New test for mysterious metabolic diseases developed at Stanford/Packard

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New test for mysterious metabolic diseases developed at Stanford/Packard

BY ERIN DIGITALE

http://med.stanford.edu/news_releases/2009/february/enns.html

STANFORD, Calif. —Scientists at Stanford University School of Medicine have

devised a much-needed way to monitor and find treatments for a mysterious and

devastating group of metabolic diseases that arise from mutations in cells’

fuel-burning mechanism.

Mitochondrial disorders can cause organ failure, seizures, stroke-like episodes

and premature death. The diseases—more than three dozen in total—arise from

genetic errors of the mitochondria, the cell structures that process oxygen and

turn food molecules into useable energy. Mitochondrial disorders affect one in

4,000 kids and one in 8,500 adults. They are difficult to diagnose, and no

treatments or cures exist.

But that could soon change. A team at Stanford and Lucile Packard Children’s

Hospital has discovered a biological marker they can use to monitor the

diseases. The finding will enable researchers to hunt for treatments and help

physicians check patients’ status before health crises erupt. The research was

published online Feb. 9 in the Proceedings of the National Academy of Sciences.

“When a car engine doesn’t work right, it smokes,” said senior study author

Greg Enns, MB, ChB, who is professor of pediatrics at Stanford University School

of Medicine and director of the biochemical genetics program at Packard. “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.

Comparing patients who have a mitochondrial disorder with healthy people in the

control group, Enns’ team searched for signs that free radicals overtax

patients’ natural antioxidant defense systems. And they found it.

“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.

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.

A second finding gave the researchers a big hint about where to hunt for

treatments. Patients taking antioxidant supplements did not have depleted

glutathione, they found. 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.”

Craigen, MD, PhD, the director of the metabolic clinic at Texas

Children’s Hospital, called this finding “the beginning of insight into the

mechanisms of mitochondrial disease.” Craigen, who is also medical director for

the mitochondrial diagnostic lab at Baylor College of Medicine, 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,” he added.

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.

The method Enns’ 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.

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, a company whose dietary supplement, PharmaNAC, is

intended to increase glutathione levels. The study was funded by grants from the

United Mitochondrial Disease Foundation, the Lucile Packard Children’s Hospital

Pediatric Health Research Fund and the Arline and Pete Harman Scholarship.

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