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Severe OTC Deficiency Disorder: A Case Study


Cartoon image of a molecule

Could treatment from before birth stave off a deadly disease until transplant?

The family had lost two children to ornithine transcarbamylase (OTC) deficiency disorder. The first died within days of birth, the death misattributed to SIDS. The second was correctly diagnosed after his health began to decline, his mother identified as the carrier, but by that point the buildup of ammonia in his system had done irreparable brain damage. He died at 16 months during an episode of high ammonia. When the mother became pregnant again, a team of specialists at Children’s Hospital Colorado had a plan.

The biology of OTC deficiency disorder

Every animal needs a mechanism for clearing ammonia, a natural byproduct of the breakdown of amino acids. In humans, that mechanism is called the urea cycle. One of its many moving parts is the gene OTC, the instruction for an enzyme called ornithine transcarbamylase that catalyzes an early stage of the chain of reactions needed to convert ammonia to urea, the less toxic substance that gives the cycle its name.

“If you have a defect in the instruction to make that enzyme, the liver can’t detoxify ammonia, and it builds up rapidly, which can cause severe brain damage,” says clinical biochemical geneticist Shawn McCandless, MD. “This family is missing the entire gene.”

The OTC gene is carried on the X chromosome. Having two X chromosomes, the mother carried a mix of normally functioning cells and OTC deficient cells in her liver her entire life without noticing. With only one OTC deficient X chromosome, her baby boys had no way to produce the enzyme at all.

Her next pregnancy, too, was a boy.

“As soon as we knew, we brought her in to get tested,” Dr. McCandless says.

Metabolic research at Children’s Colorado

Children’s Colorado’s Metabolic Service, a group of specialists dedicated to inborn errors of metabolism, is among the largest in the country. It’s led by Dr. McCandless, who also serves as a leader of the Urea Cycle Disorders Consortium, one of the first consortia established within the Rare Disease Clinical Research Network of the National Institutes of Health. The genetic testing was done at Children’s Colorado’s Anschutz Medical Campus.

The test came back positive. Until birth, the placenta would do the work of clearing ammonia from the fetus’s body, but the team wanted to start with a clean slate. Pediatric biochemical geneticist Austin Larson, MD, a member of the metabolic team, started the mother on mix of treatments to clear nitrogen from baby’s body the day before delivery, ensuring the baby would be treated from the moment the umbilical cord was cut. The mother delivered at Children’s Colorado’s Colorado Fetal Care Center, and they started IV treatment within hours of birth.

A few days later, the baby transitioned to a drug called glycerol phenylbutyrate, which accomplishes the same thing but can be taken by mouth. The Metabolic Service was involved in clinical trials for it, before it was approved by the FDA in 2013.

Free of injury: OTC deficiency treatment

Therapy continued after birth with tight monitoring from Children’s Colorado’s Level IV Neonatal Intensive Care Unit, and the baby has been there since. The NICU and Metabolic teams check his blood ammonia constantly and adjust medications and the precise amount of protein in his diet to maximize growth and minimize ammonia production.

“We keep an eagle eye on him,” Dr. McCandless says. “If there’s even a hint his ammonia levels are rising, we treat it aggressively. Every time this baby is fussy, he gets his ammonia checked.”

The good news is that the transplanted liver will contain the enzyme needed to convert ammonia. It will essentially be curative. The transplant team was consulted soon after birth, and the baby was listed for transplant as soon as the team felt it could safely be done. He’s currently listed.

“It’s really unusual for boys with severe OTC deficiency to survive,” he says. “And those who do have really bad brain injury. We expect this boy to grow up free of injury from high ammonia.”

Better yet, it’s possible that one day soon a transplant may no longer be necessary. Dr. McCandless’s team is currently involved in clinical trials for the first gene therapy for the condition.