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The age at which Huntington's disease starts is not solely determined by the Huntington's disease gene, as previously believed, but is strongly influenced by both genetic and environmental factors. More than two decades of intensive study of a unique community of families with HD in Venezuela have led to these new findings, according to a team led by Dr. Nancy Wexler, Higgins Professor of Neurology and president of the Hereditary Disease Foundation.

The dogma-breaking discovery suggests there are more ways to attack Huntington's than investigators realized and raises hope that scientists can mimic the protective genetic and environmental factors with drugs. The research was published in the March 9 Proceedings of the National Academy of Sciences. All authors of the new study belong to the U.S.-Venezuela Collaborative Research Project, a group of 57 international researchers who have participated in the project.

This discovery is due to the extraordinary contribution of more than 18,000 Venezuelans participating in the research and, for the first time, details of this large pedigree have been published and appear in the same paper.

Since 1979, Dr. Wexler's international team of researchers has traveled annually to Lake Maracaibo, Venezuela, to identify families with Huntington's disease and document their disease. Over these 23 years, they have identified 18,149 individuals, 15,409 of whom are living, spanning 10 generations. The Venezuelan families with Huntington's disease comprise 83 independent kindreds, including one with 14,761 individuals. This kindred inherited the HD gene from a woman living in a stilt village on the lake in the early 19th century.

"The Venezuelan kindreds are unique in that they encompass the world's largest genetically related HD community and have already provided a wealth of genetically and phenotypically informative data," Dr. Wexler explains. "The sheer magnitude of the overall kindreds, the size of individual nuclear families – from 1 to 21 children – the interrelationships among the branches, the high level of genetic heterogeneity, the relative immobility among the branches and their extraordinary cooperation have taught us immensely and promise to reveal more in the future." Genetic and clinical data from these Venezuelan kindreds were responsible for localizing the HD gene on chromosome 4 in 1983 – the first such localization using DNA markers when the chromosomal assignment was unknown – and subsequently discovering the defective gene itself in 1993.

Huntington's disease is invariably fatal for people who carry a disease-causing Huntington gene, but the age at which symptoms start appearing varies anywhere between age 2 and age 84.

Huntington's disease is caused by an expansion of the DNA in a gene which makes the protein huntingtin. This expansion occurs when three base pairs – CAG, coding for the amino acid glutamine – are repeated too many times. For years, HD was thought to be the epitome of genetic determinism: with more than 40 CAG repetitions, the huntingtin gene invariably causes death. Alleles with 60 or more repeats will definitely cause disease at age 20 or younger. The age of onset decreases as the number of repeats increases. However, investigation of the huntingtin genes in the Venezuelan kindreds and phenotypic analysis show that age of onset varies widely among people with the same number of repeats.

"Huntington's has been touted as the least malleable disease, but we're finding there is a huge amount of variation in age of onset and severity of symptoms," Dr. Wexler says. "We hope that our project will find the genes and environmental factors that offer treatments and cures. We do not merely want to make the disease milder. Our aim is to stop the disease altogether – either by preventing it from appearing or pushing the age of onset to 140 years, well beyond a normal lifespan."

The new study analyzed the DNA of 443 people with Huntington's disease for whom the researchers could establish accurate ages of onset.

When data from all of the 443 Venezuelans are combined, with repeat lengths ranging from 40 to 86 CAGs, the size of the repeat accounts for as much as 72 percent of the variation in age of onset.

But most Huntington's families in Venezuela and around the world have repeats within a narrower range of 40 to 50 CAGs. When investigators limited their analysis to this smaller range, the size of the repeat accounted for only 44 percent of the variability in age of onset.

What accounts for the rest? Using sophisticated statistical analyses of the Venezuelan kindreds, the group determined that 40 percent of the remaining variability can be ascribed to gene(s) other than the Huntington's gene. This figure is similar to other multifactorial diseases, including diabetes and heart disease. Environmental factors account for 60 percent of the remaining variability, and of this, approximately 20 percent is due to shared environmental factors and 40 percent is due to nonshared environmental factors.

The Venezuelan families also had a significantly earlier age of onset, 34 years, compared with 37 in the United States and 40 in Canada. Whether this earlier age of onset is due to shared genetic or environmental factors is under study.

Members of the Venezuela Project research team are now analyzing the same DNA samples for other genes that may influence the disease's age of onset and are setting up studies to find environmental factors.

"The Venezuelan families have given us many gifts," Dr. Wexler says. "In 1983 and 1993, they helped us find the Huntington's gene and understand its mistake. Now they are critical players in our search for the cure. It is important that the world understand how much they have given. It would be fitting if they could be the first to reap the benefits of all future therapies."

Research was supported by grants from the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, the W. M. Keck Foundation, and the Hereditary Disease Foundation.

—Susan Conova


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