More than a decade after Nancy Wexler first journeyed toVenezuela to search for the gene for Huntington's disease,members of James Gusella's group finally hit pay dirt inFebruary.

Huntington's disease (HD) is often described as relentless in itsprogression toward a certain death. About 30,000 Americanssuffer from the disease, and another 150,000 are at risk.

Gusella's work was reported in the March issue of Cell.

Wexler, president of the Hereditary Disease Foundation and aprofessor in the department of psychology and neurology atColumbia University, told her story recently at the NationalInstitutes of Health. She carried out her search among livingmembers of an extended family whose 13,000 members are alldescendants of an early 19th century woman "who wasappropriately named Concepcion." Two hundred members ofthe family are sick, and 1,000 have a 60 percent chance ofcontracting the disease.

Gusella, head of the Huntington's Disease Collaborative ResearchGroup and a professor of genetics at Harvard Medical School,was searching for the gene with his colleagues, studying cDNAsfrom a region of chromosome 4 that had been linked toHuntington's, when he discovered a repeated sequence of thebases CAG in one gene. Knowing that similar repeatedsequences, with greater numbers of repeats than in normalgenes, had recently been found in several other geneticdisorders, such as myotonic dystrophy, fragile X syndrome andspinal bulbar atrophy, his team checked the HD cosmid andfound a similar expansion.

They then found the same type of expansion, in varyingdegrees, in all HD patients they examined from the Venezuelanfamily, and then in members of 75 other families.

"The normal range of repeats goes up to 34, and Huntington'sstarts at 37," said Wexler. "One of the questions is, is there anyoverlap between the people with Huntington's and thenormals?"

The greater the number of repeats, the more unstable the geneappears to be. The normal allele rarely varies in size fromgeneration to generation. Moreover, changes in the number ofrepeats appear to occur exclusively during spermatogenesis. Aman with 48 repeats may produce sperm in which the numberof repeats varies roughly from 40 to 60.

There seems to be a rough correlation between the number ofrepeats, the severity of the disease, and the age of onset. Theyoungest member of the Venezuelan family to becomesymptomatic, at age 2, had the largest expansion. Whencounseling patients, however, it is dangerous to take thecorrelation too seriously, said Wexler.

Boston whalers probably brought the gene to New Guinea, andWexler's study population lives "near a gulf that communicateswith Europe. There is a huge influx of sailors and genes."

As for future research, "we need to know where the gene isexpressed, how expansion alters function. And we need tocreate animal models by knocking out the normal gene andputting the human Huntington's gene in," Wexler said.

She showed two videos in which two people from Huntington'sfamilies illustrated the limits of technology, and the ethicalproblems doctors face in dealing with patients. In one, a femalecarrier told how she had aborted three times in successionfollowing positive genetic tests, and had finally decided not tohave the next pregnancy tested. "We felt trapped by thetechnology, as though we had to do this," the woman said.Having decided not to test the final pregnancy, "we felt a greatwave of relief," she said.

In the other video, a man from an afflicted family who hadassumed he would die of the disease described his inability tocope following his own negative screen. He almost ruined abudding relationship and nearly got himself imprisoned beforeaccepting the slow progression of the disease.

-- David C. Holzman Washington Editor

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

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