Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Ornithine Transcarbamylase Deficiency

What is Ornithine Transcarbamylase Deficiency?

• Ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder (though still rare overall), is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia, which is formed when proteins are broken down in the body.​
• It is estimated that approximately 10,000 patients are affected by OTC deficiency worldwide; however, many cases go misdiagnosed or undiagnosed.​
• It is imperative to distinguish ornithine transcarbamylase deficiency from other genetic disorders that cause hyperammonemia. ​​
• Treatment includes hydration, arginine, and hemodialysis. Arginine supplementation bypasses the OTC enzyme in the urea cycle, allowing for urea creation and ammonia elimination. ​
• No known cure
• The largest percentage of living patients experience late-onset disease, representing a clinical spectrum of disease severity. ​
• Ornithine transcarbamylase deficiency can become evident at any age. The most severe form occurs in the first few days of life. ​
• This neonatal-onset form of the disorder usually affects males; it is very rare in females. ​
• An infant with the neonatal-onset form of ornithine transcarbamylase deficiency may be lacking in energy (lethargic) or unwilling to eat, and have a poorly-controlled breathing rate or body temperature.​

How Do You Get It?

• OTC deficiency belongs to a group of genetic diseases that affect the urea cycle (urea cycle disorders). ​
• It is caused by mutations in the OTC gene. This gene gives the body instructions for making the OTC enzyme.​
• The urea cycle is a chain of reactions in liver cells, which processes the nitrogen that is left over when protein is used by the body. ​
• It uses the nitrogen to make urea, which is then eliminated by the kidneys. The OTC enzyme is needed for a specific reaction in the urea cycle. ​
• Mutations in the OTC gene impair the OTC enzyme’s ability to function. This causes nitrogen to build up in the blood, in the form of ammonia. The toxicity of the ammonia in the blood damages the nervous system and causes the features of OTC deficiency.​
• OTC is inherited in an X-lined recessive manner, and males who inherit a single mutation in their OTC gene on the X-chromosome are the most commonly affected.​
•  Females may inherit single mutation in OTC on one of their two OTC genes.​
•  A carrier female is estimated to have at least a 15% chance of being affected with clinical symptoms and be at risk for hyperammonemia. ​​
• Carrier (or heterozygote) females will have a 50% chance of transmitting this mutation to each son who would be clinically affected and a 50% chance of transmitting this mutation to each daughter who would also have a 15% chance of clinical disease.​

What Are The Symptoms?

• Most commonly, symptoms of OTC deficiency begin in infancy (the early-onset form). ​
• An infant with OTC deficiency may be lacking energy (lethargic), be unwilling to eat, and have problems with breathing rate or body temperature. ​
• Some babies with OTC deficiency experience seizures, unusual body movements, or go into a coma. If not treated, this form can lead to complications including developmental delay, intellectual disability, progressive liver damage, skin problems, and brittle hair.​
• Symptoms may be triggered by eating foods high in protein, illness, or steroid medications.

• In some people with OTC deficiency, signs and symptoms are less severe and do not begin until later in life (the late-onset form). ​

• Symptoms are triggered by a build-up of ammonia and may include:​

  • Episodes of delirium, erratic behavior, or reduced consciousness​
  • Headaches​
  • Vomiting​
  • An aversion to foods high in protein
  • Seizures​

How Is It Treated?

• The treatment of OTC deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. ​
  • Dietary restrictions in individuals with OTC deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. 
  • However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with OTC deficiency are placed on a low protein, high calorie diet supplemented by essential amino acids. ​​
• Long-term therapy for OTC deficiency combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).​
  • In addition to dietary restrictions, individuals with OTC deficiency are treated by medications that stimulate the removal of nitrogen from the body.​
• Treatment of an individual with OTC deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticist, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. ​
  • Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.​
• A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula (e.g., UCD Anamix Junior, Nutricia; Cyclinex, Abbott; WN1, Mead Johnson; or UCD Trio, Vitaflo), and a calorie supplement without protein is often used (e.g., Pro-Phree, Abbott, PFD, Mead Johnson,). Essential amino acids supplements may also be used (EAA mix, Nutricia; EAA supplement Vitaflo).​ ​
• These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. ​
• These medications are unpalatable to many patients and are often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube).​
• Treatment includes hydration, arginine, and hemodialysis. Arginine supplementation bypasses the OTC enzyme in the urea cycle, allowing for urea creation and ammonia elimination. ​
  • Individuals with OTC deficiency benefit from treatment with arginine, or its precursor citrulline, which are needed in order to maintain a normal rate of protein synthesis. 
• Liver Transplant
  • In some cases, liver transplantation, either cadaveric or from a living donor, may be an appropriate treatment option. ​
  • Liver transplantation can cure the hyperammonemia in OTC deficiency. However, this operation is risky and may result in post-operative complications. ​
  • Also, after liver transplantation, patients will need to take medications life-long for immunosuppression.​
• Preventive Care
  • Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood.​
  •  In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks.​
  •  Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. ​
  • Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear. Blood tests should also be performed to monitor phenylbutyrate levels in order to assure a proper dose is used and to avoid a potential overdose.

Approved Medications Include:

• The orphan drug sodium phenylbutyrate (Buphenyl), manufactured by Hyperion Therapeutics, has been approved by the Food and Drug Administration (FDA) for the treatment of chronic hyperammonemia in OTC deficiency. ​
• In 2013, a new medication, glycerol phenylgutyrate (Ravicti), also manufactured by Hyperion Therapeutics, was approved by the FDA for treatment of chronic hyperammonemia in patients with urea cycle disorders.
• Ammonul (sodium phenylacetate and sodium benzoate), manufactured by Valeant Pharmaceuticals, is the only FDA-approved adjunctive therapy for the treatment of acute hyperammonemia in patients with urea cycle disorders.​

Where Can I Learn More???

• Check out our cornerstone on this disease here.