Scientists at Stanford University School of Medicine (Stanford, California) and Lucile Packard Children's Hospital (Palo Alto, California) have discovered a biological marker they can use to monitor a mysterious group of metabolic diseases that arise from mutations in cells' fuel-burning mechanism. Stanford said the finding would enable researchers to hunt for treatments and help doctors check patients' status before health crises erupt. The research was published online Feb. 9 in the Proceedings of the National Academy of Sciences.

Greg Enns, a professor of pediatrics at Stanford and director of the biochemical genetics program at Packard, told Medical Device Daily that the children and adults he treats have a variety of organ failures (heart failure, kidney failure, etc.) associated with their mitochondrial disorders, and that they don't really have a good way of monitoring their disease.

This made him aware of the unmet need in this area, he said, which motivated him to look for a way to monitor and find treatments for these patients. These disorders can present at any age, from before birth through old age, he noted.

"The mitochondria are important in everybody's cellular metabolism, it's critical in allowing us to function day to day," Enns said, adding that some studies suggest we age because our mitochondria ages and we develop disorders in adulthood and later in life largely because, or at least in part because, of mitochondria dysfunction.

"When a car engine doesn't work right, it smokes," Enns said. "What we looked for is, in essence, biochemical smoke."

Like a car engine, when mitochondria are not burning fuel cleanly, they kick out nasty gunk. Defective mitochondria produce large quantities of oxygen free radicals — highly reactive molecules that damage DNA and cell structures, Enns said. Comparing patients who have a mitochondrial disorder with healthy people in the control group, his team searched for signs that free radicals overtax patients' natural antioxidant defense systems. And they found it.

The team saw that levels of glutathione, the body's primary antioxidant, were significantly reduced in white blood cells from the 20 mitochondrial disease patients in the study. The observation means patients' antioxidant defenses were indeed depleted. Glutathione was also diminished in nine patients with organic acidemias, another group of metabolic diseases that researchers think may be associated with aberrant mitochondrial function.

Glutathione measurements could also help diagnose patients, Enns said, by giving physicians a clear indication that something is awry in the mitochondria. Genetic and molecular tests have already led to increases in the number of diagnoses, but the diagnosis is still difficult to pin down, he noted.

While much of what the team discovered confirmed what they had hypothesized, Enns told MDD that there were a few surprises.

"Even when these patients are coming into the clinic looking pretty healthy, they have evidence of extra metabolic stress," Enns said, noting the findings were surprising because none of the patients were in the midst of a health crisis such as organ failure when blood samples were taken. It is the first time such signs have been uniformly shown in the blood of patients across a wide range of mitochondrial disorders, he added.

Another surprising finding is that patients who were taking vitamin supplements tended to have relatively normal levels of glutathione, Enns said.

Scientists have long suspected antioxidants such as vitamin C and vitamin E might help patients with mitochondrial disease or organic acidemias, and doctors sometimes suggest the supplements to their patients. But no one has been able to test whether they work.

"As a clinician, one of the most frustrating things has been not being sure if supplements are doing any good," said Enns. "Now we're able to take a baseline blood reading and see 'before' and 'after' snapshots."

Enns said his team has been working on this research for three or four years and are just starting to publish their data.

William Craigen, MD, PhD, director of the metabolic clinic at Texas Children's Hospital (Houston), called this finding "the beginning of insight into the mechanisms of mitochondrial disease." Craigen, who also is medical director for the mitochondrial diagnostic lab at Baylor College of Medicine (Houston), was not involved in the Stanford study. "This new research provides an opportunity to start treating a heterogeneous group of diseases in a single fashion, with a simple and easy-to-administer treatment, potentially improving patients' long-term outcomes."

Enns said the method his team used to measure glutathione, called high-dimensional flow cytometry, has limitations: it requires very fresh blood samples, uses expensive equipment only available in research labs, and provides relative rather than absolute glutathione measurements. Now that the team knows what metabolic change to look for, they're working to develop a more broadly applicable measurement technique, he said.

And glutathione measurements could help scientists unravel other disease mysteries, too. "You name the disease, you can postulate mitochondrial involvement," Enns said. "It's been proposed for everything from poor vision to hearing loss, kidney disease, liver disease, autism spectrum disorders, diabetes, Alzheimer disease, cancers. Our work could lead to research on therapies for a broad range of disorders."

Enns collaborated with research associate Kondala Atkuri, PhD; associate professor of pathology Tina Cowan, PhD; professor emeritus of genetics Leonard Herzenberg, PhD; and research professor of genetics Leonore Herzenberg, PhD, who is also a member of the Stanford Cancer Center. The Herzenbergs have a financial interest in BioAdvantex (Mississauga, Ontario), a company whose dietary supplement, PharmaNAC, is intended to increase glutathione levels. The study was funded by grants from the United Mitochondrial Disease Foundation (Pittsburgh), the Lucile Packard Children's Hospital Pediatric Health Research Fund and the Arline and Pete Harman Scholarship.

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