If earthquakes were predictable, would Californians reallywant to know in advance when to expect disaster?

It's the same with Huntington disease H or used to be H until1983. Insidiously, this genetic malady usually strikes itsvictims in their 30s and 40s. By that prime-of-life age, theyhave often married and had children to carry the mutantHuntington gene into the next generation.

In 1983, molecular geneticist James F. Gusella led amultinational research team that pinpointed a missingrestriction site on chromosome 4 of Huntington disease (HD)patients. Their discovery, the first time that restrictionfragment length polymorphisms had been used to diagnose adisease, made it possible to test still-healthy, at-riskindividuals in HD families, and predict their risk of acquiringthe sneaky affliction.

Today, a decade later, Gusella and his fellow researchersannounced that they have located a gene on chromosome 4'sshort arm that shows signs of being at least closely related totheir ultimate goal G the gene that causes HD. The issue ofHuman Molecular Genetics (Oxford University Press) publishedtoday reports their finding.

"We don't know yet whether this is the gene that causesHuntington's," said Gusella, who directs the MolecularNeurogenetics unit at Massachusetts General Hospital (MGH).But two factors encourage him and his colleagues: "First of all,the gene is located on a stretch of chromosome 4 consideredthe most likely site for the HD defect." And second, "This geneproduces a protein that may be critical for proper brainfunctioning."

The protein is one of many key enzymes that orchestrate theprocess of signal transduction by which brain cellscommunicate. "It triggers a cascade of events inside the cell,"explained MGH neurogeneticist Marcy E. MacDonald, seniorauthor on the journal paper. The protein switches off signaltransduction by desensitizing an activated receptor. If theproduct of a mutant gene disrupts this process, it could explainthe slow, progressive death of brain cells in HD.

"Something has to stop that signalling," Gusella added;"Otherwise, the cell is going to be in trouble."

If that trouble is specific to HD, then it triggers the "three M's"of HD symptomology: movement, mood and mentation. Erraticchanges in one or more of these neurological functions, such asclumsiness, temper outbursts, forgetfulness, are the first hintsof impending HD, explained psychologist Kimberley A. Quaid,who directs Indiana University's pre-symptomatic HD testingprogram.

Philip Cohen, information referral specialist at the HuntingtonDisease Society of America, said that there are 25,000 knowncases of HD in the U.S., and five times as many individuals atrisk.

Last October, Quaid told the American Society of HumanGenetics 1992 annual meeting in San Francisco, that her testingcenter, with grant support from NIH's National Institute ofNeurological Disease and Stroke, surveyed the 26 U.S.laboratories that provide HD predictive genetic testing andpsychological counseling.

Between 1986, when HD predictive testing began, and April 15,1992, 296 Americans had been tested:l High-risk results: 80 individuals (27%)l Low-risk results: 169 (57%)l Uninformative: 47 (16%)

In addition, of 38 prenatal tests conducted, 13 at high-risk ledto 11 interrupted pregnancies.

-- David N. Leff Science Editor

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

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