as infections, vomiting, internal bleeding, decreased food or protein intake, changes in the uterus after childbirth, chemotherapy, high-dose corticosteroids, and unusual protein intake. There are also certain medications known to potentially trigger these ammonia level spikes.

In women who carry OTCD gene alteration on one of their X chromosomes, the chances of developing symptoms of the disease depends on which of the X chromosomes gets deactivated during early development. In particular, if a male relative with the disorder showed symptoms at birth, these women have a higher chance of developing symptoms compared to those with a male relative who developed symptoms later in life.

Risk Factors and Frequency for Ornithine Transcarbamylase Deficiency

OTCD, or Ornithine Transcarbamylase Deficiency, is a condition that affects between 1 in 14,000 and 1 in 80,000 people. Various countries have reported slightly different rates of this condition in newborns, with Finland reporting approximately 1 in 62,000, the US 1 in 63,000, and Italy 1 in 69,904.

OTCD is the most common type of Urea Cycle Disorder (UCD), which tend to affect about 1 in 8,200 live births in the US. UCDs are seen more often in the US than globally. Although OTCD can occur at any age, it’s more common in newborns and early childhood than in adulthood. Because of its genetic nature, males are more likely to experience severe symptoms in the newborn period.

• About 10% of females who carry the gene for OTCD show symptoms, but this may be an underestimation, as some people with mild symptoms may not seek medical attention.
• According to a recent study in France, Turkey, and the UK, in France 34% of cases were males, 25% were symptom-free, and 41% were females with symptoms. In Turkey, it was found that 38% were male, 16% were symptom-free, and 46% were females with symptoms. In the UK, the numbers were slightly different, with 33% male, 41% symptom-free, and 26% females with symptoms.
• The same study also found that neonatal-onset cases made up 19% in France, 12% in Turkey, and 7% in the UK, while late-onset cases made up 39%, 42% and 67%, respectively. One key point to note is that UCDs aren’t included in routine neonatal screening in these countries, which likely means the actual number of cases may be higher.
• OTCD is mostly a genetically inherited disorder, with between 36% and 60% of patients reporting a family history of the disease. Earlier data suggested that around 60% of all OTCD cases were neonatal-onset, but recent data suggest that only 18% of symptomatic patients experience this, the majority (82%) showing symptoms after the neonatal period. This is probably due to underrepresentation of mild cases in earlier data, and possibly missed severe neonatal cases in recent data.

Signs and Symptoms of Ornithine Transcarbamylase Deficiency

OTC deficiency is a health condition that isn’t usually covered in routine newborn screenings. It is often found when symptoms start to show or if genetic testing signals a problem after an occurrence in the family. Early signs of OTC deficiency in a newborn involve fast breathing, vomiting, and sluggishness, which usually surface within a few days after birth. In severe versions of this condition that develops later, symptoms can include fatigue, loss of appetite, headaches in the morning, and confusion. If OTC deficiency is not managed properly, it could lead to issues like seizures, aggressive behavior, encephalopathy (a type of brain damage), coma, or even death.

In a European research study, the most common symptoms in patients with OTC deficiency were changed mental status and encephalopathy. Vomiting was identified as the most common stomach-related symptom. Some patients also reported liver failure or high liver enzyme levels as their first symptom.

For newborn babies with severe OTC deficiency, they usually seem normal at birth but develop hyperammonemia symptoms (having too much ammonia in the blood) in 2 to 3 days. The initial symptoms are reduced food intake and low muscle tone, which then develop into sluggishness and excessive sleepiness. Hyperventilation and seizures are common, often found through brain wave monitoring. Critically sick newborns may also present additional features like hypothermia, respiratory alkalosis, and severe encephalopathy.

In infants who reveal signs of OTC deficiency after newborn days, symptoms can occur when they transition from breast milk to formula or whole milk. These infants may display periodic vomiting, irritability, failure to thrive, and delayed development.

Older kids or adults with late-onset OTC deficiency can display unpredictable behavior and delirium, typically triggered by physical or psychological stressors like significant injury or surgery, serious illness, high-protein intake, prolonged fasting, post-birth conditions, or cancer treatments.

