Mom found the medication that's changing her son's life

Thanks to Brent Bonfiglio's mother, and a Children's Hospital clinical research team, Brent (above) and Travis Brown - who have NBIA, a progressive motor-dysfunction disorder - are using a new treatment option showing remarkable results.

Brent Bonfiglio was 9 when his parents, Veronica and Gaetano, noticed him falling more than other kids his age. “It didn’t seem right,” said Veronica. “He had no reflex to protect himself, he just fell like a tree.”

There were other symptoms too, including perseveration, a speech tic that may sound like stuttering to the ear, but is actually repetition of the beginning of a sentence, “You know Mom, you know Mom, you know Mom…”

Brent was 12 when he was referred to Children’s Hospital Oakland. There he received a diagnosis of Neurodegeneration with Brain Iron Accumulation (NBIA).

But it took his mother’s perseverance to find the drug that is saving his life; and it took a clinical research team at Children’s Hospital Oakland to get FDA approval for the drug’s clinical trials—for Brent and Travis Brown, and soon for other kids with the same disorder.

Neuropsychologist Alex Peterson, MD, was the first Children’s physician to see Brent. He did an assessment and referred Brent to his Children’s colleague, Candida Brown, MD, a neurologist.

During their first appointment, Dr. Brown gathered a detailed history from the Bonfiglios. At the end, Veronica casually mentioned a turning-point fact: When Brent was having a big laugh he would begin to drool.

“My clinical intuition said there was something not quite right there,” said Dr. Brown. She said trouble with drooling is very unusual for kids who just have a learning disability, ADHD or a tic. She ordered a brain MRI.

Diagnosis in Eye of the Tiger

The MRI image was striking. “The eye of the tiger” is how neurologists describe the pattern that indicates excessive iron is accumulating in the globus pallidus part of the brain. “When you see that, you automatically know this kid has NBIA,” said Dr. Brown.

NBIA is a genetic disorder in which iron builds up in the brain’s basal ganglia, leading to progressive loss of motor control. In most cases, not enough of the enzyme pantothenate kinase is being made to properly regulate brain iron. But there are several genetic faults that can cause NBIA.
Because it’s rare, it’s called an “orphan disease,” affecting fewer than 200,000 Americans. About one to three in every 1 million children will be affected. It is progressive, and at the time of diagnosis there was no cure, only symptomatic treatments.

“I never thought a kid could have a neurodegenerative disorder, I thought that was for older people,” said Veronica. “The worst thing for me was that we couldn’t do anything. Everybody deserves a chance to put up a fight.”

Discovering Deferiprone

But Veronica and Gaetano did do something. They scoured the Web for information, stayed in touch with fellow parent-members of the NBIA Disorders Association and eventually discovered an iron-removing drug called deferiprone.

It’s an iron chelator, used since 2006 to treat complications of the blood disease thalassemia. Kids with thalassemia need regular blood transfusions. As a result, their bodies accumulate excess iron. Deferiprone and other iron chelators help keep their body iron levels in balance.

But because deferiprone is a molecule small enough to cross the blood-brain barrier, unlike other iron chelators, it’s also able to remove iron from the brain. Veronica and Gaetano wondered if it could help Brent.

Dr. Brown had already helped Brent try deep brain stimulation, a technique in which a small device is implanted in the brain to help reduce the dystonia, muscle spasms, caused by NBIA. Children’s Hospital’s Spasticity Clinic offers the service as a collaboration between Neurosurgery and Rehabilitation Services; and it gave Brent some improvement, including more energy.

But the Bonfiglios hoped for more, and were intrigued by deferiprone. Their circuitous path to hearing of the drug began in mid-2007 in Iceland.

That’s where the grandfather of two NBIA patients saw a mention of deferiprone helping kids with too much iron in their brains. In a clinical trial of 15 children in France, deferiprone appeared to stop progression of Friedreich’s ataxia, a disorder similar to NBIA.

Word from the grandparent went out on the NBIA association’s listserv. Veronica saw it and took the next step: She typed “California” and “deferiprone” into the search box on clinicaltrials.gov.

Ironically, it led her back to Oakland, and Elliott Vichinsky, MD, chief of Children’s Hematology/Oncology department. His team has been using deferiprone and other iron chelators to help kids with thalassemia for more than a year.

