After a Decades-long Quest: Answers

By Lyn A.E. McCafferty

Nearly four decades after Marsha and Allen Barnett lost two of their three sons to a puzzling and deadly childhood disease, researchers at Children’s Hospital of Philadelphia could finally answer the question: What killed Chuckie and Michael?

In the early 1980s, the brothers died two years apart, when they were 5 and 10, after a series of debilitating symptoms attacked their nervous systems and sapped their energy. Only after the first son’s death were doctors able to provide a name for the disease — Leigh syndrome, a rare mitochondrial disease. The exact gene mutation that caused the brothers’ syndrome remained a mystery for more than 35 years.

Forging ahead after unspeakable tragedy

Losing two of their children so young forever changed the lives of Marsha and Allen, and Jeffrey, their youngest and sole surviving child.

After the boys’ deaths, the couple found comfort talking about their beloved sons: Michael was exceptionally bright, and Chuckie was a happy, easygoing child. The Barnetts began to look for ways to honor their sons and support other families dealing with rare or unknown mitochondrial diseases.

Initially, the family raised funds for mitochondrial research at the nonprofit hospital in Philadelphia that had treated their boys. When the hospital privatized in the 1990s, the Barnetts transferred their philanthropic support to CHOP after learning it had developed an advanced mitochondrial disease research program and was quickly becoming a national leader. The couple later established the Michael and Charles Barnett Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases at CHOP.

For more than a decade, the Barnetts have met with CHOP leaders and two of its leading physician-researchers: Marni J. Falk, MD, Executive Director of CHOP’s Mitochondrial Medicine Frontier Program, and Douglas C. Wallace, PhD, a mitochondrial pioneer and founder of CHOP’s Center for Mitochondrial and Epigenomic Medicine. Wallace currently holds the Michael and Charles Barnett Endowed Chair.

The Barnetts remained connected to CHOP, thanks to Falk and Wallace. These relationships proved to be key in unlocking answers the family had long sought.

Hope for the next generation

Years later, when Jeffrey Barnett and his wife, Rachel, were considering having children, Marsha gave the couple all the research she had amassed about Leigh syndrome since the 1980s and encouraged them to undergo genetic testing at CHOP.

The couple turned to Falk for help understanding their risk of passing on a faulty gene to any child they would have. Though the exact genetic cause of Leigh syndrome in Jeffrey’s brothers was not yet known, Falk was able to test the young couple and reassure them that their future children were extraordinarily unlikely to inherit the deadly condition. Today, the couple’s two sons — now ages 11 and 6 — show no sign of the disease.

At long last, answers

The couple’s desire for answers prompted CHOP researchers to take a fresh look at Chuckie and Michael’s DNA through a new lens. In the 30-plus years since the boys’ deaths, the body of scientific knowledge about genetic, metabolic and mitochondrial disorders has grown significantly. Today, disease-causing mutations in nearly 100 different genes have been causally linked to Leigh syndrome.

In 2018, Falk called the Barnett family with news: Researchers had identified a mutation in a nuclear gene that may have caused their sons’ rapid deterioration and death. DNA from one of the Barnett brothers’ muscle tissue that had been frozen for three decades in Wallace’s research laboratory was the Rosetta stone. Falk determined a genetic mutation arose spontaneously in previous generations of both Marsha’s and Allen’s Ashkenazi Jewish ancestors. After more research, the specific genetic mutation was confirmed as the cause of the Barnett boys’ deaths so many years ago.

The breakthrough provided the family with a long-sought answer. While relieved to finally understand why their family’s tragedy occurred, the Barnetts also saw the discovery as a milestone in their journey — and the perfect springboard to expand their ongoing philanthropic partnership with CHOP.

‘Quantifiable magic’

The family pledged $2 million to establish the Barnett Family Mitochondrial Medicine Research Endowment, a permanent fund that will advance mitochondrial disease research, support the work of Falk and Wallace, and forever link the Barnett family with progress in the field of mitochondrial medicine.

“The Barnett family’s generous funding support will enable us to find answers for more families,” Falk says. “The ultimate impact of their support will be to improve the quality and quantity of life for children and adults affected by the diverse array of mitochondrial diseases.”

Jeffrey Barnett supports his parents’ decision to donate a substantial portion of their estate to mitochondrial research at CHOP, saying: “The things that Doug and Marni and CHOP do seem like quantifiable magic. Instead of merely saying thank you, my parents are fueling the research that will help the next generation of scientists and researchers to discover more to help real families — like mine — find answers.”