Females who are heterozygous carriers for OTC deficiency may not show any symptoms or recurrent hyperammonemia. Those with symptomatic disease might limit their protein intake and could go undiagnosed. Some heterozygous females may solely show minor cognitive deficits impacting executive functioning and motor capacity, without developing hyperammonemia or experiencing altered mental status.

Testing for Ornithine Transcarbamylase Deficiency

For newborns, the condition known as Ornithine Transcarbamylase Deficiency (OTCD) can be screened for by measuring the amount of a substance called citrulline in the blood. Another testing method involves looking at the ratio between two other substances, glutamine and glutamate. If there are low levels of citrulline and high levels of glutamine, it could indicate OTCD. However, these tests are not always fully reliable, so routine screening for OTCD isn’t typically recommended.

If the citrulline test shows unusual results, doctors can conduct more tests. These might include looking at blood ammonia levels, amino acid levels, and certain substances in the urine. Sometimes, similar results can be seen in diseases other than OTCD, such as N-acetyl glutamate synthetase deficiency or carbamoyl phosphate synthetase I deficiency. To distinguish between these, doctors will usually investigate the amount of a substance called orotic acid in the patient’s urine.

For a person to be diagnosed with OTCD, the person needs to have certain signs and symptoms, along with specific test results. These symptoms and results might include high levels of ammonia and glutamine in the blood, normal or low levels of citrulline, and no other known metabolic disorders. Furthermore, one of the following three criteria has to be met: a certain genetic variation in the OTC gene is found, or there’s an excess of orotic acid in the urine, or a liver biopsy shows decreased OTC enzyme activity in male patients. In female patients, a liver biopsy isn’t typically used for diagnosis, because of certain genetic factors that can result in incorrect results. Instead, genetic testing is preferred.

Genetic testing for OTCD usually involves analyzing the OTC gene for any anomalies. If none are found, the testing may be expanded to look for larger genetic changes. By using both of these testing methods, doctors are able to diagnose 80% to 90% of OTCD cases.

Measuring the activity of the OTC enzyme in a liver biopsy is the most definitive way of diagnosing OTCD. This test is especially useful for those who show symptoms of OTCD but don’t have any identifiable genetic issues. The amount of enzyme activity can vary, but usually, it’s less than 20% in severe cases and may reach up to 30% in milder cases.

Understanding the unique biochemical profile for OTCD is crucial. A high amount of ammonia in the blood, known as hyperammonemia, is consistently found in those with OTCD. Normal ammonia levels in infants typically rule out OTCD, but this might not be the case for adults.

Other tests are carried out, including measuring blood and urine levels of different substances. In OTCD, glutamine levels are increased, citrulline levels are decreased, and urinary orotic acid levels are elevated. Other disorders may share similar test results, but have different levels of other substances. It’s important to remember that while these biochemical tests are valuable, genetic testing is preferred where available.

Treatment Options for Ornithine Transcarbamylase Deficiency

Treatment for a condition known as Ornithine transcarbamylase deficiency (OTCD) requires both immediate and ongoing care from a team of doctors. Their primary goal is to manage the condition and stop an issue known as hyperammonemia (high ammonia levels in the blood) from happening.

Immediate Treatment of OTCD

During the initial phase of managing OTCD, the top priority is to quickly reduce high ammonia levels in the blood to 200 µmol/L or less. To do this, your doctors may make sure you are hydrated sufficiently, ask you to stop eating protein, and work to stop your body from breaking down protein, or catabolism.

Your doctors may use a dextrose-containing fluid, essentially a sugar fluid, to stop catabolism. They will monitor your glucose levels closely because having a sugar response that’s too high can lead to dangerous conditions.

Sometimes, your doctors may advise stopping protein intake for a short time to reduce the amount of ammonia your body makes. This strategy combined with using an intravenous glucose and lipids drip is usually enough if your blood ammonia levels are just slightly above normal for your age. It’s important to make sure you get enough calories from the glucose and lipid drips during this period. You should start eating protein again within 48 hours, ideally after your blood ammonia has returned to normal levels.

