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Phillips, Lisa

News From the Venezuela Kindreds Study


Variability in the age of onset of Huntington disease (HD) is the result of both genetic and environmental factors, not just the presence of the mutated HD gene. This is according to the latest study by the US-Venezuela Collaborative Research Project, an international team of researchers who have been studying a large HD community, primarily in the region of Lake Maracaibo, in Venezuela, since the late 1970s.

Investigators will focus on identifying these factors in the next phase of the study. HD is a fatal, autosomal dominant neurological illness that affects one out of every 10,000 people in the Americas, Europe, and Australasia.

The HD gene is considered fully penetrant, meaning that people who inherit the disorder will get the disease if they live a normal life span. The disease usually affects individuals in their third or fourth decade of life, but age of onset can vary widely from one person to the next. In the Venezuela Project, the mean age of onset was 34 years old, but ranged from two to 69 years old.

The most critical factor in determining the age of onset of HD is the number of repeated DNA sequences in the mutated HD gene. This gene includes an unstable trinucleotide repeat expansion of the sequence CAG, coding for the amino acid glutamine. Too many CAG repeats in the gene alter the huntingtin protein and cause neuronal dysfunction, particularly in the striatum and cortex, and eventually death.

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The study, published in the March 9 online edition of the Proceedings of the National Academy of Sciences (2004;101(10):3498–3503 [serial online]), asked whether, in addition to the number of repeats in the HD gene, other genetic and environmental factors influence age of onset.

The study, which looked at age of onset for 458 people with HD over the course of more than 20 years, determined that the repeat size of the HD gene accounted for 72 percent of the variability in age of onset for Venezuelans with repeat lengths from 40 to 86 CAGs. But when investigators focused on people whose repeat sizes were between 40 and 50 CAGS, which is typical of the majority of people with HD worldwide, they discovered the size of the CAG repeat accounted for a much smaller part of the variability in age of onset.



“To our shock, CAG repeat length accounted for only 44 percent of the variability in age of onset,” said the lead author Nancy Wexler, PhD, Higgins Professor of Neuropsychology in the Departments of Neurology and Psychiatry at Columbia University in New York, NY. She is also the President of the Hereditary Disease Foundation and the founder of the US-Venezuela Collaborative Research Project.

Through statistical analyses, they discovered that other genes – independent of the known HD gene – explain about 40 percent of the variability in the age of onset for the disease. The magnitude of this genetic effect is similar to that found in other polygenic disorders. The remaining 60 percent is accounted for by environmental factors, which can be further subdivided into shared and unique effects. Environmental factors that are shared by siblings – for example, family diet – account for 20 percent of the variability, while environmental factors that are unique to each individual, account for the remaining 40 percent.

“Analysis of the Venezuelan kindreds provides the strongest evidence to date for genetic factors influencing age of onset of HD that are statistically independent of the mutation causing the disease,” said Dr. Wexler. “We also confirmed the role of environmental modifiers in modulating age of onset. The specific genetic and environmental factors have not been identified yet. But if they are discovered in future studies, the age of onset could be delayed.”

“We want to push HD out of the life span – that's the promise of these findings,” she said. “We want to find other genes and environmental factors which can do this. If Huntington disease starts when you are 120 years old, who cares?”

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The PNAS paper is the first full publication of the Venezuelan kindred. Since 1979, Venezuela Project investigators have collected genetic and clinical information on 18,149 individuals, the world's largest and best characterized HD community. Most are descendants or relatives of descendants of a woman who lived in a stilt village on Lake Maracaibo in the early 1800s. Her chromosome, with its HD mutation, has been passed down through 10 generations with devastating effects.

Over 4,000 individual blood samples were collected and analyzed to determine the number of CAG repeats in the HD gene. There are 938 heterozygotes, 80 people with variably penetrant alleles – between 35 and 39 CAGs – and 18 homozygotes.

The Venezuela Project was launched in 1979 by Dr. Wexler, whose mother died of HD, and with the support of the Hereditary Disease Foundation, founded by her father, Milton Wexler, as well as the NIH and the W.M. Keck Foundation. Study of DNA samples from the Venezuelan kindred led to the localization of the HD gene in 1983, its isolation in 1993, and the creation of a mouse model of the disease in 1996.