Hem/Onc Chief Takes the Case

Within a week, Brent’s Fremont-based pediatrician, Patrick Burke, MD, had arranged for the Bonfiglios to meet Dr. Vichinsky.

Moved by their story and persuaded by the French study, he went to bat for them with the FDA for a single-patient compassionate use clinical trial.

“This is hope for a tragic hopeless disease,” said Dr. Vichinsky. “If deferiprone can get enough iron out of the brain, we believe it can reverse a significant part of the disease.”

By November 2007, Dr. Vichinsky and Nancy Sweeters, RN, PNP, of Children’s clinical research center, had completed an Investigational New Drug (IND) application, submitted it to the FDA, received approval and begun administering deferiprone to Brent.

He was the first child in the United States to receive deferiprone for treatment of NBIA. Improvement was gradual, but noticeable.

“Brent is a child who really couldn’t sit still and had very limited speech,” said Dr. Vichinsky. “He’s really shown a significant stabilization and improvement of functioning. He is in school getting As and you can carry on a conversation with him. If all the children with NBIA could show the benefit he has, deferiprone could mean a dramatic change in the course of this disease.”

No one is calling this a miracle cure. As Sweeters pointed out, Brent still has NBIA and deferiprone may treat it; but it doesn’t cure it. Deferiprone is also a powerful drug with effects that must be closely monitored, for example, with weekly complete blood cell counts.

But Brent and his parents are still thankful.

“I don’t think we can really express how grateful we are about all the support that we’ve gotten,” said Gaetano. “We consider ourselves very lucky to have met this team and these doctors and all the people behind the scenes. It’s been incredible.”

Breakthrough for NBIA Kids?

Veronica sees Brent’s improvement as a potential gift to all kids with NBIA. “By taking a chance with us, taking an interest in us, the Children’s team might be stumbling on a breakthrough for this disorder,” said Veronica. “So this could actually become something that a lot of families could do. And if we start earlier maybe we can prevent the progression of kids losing so many skills. It’s making history for our disease.”

The next step in that history was getting a second NBIA kid onto deferiprone: Travis Brown, living in Lathrop, Calif. with his parents, Joe and Pattie.

In 2006, he was an average boy, able to hike and camp, but by December 2008, his parents had to bring Travis to his first appointment at Children’s Hospital in a wagon. NBIA-induced dystonia and loss of motor control had progressed so quickly that Travis couldn’t walk or even talk.

After only a few months of treatment with deferiprone and baclofen, an anti-dystonia drug, Travis is showing remarkable improvement in his movement ability.

The newest step in the history of deferiprone as an NBIA treatment awaits FDA approval: a Children’s Hospital-hosted phase 1 clinical trial to include about 20 children from across the United States.

Sweeters is optimistic and hopes to get approval for the study in December. It will be one small step for deferiprone and one giant leap for children with NBIA.

There is no shortage of families wanting in. Sweeters gets emails and phone calls from parents every day. “If they could climb through the phone and sit in my lap, they would,” said Sweeters, a veteran nurse and researcher with decades of experience. “Patients from all over the world want to be involved in this study.”

Meanwhile, thanks to Mark Young, a one-on-one aide for the school district, Brent is a mainstreamed student at Washington High School in Fremont, taking classes in English, ceramics, psychology and algebra. He’s a film buff and a member of the Culinary Club; his favorite cuisine is Sicilian-style Italian food, especially pastries.

But Brent isn’t just a student, he’s also a teacher. Just ask his neurologist, Dr. Brown. “He’s taught me how to stay positive despite adversity and that there’s so much to life that’s more important than the material,” said Dr. Brown. “You look at him and you look at all the adversity that he deals with and yet he always comes in with a smile on his face—just a normal teenager, playing his video games, listening to his music and dancing.”

Resources

• Neurology at Children’s Hospital: 510-428-3590
• Pediatric Clinical Research Center at Children’s Hospital
Nancy Sweeters, RN, PNP: 510-428-4151
• NBIA Disorders Association: www.nbiadisorders.org
• Clinical trials information: www.Clinicaltrials.gov

This story, written and photographed by senior writer Tom Levy, was first published in the November/December 2009 issue of Children’s Hospital’s PEDSnews magazine.