In the language of the Fore people, a tribe inhabiting the highlands ofNew Guinea, the word kuru means "trembling with fear." In 1976,neurologist D. Carleton Gaydusek shared the Nobel Prize formedicine or physiology for solving the cause of kuru disease.

In a word, it was cannibalism. In two words, a slow virus.

When a member of the Fore tribe died, his or her relatives, in a ritualfuneral custom, would cook and eat the brains of the deceased. Yearslater, many of those who did so came down suddenly with trembling,blind staggers (ataxia), dementia, and other horrendous signs andsymptoms of neurological disintegration. Death followed in four to24 months.

Somewhat similar symptoms, Gaydusek knew, ended the lives ofsheep infected with what was then called a "slow virus" that causedscrapie. That word described the compulsive scraping off of theirwool on walls or fences. So Gaydusek, who is at the NationalInstitute of Neurologic Diseases and Stroke, ascribed kuru's cause toa "slow-acting virus."

From Cannibalism To Tourism

Fast forward to 1982. Neurologist Stanley Prusiner at the Universityof California, San Francisco, did not buy the slow-virus etiology ofscrapie or kuru. (By then, the latter entity was presumed extinct, ascannibalism waned in New Guinea, now a tourist Mecca.)

Prusiner noted that scrapie brain tissue could be transferred to thebrains of hamsters, which promptly came down with the deadlysymptoms. He found a strange protein in the cerebral detritus of thatrodent model, and postulated that it came from an even strangergene, which he dubbed "prion." It stood for "proteinaceousinfectious particle."

In May 1985, Prusiner, jointly with Leroy Hood at CaliforniaInstitute of Technology, and Charles Weissmann, University ofZurich, succeeded in cloning the scrapie prion protein gene.

Prusiner strongly suspected that his unknown, invisible prion ("100times smaller than the smallest virus, and without a trace of nucleicacid") was behind other neurodegenerative diseases, such asAlzheimer's and Creutzfeldt-Jakob disease (CJD).

These two afflictions of old age share many symptoms, but twotelling differences: Alzheimer's disease may drag on for years oreven decades, and is increasingly prevalent _ 15 to 20 percent ofpeople over 80 get it. CJD, like kuru, takes years to incubate aftercontamination, but kills in a matter of months. Unlike Alzheimer's,CJD is mercifully rare _ striking only one in a million people.

Hans Creutzfeldt and Alfons Jakob, two German neuropsychiatrists,described the grim syndrome that bears their name in the early1920s. French genetic epidemiologist Philippe Amouyel, confirmsPrusiner's premonition that CJD is indeed "a prion disease."Amouyel, who heads epidemiology and public health at theUniversity of Lille, in France, links abnormal prion gene products inthe brains of affected patients with apolipoprotein E, alreadyimplicated in Alzheimer's. (See BioWorld Today, Nov. 3, 1994,p.1.)

His paper in this week's Lancet, dated Nov. 12, is titled: "Theapolipoprotein E alleles as major susceptibility factors forCreutzfeldt-Jakob disease."

Amouyel defines the disease as a dementia associated with fourearly, telltale clinical features or hallmarks:

* myoclonus _ rapid, uncontrollable muscle twitching;

* nystagmus _ aberrant eyeball movements, then blindness;

* trembling;

* akinetic mutism _ inability to speak.

"Afterwards," the French scientist told BioWorld Today, "it's onlydeath." To tell CJD apart from Alzheimer's, he explained, "If thepatient has only one of the four clinical features, perhaps it'sAlzheimer's. If two or three, it's probably CJD." In both diseases,the only positive confirmation is autopsy.

Like colorectal cancer and breast cancer, CJD comes in two forms,familial, of genetic origin, and sporadic, arising 10 to 20 years afterinfectious contamination. Only about 15 percent of cases are genetic,he said.

The two forms differ clearly in their age of onset. Sporadic casesbegin to show signs of CJD at 65, on average; familial, at around 58.

Amouyel cited two quite current instances of iatrogenic (medicallycaused) CJD contamination by prion particles. One is the practice ofsurgeons to seal holes in the bodies of patients with a transplant ofcadaver dura mater, the tough, fibrous membrane that sheaths thehuman brain.

His other example has direct bearing on biotechnology. Early in1985, three Dutch children, being treated with human growthhormone for dwarfism, died of Creutzfeldt-Jakob disease. The onlyhormone then available was extracted from cadaver pituitary glands,which lie within the brain.

Accordingly, commercial laboratories in the U.S. and Europestopped delivery of the natural product. At that time, Genentech'srecombinant human growth hormone, Protropin, was still in pre-approval clinical trials. The FDA quickly cleared it for distribution,in October 1985.

Amouyel had a hunch that the apolipoprotein E (APOE) found insuspicious embrace with mutant prion protein boded ill, not just forAlzheimer's but "should be specific, probably, to troubles of brainmetabolism generally." To verify this hypothesis, he set about "totest it in another type of dementia, CJD, which is mechanisticallydifferent from Alzheimer's," but which involves prion.

Apolipoprotein is best known for shunting cholesterol around theblood. Its gene exists in three alleles, or variants, e2, e3 and e4.These isoforms, he explained, correspond to frequent APOEmutations at the DNA level.

In the DNA of 61 French patients with CJD, as Amouyel's Lancetpaper testifies, "we found that an e4 allele of the APOE gene was arisk factor for the disease." Not only that, "subjects with anotherallele, e2, have less risk of developing Alzheimer's disease thanthose with e3 or e4."

In his CJD patients, Amouyel determined that those with a single e2variant had a life expectancy of 10 months; those with e4, only four.But one subject with two e2 gene isoforms lived for 30 months.

Do APOE Alleles Arbitrate Cognition?

Dementia, of course, is the deterioration of cognitive performance,the impairment of reasoning, judgment and memory; the emergenceof bizarre behavior.

Amouyel next asked: What role does the e4 allele play in decay ofcognition? He is giving a standard test that measures this complextrait to a random sampling of one thousand oldsters living in Frenchretirement homes.

"What we expect to find," he predicts, "is that people carrying the e4allele will have lower cognitive performance scores that those withthe xe2 allele. Such a result," he added, "would convey a very strongmessage. It would mean that a genetic polymorphism has a stronginfluence on cognitive functions."

For future such messages, he suggests, look also to veterinarians."There are very well known equivalent prion diseases in domesticanimals." Coming full circle to sheep and scrapie, he cited bovinespongiform encephalopathy (mad-cow disease). "In some herds,Amouyel pointed out, "not all the animals get those diseases,although they all have eaten the same bad prion proteins. This shouldmean that in cows, as in humans, there are some susceptibility riskfactors that decide whether you do or don't develop the diseases."

An article by Stanley Prusiner in last month's Proceedings of theNational Academy of Sciences,NULL, dated Oct. 11, noted that "more than45 young adults previously treated with human growth hormonederived from human pituitaries have developed CJD." He added that"The full extent of iatrogenic CJD in thousands of people treatedwith human growth hormone worldwide will not be revealed fordecades due to long incubation times that may exceed 30 years inhumans." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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