Advance at Children's toward treating mitochondrial disease

Pediatrician Marni Falk, a genetics specialist at Children's, with Juliet Belcher, 8, who has a rare form of mitochondrial disease that saps her energy. Falk led the research team trying to fix the faulty "fuse box."
Pediatrician Marni Falk, a genetics specialist at Children's, with Juliet Belcher, 8, who has a rare form of mitochondrial disease that saps her energy. Falk led the research team trying to fix the faulty "fuse box."
Posted: August 19, 2013

Juliet Belcher does not have the strength or dexterity to eat a piece of chicken on her own. Even if she did, her cells could not turn the food into enough energy to properly fuel her 8-year-old body.

Juliet, who lives in Blue Bell, is diagnosed with a mitochondrial disease so rare that it hasn't been named yet. Doctors have identified only eight others in the world with the same genetic mutation.

Mitochondria are the structures in cells that produce energy for life. Malfunctions come in different forms, and an estimated one in 5,000 Americans has some type of mitochondrial disease at any given time.

Severe forms can cause children, in a matter of months, to lose the ability to walk and even talk. A missed meal, or even an overnight fast, is enough to wreak havoc on Juliet's body. She takes 30 doses of medicine a day, from 5:15 a.m. to 11 p.m., to boost cellular health and counter symptoms of the disease.

A team of physicians at Alfred I. duPont Hospital for Children in Wilmington treat her weak heart, seizures, and other illnesses caused by lack of energy, and a doctor at Children's Hospital of Philadelphia monitors her gastrointestinal issues.

Another team at Children's Hospital is using her mitochondria to develop new treatments.

For decades, vitamin cocktails and exercise have been the most common treatments, although there is little evidence that they are effective. The genetic origins of mitochondrial diseases were discovered in 1988 by a researcher now at Children's, Douglas C. Wallace. Since then, a few repurposed drugs have been found to treat symptoms, but the field is still in its infancy.

Marni Falk, a pediatrician and specialist in genetics at the hospital, hopes a recent study she led will jump-start research on treatments for mitochondrial diseases that are caused by problems in the last step of energy production.

A member of the team, genomic analyzer Zhe Zhang, found that Juliet and more than a dozen other mitochondrial patients have dysfunctional master-signaling systems in their cells that respond, sometimes incorrectly, when something goes awry in the complex energy-making process.

Instead of seeking remedies to resolve symptoms caused by the malfunctions, Falk's team is now trying to fix part of what went wrong to begin with - what she calls the master "fuse box" that sends out the signals.

"This is a newer way of looking at it," said Falk, whose work was published this month in the journal PLoS ONE. "It's not thinking about the site where the problem is; it's trying to treat the response of the cell to that problem."

The study comes amid a wave of research on the disease spurred by advances in technology and genetics. As recently as the mid-2000s, only 10 or 12 of perhaps 300 mutations known to lead to mitochondrial disease could be tested for, Falk said. Just this summer, she finally was able to track down the faulty gene in Juliet's cells - the one that is shared with eight other patients worldwide.

"It really is all the difference for us just knowing the identified gene causing disease," said Janice Belcher, Juliet's mother, adding that it opened up the possibility for personalized gene therapy down the road.

Falk said the beauty of the discovery of the "fuse box" has been that it might lead to effective treatments for many mitochondrial dysfunctions, even in diseases for which they are not a major factor, such as diabetes, Parkinson's, and Alzheimer's.

Her study found that vitamin B3 helps the body make more mitochondria and process energy better. Whether the evidence will continue to hold up and move on to a clinical trial is uncertain (and Falk is not recommending B3 as a treatment). But, she said, the discovery that some drug possibly could make mitochondria function properly actually was more important.

"What she's figured out," said Suzanne Debrosse, a neurogeneticist at University Hospitals Case Medical Center in Cleveland, who was not involved with the study, "is that we might be able to improve the health of cells regardless of" the type of mitochondrial disease.

News of Falk's research has spread excitement among families across the country, said Dan Wright, a member of the board of the United Mitochondrial Disease Foundation.

"In the last couple of years, we're seeing a groundswelling of things happening," said Wright, "and that gives us a much greater sense of hope." His daughter Kelsey lives with him in Dallas and is still unable to talk at age 33.

"It may not help our daughter at her state in this disease," he said, "but the main thing is we can help the future Kelseys."


Contact Summer Ballentine

at 215-854-2415 or SBallentine@philly.com, or follow

on Twitter @ESBallentine.

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