Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase deficiency is a rare genetic condition that causes ammonia to build up in the blood. 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.

Ammonia is a normal waste product formed when the body breaks down proteins, however it becomes toxic if levels are high, as happens if it is not properly removed from the bloodstream. The brain is especially sensitive to high levels of ammonia; increased ammonia can cause severe, permanent brain damage.

Ornithine transcarbamylase is an enzyme that is critically important in the conversion of ammonia to urea in the liver. 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. OTC deficiency is one of several disorders among the class of genetic diseases called urea cycle disorders.

OTC deficiency is an “X-linked” disorder because the gene is on the X chromosome. Since boys have only a single X chromosome, they will have severe disease if that one copy of the gene is abnormal. Girls have two X chromosomes and so even if one copy is abnormal, they usually are well because the other X chromosome is functional.

OTC deficiency is most common in newborn boys and symptoms generally appear anywhere between 24 hours to a few days after birth. This is known as an early-onset form of the disorder. Estimates of an early occurrence OTC deficiency range from 1 in 14,000 to 1 in 77,000 people.

Severe OTC deficiency causes symptoms soon after birth. These symptoms may include:

• Increased sleeping, progressing to lethargy and coma
• Poor sucking or inability to feed in an infant
• Vomiting
• Problems with breathing rate or body temperature

If not treated, the early-onset form of OTC deficiency can lead to coma, seizures and brain damage (i.e., cerebral palsy, intellectual disability). The longer the infant remains untreated (over hours to days), the greater the likelihood that severe brain damage and life-threatening complications will develop.

There is a less severe form sometimes called “partial OTC deficiency” which occurs mainly in girls/young women and can present in adolescence or young adulthood. These girls/women often notice symptoms after eating meat (because the large protein load results in higher ammonia levels) and therefore often eat very little meat or are vegetarians. Symptoms may also be unmasked by physical stresses such as pregnancy, surgery, fasting/dieting, or other illnesses.

Symptoms of late-onset OTC deficiency may include:

• Migraines
• Nausea/vomiting
• Mild developmental delays
• Intermittent episodes of confusion

Ornithine transcarbamylase deficiency is caused by changes in the OTC gene, which instructs the body to make the OTC enzyme. In OTC deficiency, the OTC gene is either damaged or missing.

OTC deficiency is an X-linked genetic condition because the OTC gene is located on the X chromosome. Girls have two X chromosomes, boys have one X and one Y. Since boys have only one X chromosome, if there is an abnormal or missing gene for the OTC enzymes, they have no back up and will have disease. Girls/women have two X chromosomes and therefore can generally tolerate one missing or abnormal copy (though some will experience symptoms as described above).

Women with one abnormal OTC gene will pass that onto their children 50% of the time. If the infant is a girl, she will be a carrier (her other X will be normal). If the infant is a boy, he will have disease as the abnormal X is his only copy. If a man with OTC deficiency has a child, there is a 50% chance the child will be a boy – inheriting a Y chromosome from his father and an X chromosome from his mother – and will not have OTC. If the infant is a girl, she will inherit his abnormal X chromosome and be a carrier for OTC deficiency.

Some infants with OTC deficiency are initially identified through newborn screening programs, but because the disorder is so rare, it is not mandatory in many states including Pennsylvania, New Jersey and Delaware.

In states that do not include testing for OTC deficiency as a newborn, the disorder is typically diagnosed after an evaluation of symptoms, a complete patient history, physical examination and blood tests.

It is important to talk to your child’s doctor about the best way to treat OTC deficiency in your child. While treatments can vary, the goal remains the same: to maintain normal ammonia levels to prevent brain damage.

Treatments may include:

• Newborns generally will require dialysis in an ICU setting to lower blood ammonia levels quickly
• After initial treatment in the hospital, disease management may include:
  • A diet low in protein
  • Special infant formula or food
  • Amino acid supplements like arginine and citrulline to help lower ammonia levels
• In many cases, a liver transplant is recommended as peaks in ammonia levels can cause repeated brain injury and permanent brain damage.

In addition to standard therapies, there are several clinical trials being conducted around the county to better understand OTC deficiency and propel new advances in treatment and long-term management of the condition.

Individuals living with a rare genetic disorder are impacted daily, but there are some preventative steps patients can take to help them anticipate the onset of an OTC deficiency episode, including periodic blood tests to determine levels of ammonia in the blood. Elevated levels of glutamine, an amino acid, in the blood is often a precursor to a peak in ammonia.

Genetic testing is recommended for individuals with OTC deficiency and their families.