Pediatricians ID cause of muscle breakdown in rare disease found on newborn screening

PITTSBURGH, June 28, 2021 — It was a nagging mystery: A rare disease expert at UPMC Children’s Hospital in Pittsburgh had found successful treatment for two of the deadliest symptoms of one of the most common classes of rare diseases identified. diagnosed by newborn screening, but one symptom — painful episodes of muscle wasting that landed victims in intensive care — persisted.

Today, the scientists announce in the journal Clinical & Translational Immunology that they’ve gotten to the bottom of self-destructive syndrome and are well ahead of treatment.

“These episodes were a lot like inflammatory muscle disease, but usually that’s persistent and doesn’t increase and decrease, so it wasn’t a perfect fit,” said senior author Jerry Vockley, MD, Ph.D., chief of Genetic and Genomic Medicine. and director of the Center for Rare Disease Therapy at UPMC Children’s and professor of pediatrics and human genetics at the University of Pittsburgh School of the Health Sciences. “Still, I couldn’t shake the thought that there was an inflammatory link, so we tested blood samples from patients. Sure, when the episodes happened, certain inflammatory markers were high and when the patients were healthy, they were lower. Knowing this, we can try to figure out why this inflammation occurs and prevent it.”

Very long chain acyl-CoA dehydrogenase deficiency – VLCADD – is a genetic disease in which a mutation prevents an enzyme from breaking down fatty acids into energy. It affects about one in 40,000 people, but is part of a class of diseases that is four times more common, making it one of the most common rare genetic diseases US doctors now universally test for in newborns.

If left untreated, the disease can cause heart failure and low blood sugar — two life-threatening conditions. In combination with a modified diet, a recently approved drug in which Vockley was involved in the development can control those symptoms. But patients still experience rhabdomyolysis – muscle breakdown – indicating that the disease works through a different pathway.

Suspecting that inflammation could be behind rhabdomyolysis, Vockley consulted with Abbe de Vallejo, Ph.D., an associate professor of pediatrics, immunology, and rheumatology at Pitt’s School of Medicine and director of the Flow Cytometry Core Facility at the John G. Rangos Sr. Research Center at UPMC Children’s.

Their teams tested blood samples from patients that Vockley kept from his previous research and obtained additional samples from new patients. One patient – Bella Linz, 15, of Meadville, Pa. – had particularly persistent bouts of rhabdomyolysis requiring a week’s hospitalization more than 12 times a year. She agreed to give blood samples and participate in the study for several years. Regular infusions of an anti-inflammatory drug saved her from hospitalization for nearly 10 months, and then only intermittently.

“Bella is a very empathetic child, very caring,” said her mother, Carrie Linz. “So when she was trying out the different drugs and the pain that came with the injections, we talked about the other kids, this would help — how what she was doing would benefit other kids, faster and for a longer period of time. That helped us find a purpose.”

The team found that when the patients went through episodes of rhabdomyolysis, they had what’s called a “cytokine storm” — when various inflammatory molecules are produced in excessive amounts by immune cells, causing them to attack the body. Even if they didn’t have these episodes, the patients had elevated inflammatory markers, although in lower numbers than when they were symptomatic.

Still, the solution isn’t as clear-cut, de Vallejo said.

“The cytokines activate cells, but those cells don’t follow the rules,” he said. “In the immune system, cytokines and cells ‘talk’ to each other to regulate and counter-regulate their actions accordingly. But that doesn’t happen as you would expect in VLCADD patients. It’s paradoxical and is our next challenge. If we can If If we find the disconnect, maybe we can find out what’s causing the inflammatory response and stop it happening altogether.”

In the meantime, the team is also investigating the off-label and compassionate use of certain anti-inflammatory drugs to treat and prevent acute, symptomatic rhabdomyolysis.


Other authors of this study are Henry J. Mroczkowski, MD, Ph.D., Joshua J. Michel, Michael Woolford, Harry C. Blair, MD, Patricia Griffin, Elizabeth McCracken, MS, CGC, Stephanie J. Mihalik, Ph. D., and Miguiel Reyes-Mugica, MD, all of Pitt at the time of the study.

This research was funded by National Institutes of Health grant R01 DK78755 and an IRG Award from the Nancy E. Taylor Foundation for Chronic Diseases Inc.

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Regionally, nationally and globally, UPMC Children’s Hospital of Pittsburgh is a leader in the treatment of childhood conditions and diseases, a pioneer in the development of new and improved therapies, and a leading educator of the next generation of pediatricians and pediatric subspecialists. With generous community support, UPMC Children’s Hospital has fulfilled this mission since its founding in 1890. UPMC Children’s is consistently recognized for its clinical, research, educational, and advocacy-related achievements, including a top 10 place on the US News 2021-2022 Honor Roll of America’s Best Children’s Hospitals. UPMC Children’s also ranks 15th among children’s hospitals and medical schools in pediatric research funding by the National Institutes of Health (FY2019).

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