Unknown disease surfaces at Harborview

A middle-aged Alaskan woman who died in Harborview Medical Center with dementia hinting of an ailment similar to mad cow disease appears to have succumbed to an unknown kind of neurodegenerative disease.

"It's an enigma," said Dr. Thomas Montine, director of neuropathology at Harborview and the University of Washington. "This is something new."

The woman's ailment hinted of a prion disease, a class of rare illnesses that includes mad cow.

After the unidentified woman died in August, Montine asked scientists at the National Prion Disease Pathology Surveillance Center in Cleveland to test her brain tissue for evidence of prion disease. The center reported to him earlier this week that it had found no evidence of the infectious, abnormal prion proteins believed to cause these illnesses.

But at the same time, they found evidence that the normal, non-infectious version of these proteins was somehow involved in the woman's illness.

"You would like the answer to these questions to always be black and white," said Dr. Pierluigi Gambetti, director of the Ohio prion disease center. "Sometimes, it's gray."

Gambetti, one of the world's leading experts at identifying prion diseases, declined to comment on the specifics of the case and referred all questions to Montine.

"The good news is that there's no evidence of the transmissible agents, the prions," Montine said.

Gambetti plans further testing to confirm that the woman's illness is not potentially infectious, as can happen with mad cow disease.

Prions are abnormal proteins found in rare brain diseases such as Creutzfeldt-Jakob disease (CJD), new variant CJD (the human form of mad cow) or kuru (a disease of cannibals). Although rare, some prion diseases -- such as mad cow -- can be transmitted by eating contaminated meat. Scientists still do not fully understand the mechanism of infection.

Montine, an expert in the biochemistry of neurodegenerative diseases, said it was clear at the outset of this case that the woman did not have regular CJD or the new variant "mad cow" version of CJD.

But he and his colleagues at Harborview wondered whether it might be another form of prion disease, so they used specialized antibodies to look for evidence of proteins characteristic of other prion diseases. They found some indication of a rare, genetically inherited form known as GSS (Gerstmann-Straussler-Scheinker).

"That's what we suspected at first," he said. But the tests for GSS weren't definitive, either, he said, so with the family's permission, they sent the woman's brain tissue to Gambetti for more thorough testing.

Gambetti and his team first looked for the abnormal prions, which are resistant to enzyme degradation. Normal versions degrade in the presence of enzymes. Gambetti and his colleagues found no evidence of prion proteins after the enzyme tests.

"Without this, it doesn't have the defining feature of a prion disease," Montine said.

And yet, Gambetti's lab did find an abnormal reaction using the antibody test. This, Montine said, indicates that the proteins -- although not infectious prions -- still may have played some unknown role in causing this woman's brain to degenerate and die.

"We're at the boundary of what we know about neurodegenerative disease with this one," Montine said.

Gambetti's lab plans to continue testing the woman's brain tissue for any sign of infectivity using mice injected with the brain tissue. The mice are watched over a two-year period for signs of disease. Montine and his colleagues plan to focus on some of the key biochemical questions and collaborate with Gambetti to publish their findings.

Public attention to these rare neurodegenerative diseases exploded a year ago when a slaughtered cow in Washington state was determined to have had mad cow disease, or bovine spongiform encephalopathy.

There are no confirmed human illnesses associated with mad cow in the United States. But in Britain, consumption of meat from millions of contaminated cattle in the 1980s was blamed for 148 confirmed deaths by new variant CJD.

Part of the problem with identifying a prion disease is the lack of direct evidence of transmission. Some scientists believe the prion protein itself is the primary cause of the disease. Others point out that there is no direct evidence or good biological explanation for this -- because proteins don't have genetic material, which is what does the infecting in all other transmissible disease.

Montine said the mysterious new neurological disease that led to the Alaska woman's death, although perhaps not a prion disease in the classic sense, may still lead to important new insights about these rare brain-wasting illnesses. It's possible that they have found the prion protein at a key transition point just before it becomes resistant to enzymes.

Or maybe they've found an entirely new kind of neurological disease. "We know a lot less here than we think we know," Montine noted.

P-I reporter Tom Paulson can be reached at 206-448-8318 or tompaulson@seattlepi.com

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