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The next step for the Venezuela Project is to try to genetically map the locations of major contributors to the genetic variation of age on onset, said David E. Housman, PhD, a molecular geneticist at the Massachusetts Institute of Technology in Cambridge and one of the authors of the study. “Some of the hunches are based on our guesses about the roots of pathology in HD. There's quite a maelstrom of different points of view and pathways that we're trying to sort out. One source is those pathways that are suggested from other kinds of biological model-based analysis.”

Kenneth H. Fischbeck, MD, Senior Investigator in the Neurogenetics Branch at the NINDS and a researcher in the Venezuela project, said he would like to see further studies on the impact of the glutamate receptor 6 gene (GluR6). “If there's too much activity in that transmitter, it's harmful for nerve cells and that could be part of the mechanism of Huntington disease,” he said.

Dr. Fischbeck pointed out that a 1997 study published in PNAS showed that, of the variance in the age of onset of HD that was not accounted for by the CAG repeats, 13 percent could be attributed to GluR6 genotype variation (Proc Natl Acad Sci USA 1997; 94(8):3872–3876). According to the study, GluR6 was investigated because excitotoxity became a favored mechanism to explain cell death in HD after intrastriatal injection of excitatory amino acids in animal models of HD was discovered to create an HD-like pathology.



Dr. Fischbeck said another possibility for study is ubiquitin carboxyl-terminal esterase L1 (UCHL1), a “factor in protein degradation.” He said, “If there's genetic variation in this pathway, that could have an effect on disease severity.”

As for possible environmental factors for study, Dr. Wexler said one starting point will be that the average age of onset for HD in Venezuela, 34 years, is earlier than it is in the United States (37) and Canada (40). The differences, though small, are “statistically significant,” she said.

“What we're trying to do by looking at these potential clues is to ask what we can learn from them,” she said. “We'll look at whether there is any influence of hot weather. We'll look at the age of onset in other populations and see if there are any consistent changes in different latitudes and longitudes.”



The Project is also assessing the potential roles diet, smoking, alcohol, socioeconomic status, and water quality in the region of Lake Maracaibo, where the community lives, may play on modifying age of onset. “The lake is polluted by a huge amount of sewage and oil. There are major sanitation problems,” she said.

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Merit E. Cudkowicz, MD, Associate Professor of Neurology at Harvard Medical School and an associate neurologist at Massachusetts General Hospital in Boston, called the study “enormously important.”

“It was a major collaborative effort to collect enough patients and gather enough samples to identify the gene,” she said. “They didn't stop at that. They continued to use the data and to go back there and collect more data so they could learn more about the illness.”

She said it will take a while before the research has clinical applications. “It's not imminently going to change anything in the therapeutic world, but we can't get good therapies until we understand factors that trigger the disease,” she said. “Identifying that there are other genetic and environmental components that can influence the disease phenotype helps people focus on trying to figure out what they are.”

Michael Hayden, MD, PhD, Professor in the Department of Medical Genetics at the University of British Columbia in Vancouver, Canada, said that “it's great to see this new data,” in particular the data that compares the mean age of onset for homozygotes to that of heterozygotes.

“It looks significant, but there's not enough data in the study,” Dr. Hayden said. “I'd like to have known more about homozygotes, more details about the CAG contribution to age of onset at specific ages and specific CAG sizes. It sets the stage for additional reports,” Dr. Hayden said.

Dr. Hayden was one of the principle authors of a study on CAG length and the age of onset for HD, published in the April 2004 issue of Clinical Genetics. The study analyzed data from the largest group of HD patients analyzed to date, 2,913 people from 40 centers on four continents, to develop a parametric survival model based on CAG repeat length to predict the probability of neurological disease onset at different ages.

Dr. Hayden said the results “were consistent” with the results in the Venezuela study. “CAG size contributes significantly, but it's not the whole story,” he said.

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✓ Through an analysis of data on repeat CAG lengths, age of onset, and familiar correlations from the Venezuelan Huntington disease (HD) kindreds – a large population with HD studied since the 1980s – a new study determined that genetic modifier genes other than the HD gene account for 40 percent of the variability in the age of onset and environmental factors account for 60 percent.

©2004 American Academy of Neurology