Rare Daily Staff

Very long chain acyl-CoA dehydrogenase deficiency is a genetic disease where a mutation prevents an enzyme from breaking down fatty acids into energy.

The disease, known as VLCADD, afflicts about one in 40,000 people but is part of a class of diseases that affect four times that number, making it one of the more common of the rare genetic diseases that U.S. doctors now universally test for in newborns.

If untreated, the disease can cause heart failure and low blood sugar—two life-threatening conditions. When coupled with a modified diet, a recently approved drug can manage those symptoms, but patients still experience rhabdomyolysis—muscle breakdown—indicating that the disease acts through another pathway.

Jerry Vockley, a rare-disease expert at UPMC Children’s Hospital of Pittsburgh, found a successful treatment for those two deadly symptoms of the disease, but painful episodes of muscle breakdown that land victims in intensive care persisted.

Now, Vockley and his colleagues report in the journal Clinical & Translational Immunology that they’ve discovered why the muscle breakdown occurs and have a good lead on a treatment.

“These episodes looked a lot like inflammatory muscle disease, but usually that is persistent and doesn’t wax and wane, so it wasn’t a perfect fit,” said senior author Vockley, chief of Genetic and Genomic Medicine and director of the Center for Rare Disease Therapy at UPMC Children’s. “Still, I couldn’t shake the thought that there was some inflammatory link, so we tested patient blood samples. Sure enough, when the episodes were happening, certain inflammatory markers were high, and when the patients were well, they were lower. Knowing this will allow us to try to figure out why this inflammation is happening and prevent it.”

With his hunch that inflammation might be behind the rhabdomyolysis, Vockley consulted with colleagues who specialize in immunology and rheumatology. Their teams tested patient blood samples that Vockley had stored from his previous research and obtained additional samples from new patients.

One patient had particularly persistent bouts of rhabdomyolysis requiring week-long hospitalizations more than a dozen times per year. She consented to give blood samples over several years and participate in the study. Regular infusions of an anti-inflammatory medication kept her from needing to be hospitalized for nearly 10 months, and then only irregularly since.

The team found that when the patients were experiencing episodes of rhabdomyolysis, they were having what’s known as a “cytokine storm”—when various inflammatory molecules are produced by immune cells in excessive quantities, leading them to attack the body. Even when they weren’t having these episodes, the patients had elevated inflammatory markers, though at lower numbers than when they were symptomatic.

Researchers are now trying to find how to best treat these flares. One challenge is that the cytokines activate cells, but those cells don’t behave as they should.

“In the immune system, cytokines and cells talk to each other to regulate and counter-regulate their actions accordingly,” said Abbe de Vallejo, associate professor of pediatrics, immunology and rheumatology in Pitt’s School of Medicine and director of the Flow Cytometry Core Facility at the John G. Rangos Sr. Research Center located at UPMC Children’s. “But that’s not happening the way you’d expect in VLCADD patients. It’s paradoxical and is our next challenge. If we can find the disconnect, we may be able to learn what is triggering the inflammatory response and stop it from happening altogether.”

In the meantime, the team also is exploring the off-label and compassionate use of certain anti-inflammatory medications to treat acute, symptomatic rhabdomyolysis and prevent it from occurring.

Photo: Jerry Vockley, chief of Genetic and Genomic Medicine and director of the Center for Rare Disease Therapy at UPMC Children’s Hospital of Pittsburgh

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