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Huntington Facts

Hereditary Genomics Research

FACTS ABOUT FINDING THE HD GENE, DNA BANKING AND GENETIC TESTING FOR HUNTINGTON DISEASE

In 1983, a major breakthrough was made in the search for the cause of Huntingtons Disease. A DNA marker for the HD gene was found by Dr. James Gusella, of Massachusetts General Hospital. Although this marker was not the gene itself, its discovery meant that scientists were close to locating the gene. Subsequently, many other markers were found. Finding these markers made it possible to offer a presymptomatic test to persons who were at-risk for HD. However, not everyone could use this test because it required that an at-risk person have blood samples available from extended family members, both affected and unaffected. Our recommendation at that time was that regardless of whether or not a family member had decided to use testing, families should go ahead and store samples from family members who were affected, elderly or crucial to the testing process.

After nearly ten years of effort, an international team of scientists headed by Dr. Gusella has identified the gene which causes HD. It took an intense scientific effort and the phenomenal cooperation of families to accomplish this task. Along with finding the gene, comes a host of new questions:

HOW IS THE DISEASE INHERITED?

This is a genetic disease. Each child of an affected parent has a one in two chance, or 50%, likelihood of inheriting the genetic mutation or change that causes HD.

WHAT IS INHERITED?

The gene for HD is located on chromosome 4. The genetic code of this gene has three DNA bases, CAG, which are repeated several times. Among persons with HD, the number of repeats of this CAG sequence is approximately doubled. Exactly how this variation in sequence causes HD has not yet been established. Much research will be needed to determine the exact mechanisms which cause brain cells to die as HD progresses.

For some reason, yet unknown, the gene expands much more in the affected male to offspring transmission than in the affected female to offspring transmission.In general, the average CAG expansion in transmission from father to child is 9.0 repeats while the average CAG expansion from mother to child is .4 repeats.

In general, those who inherit the abnormal CAG repeat (40 CAG repeats and above) will develop HD unless they die of other causes prior to developing the signs and symptoms. However, finding the gene and the research that has followed has enabled us to refine our knowledge and, we now know that inheritance of HD is not as straightforward as originally thought. For example, we now know that there is a range of CAG repeats (27-35) in which you yourself will not develop HD (non-penetrance), but that the CAG repeat is unstable and might expand into the HD range when passed to your children (Meiotic instability). This expansion into the HD range will occur more often when the gene is passed from father to child than when the gene is passed from mother to child because of the differences in the rate of CAG expansion between the two sexes. We also know that there is a range of CAG repeats (36-39) in which you may or may not develop HD (variable penetrance) but that might expand into the HD range when passed to your children (Meiotic instability).

To clarify this further, the number of CAG repeats has been divided into the following 4 categories.

 

CAG REPEAT SIZE  INTERPRETATION 
 26 and below  Normal
 27-35  Not predictive of HD. May or may not be stably transmitted
 36-39  MAY BE predictive of HD.  Not stably transmitted
 40 and above  HD.  Not stably transmitted
WHAT DOES THIS MEAN FOR ME?

In the immediate future, there will be no changes. The methods for diagnosing and treating HD will remain the same. However, with continued investigation, many new possibilities will arise. Finding the gene is expected to simplify the testing process. Until now, many blood specimens from specific family members were necessary in order for an at-risk person to undergo presymptomatic testing. Now that the gene has been located, a two step testing process has been proposed. First, an affected family member's sample will be tested for the presence of the HD gene. Second, if, in fact, the gene is present (meaning HD was the correct family diagnosis), then the at-risk person who desires to know whether or not he too has inherited the gene, could be tested for its presence. Thus, it is our recommendation that families continue to store DNA on persons who are presumed to have HD.

Of course, genetic testing for Huntingtons Disease remains a personal decision which should be considered very carefully. Although the test may be technically less complex, the personal implications remain the same and are substantial. Our recommendation is that anyone seeking genetic testing do so only through programs in which protocols for testing have been submitted to the Huntingtons Disease Society of America and which are known to have reputable pre-test and post-test counseling programs.

Finding the gene also means that in the future we may be able to diagnose or rule out HD in families where the diagnosis is questionable. For example, if an individual has been diagnosed as having HD, but the diagnosis is questionable because of a lack of family history of HD, this diagnosis can be confirmed by looking to see if the person carries the gene for HD.

WHO SHOULD STORE DNA?

As previously mentioned, we recommend that families continue to store DNA from persons who are presumed to have HD. This will later assist in confirming the diagnosis of HD in the family. We also recommend that in the unfortunate event of the death of an at-risk person who has children, you call the DNA bank immediately about obtaining a blood or tissue sample from this person. If the person expires during non-office hours, we suggest that blood samples be taken from that individual as soon after death as possible. BLOOD MUST BE TAKEN SOON AFTER DEATH AND DEFINITELY BEFORE EMBALMING. The blood should be collected in tubes that contain the preservative EDTA (typically these are tubes with purple tops on them). Once the blood sample has been taken, the tubes should be refrigerated until you can speak with someone at the DNA bank. DO NOT FREEZE THE TUBES.

Collecting a sample from a person who is at risk, showing no signs of the disease, but who has children, means that at a later time the sample could be tested and the children can be told if they are at 50% risk (their deceased parent carried the HD gene), or at 0% risk (their deceased parent did not carry the HD gene).

WHAT NEXT?

Finding the gene for HD does not mean that there is a new treatment or cure for HD. It does, however, mean that the hopes of finding a treatment or cure are much greater than ever before. The search will be difficult because the mechanism by which this gene causes the disease has not been determined. Preliminary results indicate that this is a gene which has not been previously studied. There are many questions about this gene that need to be answered before a treatment or cure can be developed, but at least scientists are an enormous step closer to this event. Roster families will be informed of any research studies that may be open for participation. Participation in brain tissue donation programs is still invaluable for confirming the diagnosis of HD in families and for continued research. If you are interested in obtaining brain tissue donation information, please call the Brain Tissue Resource Center at (617) 855-2400.

If you would like to obtain a DNA kit for a family member, please call the DNA bank at (317) 274-5744. If an emergency arises concerning obtaining a blood sample call this same number. If the office is not open, please follow the emergency instructions above.

For further information concerning predictive testing we suggest that you contact the test center nearest you.You may also reach us at the following e-mail address: sburn@iupui.edu. Please include the word "Roster" somewhere in the subject.

 

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