NEONATOLOGY AND METABOLICS
Case Study: Eagle Eye
Could treatment from before birth stave off a deadly disease until transplant?
The family had lost two children to 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.
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. 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.
Children’ s Hospital 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 a 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.
The plan: a timeline of treatment
June 2020: Mother becomes pregnant
Feb 2021: Genetic testing confirms OTC deficiency diagnosis
Feb 2021: Treatment with IV sodium phenylacetate begins hours before birth
8 | CHILDREN’ S HOSPITAL COLORADO