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Pioneering Treatment Cures Infant Of Often-Fatal Metabolic Disorder At Packard Children’s Hospital


PALO ALTO, Calif.
-- As he was being born at Lucile Packard Children’s Hospital, Dean Thao received infusions of a medication — never before given prenatally — for a rare metabolic defect that usually causes permanent brain damage, and often death. Thanks to medical geneticists at the hospital who identified the defect at 34 weeks gestation, the doctors were prepared to begin treatment at labor and continued to guard and treat his condition over the next three months until, on March 8, he could get a new liver.
 
Now, baby Dean is believed to be the first case of ornithine transcarbamylase deficiency to be cured with this novel one-two punch of an approach to treatment.

 

Replacing Dean’s liver is a perfect example of “gene therapy with a scalpel,” said Gregory Enns, MB, ChB, director of the biochemical genetics program at Packard Children’s. “Our job was to keep his brain as safe as possible — through labor, to birth and then to transplant — so that he would have the best chance of a good outcome.”
 
Ornithine transcarbamylase, or OTC, deficiency, is a genetic disorder that appears in one in 40,000 births. Because of a genetic defect, the body’s metabolic machinery is jammed, with the liver failing to function properly. The result can be sudden spikes of ammonia, from normally small amounts naturally occurring in the body to levels that are toxic. Although the disease has its primary metabolic effect in the liver, it is the brain that bears the brunt of OTC deficiency.
 
Doctors have rescued children with OTC deficiency and other metabolic disorders before by using specialized medicine infusions, intensive nutritional support, and liver transplantation. Indeed, Enns, who is also associate professor of pediatrics in the Division of Medical Genetics at Stanford University School of Medicine, has worked with Packard Children’s pediatric liver transplant team to treat eight children with OTC deficiency at the hospital.
 
But often by the time Enns and others intervened after birth, the children’s brains had suffered damage. More than half of kids surviving OTC deficiency crises have brain damage, and about 80 percent have developmental issues, Enns said. “The neurological outcome is typically very poor,“ he noted. “We have a number of children with urea cycle disorders with normal intelligence, but often the damage is already done at the time of diagnosis, since these disorders are so severe and strike so quickly.”

 

The solution, Enns said, would be to switch out the liver with one that has intact genes — before the brain takes a hit.
 
With OTC deficiency, a crisis often occurs in the first day or so of life. Parted from the mom’s nutrient stream, the baby’s metabolism kicks into high gear. Diagnosis is by symptoms: lethargy, poor feeding and coma, in rapid order. Prenatal diagnosis is still quite uncommon. So when an amniocentesis a few months before Dean’s delivery confirmed that he had the disease, Enns was ready to implement a bold new approach.
 
At Risk
 
Shoua Yang came to Packard Children’s worried she had a fetus at risk. Her own mother had lost two sons, though no one had attributed those deaths to genetics. When Yang lost her own firstborn son 10 years ago, she was told the cause was an OTC deficiency. But it was easier back then to leave it as “God’s will,” she said, than to acknowledge the gene defect. She went on to have two daughters and a son, all healthy.
 
When Yang became pregnant last year with Dean, midwife Renee Halstead, MD, of Women’s Specialty Center in Clovis, CA, urged her to get the amniocentesis. “Dr. Halstead was hard to say no to,” said Yang. “She pushed me to get tested. Now, I am so thankful.”

“And I needed to find out,” she added, “for my girls.”
 
The disorder is caused by a defect on the X chromosome. What that means is that OTC deficiency fully affects only boys, as males have only one X chromosome. In girls, with two X chromosomes, the normal one can compensate for the bad one. Her daughters could be carriers. But the vital question was whether Yang was passing the OTC gene to this new son. ”Our prenatal and biochemical genetics team is among a select group nationally that has the expertise to identify and care for OTC deficiency,” said Enns. “We had to sequence the gene in the mom, then look for it in the fetus.” The particular mutation had to be found and sought in the fetal cells obtained. And indeed, the amnio showed it was there.
 
To prevent an ammonia spike during Yang’s labor on November 17, 2009, Enns and his colleagues put part one of their plan in motion, first infusing a solution of sodium phenylacetate and sodium benzoate, along with arginine hydrochloride, into Yang’s bloodstream to safely capture the toxin. These infusions help to ‘scavenge’ excess ammonia in urea cycle disorder patients. This was the first time the combination of infusions was carried out during labor as far as we know, Enns said.
 
After the birth, mom and baby stayed close to Packard Children’s at the Ronald McDonald House at Stanford to await a donor liver and transplant, which would effect the cure. Yang fed Dean a special low-protein formula and she watched for low body temperature or tiredness that could indicate another ammonia spike — he had a mild one in December that was treated quickly in the hospital’s Neonatal Intensive Care Unit.
 
On March 8, Yang was told that a matching liver for Dean was available. Carlos Esquivel, MD, PhD, director of transplantation, led the surgical team in a four-hour procedure.  According to medical literature, Enns said, this makes Dean the first documented infant with OTC deficiency to undergo a liver transplant after continuous treatment with this combination of medications and monitoring from before birth.
 
Now, with regular outpatient visits to clinics at Packard Children’s to check Dean’s progress, Yang and her growing boy are looking to the future and what will hopefully be a normal life back home with his sisters and brother. “We are looking forward to the happy days ahead,” said Yang.
 
Dean’s experience is definitely a new standard of care, “but only specialized institutions are able to do this,” said Enns. “You need the experience. It’s setting the bar high, but it does set a goal in place.”
 
“Our whole focus was to provide treatment that would keep his brain healthy, and so far things are looking great,” said Enns, who plans to publish the case. “Though Dean will always need medications to help avoid transplant rejection and there may be other issues, he now has an excellent chance at a full, active life.”

Authors

About Stanford Children’s Health and Lucile Packard Children’s Hospital Stanford
Stanford Children’s Health, with Lucile Packard Children’s Hospital Stanford at its core, is an internationally recognized leader in world-class, nurturing care and extraordinary outcomes in every pediatric and obstetric specialty from the routine to rare, for every child and pregnant woman. Together with our Stanford Medicine physicians, nurses, and staff, we deliver this innovative care and research through partnerships, collaborations, outreach, specialty clinics and primary care practices at more than 100 locations in the U.S. western region. As a non-profit, we are committed to supporting our community – from caring for uninsured or underinsured kids, homeless teens and pregnant moms, to helping re-establish school nurse positions in local schools. Learn more about our full range of preeminent programs and network of care at stanfordchildrens.org, and on our Healthier, Happy Lives blog. Join us on Facebook, Twitter, LinkedIn, and YouTube.

Lucile Packard Children’s Hospital Stanford is the heart of Stanford Children’s Health, and is one of the nation’s top hospitals for the care of children and expectant mothers. For a decade, we have received the highest specialty rankings of any Northern California children’s hospital, according to U.S. News & World Report’s 2014-15 Best Children’s Hospitals survey, and are the only hospital in Northern California to receive the national 2013 Leapfrog Group Top Children’s Hospital award for quality and patient care safety. Discover more at stanfordchildrens.org.

About Stanford University School of Medicine
The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.