Ornithine Transcarbamoylase Deficiency

Ornithine transcarbamoylase deficiency is a rare inherited disorder that prevents the body from safely removing ammonia from the blood, potentially causing severe brain damage if ammonia levels become too high.

Table of contents

• What is Ornithine Transcarbamoylase Deficiency?
• Causes and Inheritance Pattern
• How Common is the Condition?
• Signs and Symptoms
• Diagnosis
• Treatment and Management
• Complications and Prognosis

What is Ornithine Transcarbamoylase Deficiency?

Ornithine transcarbamoylase deficiency is a rare genetic condition that causes ammonia to build up in the blood^[1]. The condition, more commonly called OTC deficiency, is more common in boys than girls and tends to be more severe when symptoms emerge shortly after birth^[1].

Ammonia is a normal waste product formed when the body breaks down proteins. However, it becomes toxic if levels are high, particularly because the brain is especially sensitive to elevated ammonia levels^[1]. When not properly removed from the bloodstream, increased ammonia can cause severe, permanent brain damage^[1].

The enzyme ornithine transcarbamoylase is critically important in the conversion of ammonia to urea in the liver^[1]. After urea is formed in the liver, it travels through the bloodstream to the kidneys, where it is eliminated from the body in the urine^[1]. OTC deficiency is one of several disorders among the class of genetic diseases called urea cycle disorders^[1].

• Liver
• Kidneys
• Brain

Causes and Inheritance Pattern

OTC deficiency is caused by changes in the OTC gene^[3]. This gene provides instructions for making the ornithine transcarbamoylase enzyme^[3]. Researchers know of at least 400 different DNA changes that can cause this condition, although about 1 in 5 cases don’t have a DNA change that tests can detect^[4].

OTC deficiency is an X-linked disorder because the gene is on the X chromosome^[1]. This inheritance pattern explains why males and females are affected differently. Since boys have only a single X chromosome, they will have severe disease if that one copy of the gene is abnormal^[1]. Girls have two X chromosomes and so even if one copy is abnormal, they usually are well because the other X chromosome is functional^[1].

There are two ways that DNA changes can happen. A baby can inherit the DNA change from their mother, which happens in between 36% and 80% of OTC deficiency cases depending on the country^[4]. Male children who get the DNA change develop the disease, while female children who get the DNA change become carriers^[4]. Alternatively, these are DNA changes that a baby didn’t inherit but happened randomly at some point during fetal development^[4].

In females who carry one altered copy of the OTC gene, the severity of symptoms depends on a process called X-inactivation. Some females with only one altered copy of the gene show signs and symptoms of ornithine transcarbamoylase deficiency, while others may have no symptoms at all^[3]. Research shows that between 10% and 20% of female carriers develop symptoms at some point^[4].

How Common is the Condition?

Estimates of the prevalence of ornithine transcarbamoylase deficiency have ranged from 1 in 14,000 to 1 in 80,000 people^[3]. OTC deficiency is rare overall, but it’s the most common urea cycle disorder^[4]. Individuals with the neonatal-onset form of the disorder are more likely to be counted in these estimates, because people with the late-onset form are less likely to come to medical attention^[3].

Signs and Symptoms

Ornithine transcarbamylase deficiency can become evident at any age^[3]. The symptoms depend partly on when it first develops, with symptoms usually much more severe with the neonatal form^[4].

Neonatal-Onset Form

The most severe form of OTC deficiency occurs in the first few days of life, usually affecting males^[3]. This neonatal-onset form is very rare in females^[3]. An infant with the neonatal-onset form may be lacking in energy (lethargic) or unwilling to eat, and have a poorly-controlled breathing rate or body temperature^[3].

Symptoms in newborns include^[4]:

• Refusing to eat
• Vomiting
• Irritability
• Lethargy
• Seizures
• Weak muscle tone (hypotonia)
• Enlarged liver (hepatomegaly)

Infants with this disorder may be described as “floppy” and can experience seizures or coma^[3]. Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia (high ammonia levels in the blood) in the first week of life, most often on day two to three of life, and are usually catastrophically ill by the time they come to medical attention^[7].

Late-Onset Form

In some affected individuals, signs and symptoms of ornithine transcarbamylase deficiency may be less severe, and may not appear until later in life^[3]. The late-onset form of the disorder occurs in both males and females^[3]. OTC deficiency has three types based on age of onset: neonatal (first 30 days of life), intermediate (between 1 month and 16 years), and late (after age 16, which can appear as late as age 60)^[4].

Children between 1 month and 16 years old can have the same symptoms as newborns, plus^[4]:

• Confusion
• Delirium
• Loss of coordination (ataxia)

People with late-onset ornithine transcarbamylase deficiency may experience episodes of altered mental status, such as delirium, erratic behavior, or a reduced level of consciousness^[3]. Headaches, vomiting, aversion to protein foods, and seizures can also occur in this form of the disorder^[3].