Managing High Ammonia

Medicines that remove excess nitrogen from the blood, known as nitrogen scavengers, can help reduce high levels of blood ammonia in OTCD. These medicines offer a different path for getting rid of excess nitrogen, and can be used quicker than kidney replacement therapies. Some of these include sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, and glycerol phenylbutyrate. Doctors will closely monitor their patients for side effects of these medications, such as nausea, vomiting, metabolic acidosis (when the blood gets too acidic), and changes in mental status.

In some cases, a procedure called hemodialysis may be needed to control hyperammonemia. This approach is especially effective when blood ammonia levels are extremely high or if the patient is not responding to intravenous nitrogen scavenger medications.

Managing Acute Hyperammonemia

Optimal caloric intake is essential in reversing the catabolic state often present in patients with OTCD who are experiencing a hyperammonemic crisis.

Long-Term Management

In the long-term, the focus of OTCD treatment is on preventing further hyperammonemia episodes and ensuring the patient develops adequately. This involves sticking to a low-protein diet, taking adequate amounts of citrulline and arginine supplements (two amino acids our bodies need), having enough essential amino acids, vitamins, and minerals, and taking the right doses of nitrogen scavenger therapies. Your doctor will work with you to draw up a detailed treatment plan that includes potential triggers for hyperammonemia, such as infections and surgeries, to prevent future episodes of hyperammonemia and ensure that you can manage these situations in the best possible way.

Liver Transplantation

Liver transplantation is the most effective treatment for patients with severe OTCD that started from birth. This surgery can prevent recurrent hyperammonemia episodes and stop the patient from further neurodevelopmental deterioration. However, the procedure can often have complications, especially in children, which limits how often it’s used. Advancements in transplantation techniques have made liver transplantation a viable option for patients with OTCD. Liver transplantation can minimize and, in some cases, completely prevent cognitive impairment. Significant improvements in nutrition and development, especially in those undergoing early transplantation, have been noted.

Other Treatments

Emerging molecular treatments, such as adeno-associated viral (AAV) vectors, are currently being explored as potential options for treating OTCD.

After a successful liver transplant for OTCD, patients can stop their dietary restrictions. However, any existing neurodevelopmental problems do not improve after the surgery.

What else can Ornithine Transcarbamylase Deficiency be?

It’s important to differentiate between Ornithine Transcarbamylase Deficiency (OTCD), a rare genetic disorder, and other conditions that can cause high blood ammonia levels. Such conditions can range from other Urea Cycle Disorders (UCDs), issues with breaking down organic acids or fats (organic acidemias or fatty oxidation defects), or problems with processing a key energy molecule, pyruvate.

Guiding signs that point more towards a UCD are high respiratory activity leading to alkalosis (an imbalance in body chemistry boosting basic substances), normal levels of anions (negative ions) and blood sugar, and a big increase in blood ammonia levels.

For a newborn male with high ammonia levels, the doctors would look into ruling out the following conditions:

• Deficiency of N-acetyl glutamate synthase (NAGS), an enzyme that activates the first step in the urea cycle
• Carbamyl phosphate synthetase I (CPSI) deficiency, which hinders the ammonia removal process
• Argininosuccinate synthetase (ASS) deficiency, a disruptor to the urea cycle
• Argininosuccinate lyase (ASL) deficiency, which can affect the breakdown of certain amino acids
• Rapidly progressing Hepatitis leading to liver failure (Fulminant hepatitis)

For cases of disease onset later in life, doctors would consider the aforementioned conditions and these additional conditions:

• Citrin deficiency, an issue with protein transportation in the liver
• Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, another urea cycle disorder
• Failure of multiple organs due to a lack of oxygen (hypoxia) or blood (ischemic injury)
• A potentially fatal blood clot in the major liver vein (Portal vein thrombosis)
• Sudden liver failure due to various causes such as damage from paracetamol (Acetaminophen toxicity)

What to expect with Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase deficiency (OTCD) is a condition that can cause serious health problems and even death, especially in newborns. A study found that the death rate was 24% for newborns with this condition and 11% for those who developed it later.

One important factor for a newborn in a severe state of high ammonia levels in blood (hyperammonemic crisis) is how long the high ammonia level lasts. The longer this occurs, the worse the outlook becomes. Interestingly, the peak level of ammonia doesn’t always accurately predict the situation’s severity, as those who receive rapid treatment fair better, even if they had higher peak levels.

