Newborn Screening for Rare Disorders Becomes Researcher’s Lifelong Mission

Kaitlyn and Ryan Wyckoff travel from their hometown of Wasilla, Alaska, to Seattle Children’s so Dr. Sihoun Hahn (center) can monitor and treat them for Wilson disease — a rare genetic disorder.

For the first 15 years of his life, Ryan Wyckoff appeared to be a perfectly healthy, active teenager, living with his family in Wasilla, Alaska.

But during New Year’s weekend in 2009, Ryan began to feel seriously ill. He was lethargic and had a high fever that could not be controlled by acetaminophen.

Ryan was so sick he could barely make the trip to his family doctor. The doctor thought Ryan looked jaundiced and referred him to their local hospital, but providers there found nothing wrong so they sent him home.

Ryan’s symptoms worsened. He gained 15 pounds in just a couple days as fluid built up in his abdomen. Ryan’s mom, Lisa Wyckoff, remembered how her tall, slender son looked like he was pregnant.

An MRI revealed Ryan had cirrhosis — advanced scarring in his liver. His condition was life-threatening, so he was flown to Seattle Children’s by Medivac.

“It’s terrifying to have something seriously wrong with your son that no one can figure out,” said Lisa. “We felt so helpless.”

The beginning of a lifelong mission

Nearly 20 years before Ryan became ill, Dr. Sihoun Hahn, medical director for Biochemical Genetics, director of the Wilson Disease Center of Excellence and an investigator in Seattle Children’s Research Institute’s Center for Integrative Brain Research, began treating patients with similar symptoms as a fellow at the National Institutes of Health.

Like Ryan, Hahn’s patients appeared perfectly healthy until they reached about 10 to 15 years of age and their health suddenly and rapidly declined.

The patients each had Wilson disease — a genetic disorder where excessive copper accumulates in the body.

Although copper accumulation begins at birth, symptoms of the disorder do not appear until late childhood or early adolescence. By that time, patients often have serious, permanent effects, including liver failure or neurological deterioration.

One-third of people with Wilson disease experience psychiatric symptoms, such as abrupt personality change, bizarre and inappropriate behavior, depression, neurosis or psychosis.

While Wilson disease is rare — affecting around 150 newborns in the United States each year — the patients Hahn treated left a lasting impression on him.

“It was very sad,” Hahn said. “These children seemed perfectly healthy and then suddenly they rapidly deteriorated. Many had permanent brain damage or needed liver transplants. Some had tremors, slurred speech, or could not walk or swallow.”

Hahn began studying the molecular biology of Wilson disease and discovered the disorder was caused by a genetic defect in the ATP7B gene. While this led to a better understanding of the disease, Hahn’s patients were still being diagnosed after developing significant effects.

A shift to early detection with newborn screening

Hahn realized the best way to help children with Wilson disease was to focus on early detection.

“I recognized the only way to prevent these effects is to treat kids before they show symptoms,” Hahn said. “That’s when I changed my research paradigm and began focusing on developing a newborn screening.”

Hahn knew Wilson disease results from mutations that cause absent or diminished levels of the ATP7B gene. He predicted ATP7B could serve as a marker for screening if it could be detected in the same standard newborn blood samples taken at birth, which consists of five drops of blood from a pin prick on the heel.

Hahn’s team developed a method of measuring ATP7B in dried blood spots, accurately identifying blood from patients with Wilson disease. A proof-of-concept paper with their findings garnered widespread support from the global scientific community.

While Hahn’s latest research is significant, there is still much work to be done before the Wilson disease screening can be applied clinically. Hahn’s research team needs to validate their method by testing samples from many more Wilson disease patients.

They will need to conduct pilot studies on newborns and work with family advocates and federal agencies to have their test included in the nationally-recommended newborn screening panel. This work will require additional funding, new instruments and potentially an industry partner to help produce testing kits.

If all goes well, Hahn’s method could be used to diagnose 11 to 15 primary immune deficiency disorders, for which infants are not yet tested. Since joining the Newborn Screening Advisory Committee in 2007, his efforts have already added 15 disorders to newborn screening tests provided for the 88,000 babies born in Washington state each year.

“This is just the tip of the iceberg,” Hahn said. “This research could impact more children beyond those with Wilson disease.”

Same disease, different outcome

Lisa knows how significant early detection is for a child with Wilson disease.

Although Ryan was diagnosed less than 48 hours after arriving at Seattle Children’s, he already had permanent damage to his liver. He quickly started treatment of Syprine – a chelating agent that removes copper from the body. Years later, Ryan’s cirrhosis caused his spleen to swell, requiring emergent, life-threatening surgery to remove it.

“Each time we come to Seattle, Dr. Hahn takes a picture with Ryan and Kaitlyn,” Lisa said. “He is so invested in his patients. He takes the time to get to know them.”

“Ryan wouldn’t have sustained so much damage to his organs if we had found out about his disease sooner,” Lisa said. “I think about every time he ate high-copper foods like chocolate or a peanut butter sandwich. Those things were terrible for him, but we had no idea.”

Once Ryan was diagnosed, Hahn tested his two siblings for Wilson disease, as well. Ryan’s older brother was negative, but his younger sister, Kaitlyn Wyckoff, then 9, was positive. While tests revealed she had elevated liver enzymes, the copper accumulation had not caused any damage.

“With treatments and diet regulation, Kaitlyn is able to live a normal life,” Lisa said. “She always says, ‘My brother saved my life,’ and it’s true!”

A promising future

Under Hahn’s clinical care, the future looks bright for Ryan and Kaitlyn, now young adults. They will both take medications to prevent copper accumulation and adhere to a special, low-copper diet for the rest of their lives.

The siblings have also contributed blood samples to Hahn’s research. Lisa says they will do anything they can to prevent other children from facing the traumatic effects Ryan has experienced.

“I understand Wilson disease is rare,” Lisa said. “But if a newborn screening could prevent just one kid from having to deal with the trauma my son has faced, then we will do anything we can to help.”

After 30 years, Hahn’s dedication to this research has only grown.

“I would like to retire in the next 10 years, but not until we have a screening for Wilson disease,” he said. “This work is like my baby. It’s my mission in life.”