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