Having seizures or not doesn’t necessarily reflect on the prognosis. However, blood ammonia and glutamine levels can provide insights into brain health outcomes.

European guidelines suggest having discussions about goals of care in patients who might not fully recover mentally before beginning treatment. Some signs that could lead to this approach include a hyperammonemic coma lasting for three days or more, increased pressure within the skull, and an extremely high level of ammonia in the blood.

It’s important to note that how long an individual has high ammonia levels tends to be a more accurate predictor of their outlook rather than their highest level of ammonia. A swift diagnosis and urgent treatment can improve outcomes, as can sticking to a low-protein diet and taking medication that helps the process usually handled by the OTC enzyme in the body process known as the urea cycle.

Those who develop OTCD later tend to have better outcomes as they may have some working OTC enzyme. The amount of remaining enzyme activity can show a later age of onset, lower initial peak ammonia level in blood, fewer hyperammonemic crisis incidences, and better survival rates. Having at least 4.3% remaining enzyme activity usually means a milder condition.

Possible Complications When Diagnosed with Ornithine Transcarbamylase Deficiency

Immediate complications of OTCD (ornithine transcarbamylase deficiency), a genetic disorder, can include acute liver failure and a serious condition called hyperammonemic encephalopathy. This can progress to the point that the patient falls into a coma and needs mechanical assistance to breathe due to acute respiratory failure. Long-term complications can include brain-related, neurological, and physical disabilities. There have also been reports of patients developing a type of liver tumor called hepatocellular adenoma.

Furthermore, OTCD can lead to psychological issues such as intellectual disability, delayed development, attention-deficit/hyperactivity disorder (ADHD), and emotional and behavioral problems. Studies have found a correlation between peak ammonia levels, frequency of hyperammonemic crises (dangerously high levels of ammonia in the body), and lowered cognitive and intellectual capacities. This negatively affects personal well-being, from school performance to the ability to carry out day-to-day tasks.

• Intellectual disability with developmental delay
• ADHD
• Emotional and behavioral problems
• Lowered cognitive and intellectual capacities

Quite surprisingly, around half of the school-age children fighting this disease might face internalizing problems, such as withdrawal, depression, anxiety, or bodily complaints. Even carrier females of the OTCD gene (heterozygous females), who have not shown any past signs of hyperammonemia, can experience mild cognitive impairment, trouble performing and coordinating skilled movements, and challenges in fine motor tasks despite having an average IQ.

A particular pattern of cognitive weakness has been identified in individuals with OTCD, which may affect fine motor skills, nonverbal intelligence, visual memory, attention, executive skills, and mathematical ability while leaving their verbal intelligence, learning, and reading abilities unaffected.

Complete psychoeducational evaluations in individuals fighting OTCD are fundamental, including those deemed as mere carriers. This is crucial to thoroughly understand the extent of cognitive and motor function implications that might be brought about by this condition.

Preventing Ornithine Transcarbamylase Deficiency

Newborn screening for OTCD, a gene mutation disorder, is not usually done because it may not be very useful. This is because the symptoms of the disorder in severe cases often show up before the screening results are available. Moreover, it can be challenging to accurately measure certain substances in the lab that are associated with OTCD. Furthermore, using levels of a substance called citrulline to screen for OTCD isn’t always reliable. Although it would be beneficial to have a reliable screening test, there isn’t enough data right now to recommend routinely screening all newborns for OTCD.

If OTCD is detected in a patient, either male or female, genetic counseling and testing of family members is recommended. This can help identify and treat family members who have no symptoms or only mild symptoms, preventing a condition called hyperammonemia, which is an excess of a waste product, called ammonia, in the blood. It’s also highly advised that these patients see a metabolic specialist, a geneticist, and a dietitian who specializes in metabolic disorders.

Treatment for OTCD patients includes medication that helps the body eliminate excess nitrogen, supplements associated with the urea cycle (the process in which the body breaks down proteins), and a carefully monitored protein intake. Recommended protein intake varies by age, but it’s important to work with a dietitian who specializes in metabolic disorders to determine the right protein level for each patient in order to avoid recurrent crises.