Adult symptoms can include any of the same symptoms as in newborns and children, plus^[4]:

• Nausea
• Migraines
• Trouble speaking (dysarthria)
• Hallucinations
• Blurred vision or other vision disruptions

A detailed dietary history of an affected individual with undiagnosed OTC deficiency will often reveal a history of protein avoidance^[5]. Although late onset forms of the disease are often considered milder than the classic infantile presentation, any affected individual is at risk for an episode of hyperammonemia that could still be life-threatening, if presented with the appropriate stressors^[5].

Diagnosis

The diagnosis of OTC deficiency is established through a combination of clinical findings, laboratory tests, and genetic testing^[7].

Blood testing can determine if there are excessive amounts of ammonia in the blood^[8]. However, high levels of ammonia may characterize other disorders as well^[8]. In suspected individuals, genetic testing is usually confirmatory, although studies have documented instances where routine gene sequencing did not identify any disease-causing variants, underscoring the importance of clinical and biochemical suspicion in diagnosing this rare yet potentially devastating disorder^[2].

The diagnosis of OTC deficiency is established in a male patient with suggestive clinical and laboratory findings and at least one of the following^[7]:

• A hemizygous pathogenic variant in OTC by molecular genetic testing
• A markedly abnormal increase of orotic acid excretion in a random urine collection or after an allopurinol challenge test, along with a past medical history of biochemical features consistent with OTC deficiency (such as elevated ammonia, elevated glutamine and low-to-normal citrulline)
• Decreased OTC enzyme activity in liver

The diagnosis in females usually requires similar testing approaches, with genetic testing identifying a heterozygous pathogenic variant in OTC or urine testing showing increased orotic acid excretion^[7].

DNA genetic testing would be performed to confirm a diagnosis of OTC as part of a thorough genetics work up^[8].

Treatment and Management

The mainstay of treatment of OTC deficiency is dietary protein restriction and ammonia scavenging agents^[10]. A multidisciplinary team approach involves pediatricians, neurologists, geneticists, dieticians and physicians^[8].

Acute Management

Immediate temporary discontinuation of protein intake in a symptomatic individual with ornithine transcarbamylase deficiency is mandatory, with compensatory increases in carbohydrates and lipids in order to offset any catabolic tendency to draw on muscle amino acids for energy^[10]. However, prolonged cessation of protein intake should be avoided due to risk for catabolism^[10].

In a patient who is comatose with extremely high blood ammonia levels (in some cases exceeding 2000 mg/dL), rapid reduction can be achieved with hemodialysis^[10]. Intravenous administration of sodium benzoate, sodium phenylacetate, and arginine is important; however, these drugs should be administered in a large medical facility setting with close laboratory monitoring available^[10].

Long-Term Management

Treatment for OTC deficiency is aimed at preventing excessive ammonia from being formed or removing excessive ammonia^[8]. Dietary restrictions in individuals with OTC deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia^[8].

Infants with OTC deficiency are placed on a low protein, high-calorie diet supplemented by essential amino acids^[8]. Additionally, patients with OTC deficiency are treated by medications that stimulate the removal of nitrogen from the body^[8].

A biochemical geneticist and a highly trained nutritionist should administer long-term outpatient care with laboratory monitoring available^[10]. Close attention should be paid to growth and nutrition^[10]. Scrupulous adherence to the dietary and medication recommendations is mandatory for optimizing outcomes and survival^[10].

Liver Transplantation

Liver transplantation is considered curative for OTC deficiency^[10]. It allows for cessation of dietary protein restriction and ammonia scavenging agents, but will not reverse pre-existing neurologic injury^[10]. For this reason, early liver transplantation (typically, by 6 months of age) is recommended for individuals with severe neonatal-onset disease^[10]. Late-onset males and heterozygotes may undergo liver transplantation if deemed favorable to medical management^[10].

For those with more severe or non-responsive cases of OTC who progress towards liver failure, the next treatment option is liver transplantation^[8]. Fortunately, this group of patients has a favorable long-term outlook^[8].

Complications and Prognosis

OTC deficiency can lead to high ammonia levels that poison the brain, causing metabolic encephalopathy^[4]. Ammonia is only toxic to the brain; other tissues can handle elevated ammonia concentrations without problems^[5].

When high ammonia levels are severe and last longer, they can cause the following complications^[4]:

• Intellectual disability and developmental delays
• Cerebral palsy
• Coma
• Death

Complications from ornithine transcarbamylase deficiency may include developmental delay and intellectual disability^[3]. Progressive liver damage may also occur^[3]. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits^[7].

Complications are more likely and often more severe with the neonatal type of OTC deficiency^[4]. The prognosis with severe OTC deficiency is well correlated with the length of the hyperammonemic period rather than the degree of hyperammonemia or the presence of other symptoms, such as seizures^[5].

No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life^[7]. The severity of OTCD ranges from potentially lethal to enduring neurocognitive deficits^[2].

OTC deficiency can also be very dangerous when a woman is pregnant^[4]. OTC deficiency does not affect fertility or the ability to have children^[18]. However, pregnant women with OTC deficiency must follow a careful diet with special guidance from a dietician and health care providers, and must be followed very carefully by their doctors^[18].

OTC deficiency, Ornithine Carbamoyltransferase Deficiency