Ataxia with a new twist: CTG repeats cause spinocerebellar ataxia type 8 (SCA8).

Editors Note: Dr. Melinda Moseley, University of Minnesota, presented a talk on SCA8 at the 1999 Annual Membership Meeting. In lieu of publishing a summary of her presentation, we are including the article on SCA8 written for Generations by Amy Durand.

We are excited to report that we have identified the gene for a new type of ataxia, spinocerebellar ataxia type 8 (SCA8). SCA8 was found using a technique we developed, called RAPID cloning. RAPID cloning pulls out regions of DNA containing long stretches of repeated DNA sequences that have been found to cause several inherited forms of ataxia. This method is unlike more traditional genetic methods because it allows disease-causing genes to be isolated from a single individual. In the past, large families with many affected people have been necessary to isolate disease genes. SCA8 is unique among ataxia genes because SCA8 is caused by a long CTG repeat instead of a CAG repeat. In addition, the genetics of SCA8 is more complex than for other ataxias. Eventually understanding precisely how CTG and CAG repeat expansions cause neurons in the brain to die will teach us more about ataxia. We hope a better understanding of the causes of ataxia will lead to a cure. Researchers who identified and characterized SCA8 include: Michael Koob, Melinda Moseley, Lawrence Schut, Kellie Benzow, Amy Durand, Thomas Bird, John Day and Laura Ranum [Nature Genetics 21,379-384 (1999)].

A background summary of genetics ...

In order to understand the genetic changes that cause SCA8, it is important to know that our body is made of millions of cells, each containing 23 pairs of chromosomes. Chromosomes are rods of DNA that we inherit from our parents -- one chromosome in each pair comes from our mother and one from our father. Each chromosome is made up of thousands of genes and contains the genetic directions that our cells need to function and make proteins (proteins do most of the work in a cell). These genetic directions are written in the chemical language of DNA using four letters (A, C, T, and G), that correspond to the four building blocks of DNA. The four letters are arranged in three letter "words", which the cell can "read" and translate into proteins. Some regions of DNA have the same three genetic letters repeated over and over (for example: CTGCTG-CTG-CTG). These repetitions of the same three letters are a normal genetic feature, called trinucleotide repeats. If the repeat number gets too long, however, it can disrupt the functioning of the cell. Since so many forms of ataxia are caused by trinucleotide repeat expansions we spent a long time developing a method that selectively identifies these genetic changes. An analogy we use is that these long stretches of repeats are a `needle in the haystack' and our RAPID cloning method is a powerful `magnet' that can be used to directly isolate the `needle' or the long repeat without having to sort through all the hay.

In search of a long CAG repeat we found a CTG repeat ...

When we began our search for ataxia genes using the RAPID cloning method, we went looking for long CAG repeats because that is what causes ataxia in the other SCAs (SCA1, SCA2, SCA3, SCA6 and SCA7), but instead of a CAG repeat - we found a CTG repeat! At first we didn't think the CTG repeat was likely to cause ataxia, even though a CTG repeat and a CAG repeat may sound similar. It took a lot of time for us to be sure that the CTG repeat actually does cause ataxia. We named this newly discovered ataxia gene SCA8.

The genetics and inheritance of SCA8 is complicated ...

The CTG repeat that causes SCA8 is located on chromosome 13. When we look at DNA from the general population without ataxia, nearly all (over 99%) SCA8 genes have between 16-50 CTG repeats. Affected individuals usually have 110 or more CTG repeats. It appears that the length of the CTG repeat determines whether or not a person will develop ataxia, because people with fewer than 100 repeats tend not to develop the disease whereas people with over 110 repeats are likely to develop the disease.

It is still unclear if someone with CTG repeats in the range of 51 to 109 repeats is at an increased risk of developing SCA8. Because the repeat length can change from generation to generation, someone with 51-109 repeats may not develop ataxia, but the offspring of that individual might be at increased risk. Surprisingly, it is also unclear if a person with greater than 250 repeats is at an increased risk. We have seen some individuals with repeats larger than 250 without symptoms of ataxia. Further study of SCA8 families will help us better define the risk of repeat lengths between 50 and 109 and over 250.

Because we all have two copies of each chromosome, we also have two copies of the SCA8 gene (one from each of our parents). We only need one copy of SCA8 with a long CTG repeat in order to have ataxia. Thus, a person with SCA8 wilt have 110 or more CTG repeats in the SCA8 gene on one chromosome, but the number of CTG repeats on the other chromosome will be in the normal range. When a person with SCA8 has a child, that child will inherit either the chromosome with the long CTG repeat or the one in the normal range.

The inheritance pattern of SCA8 is often complicated, because the length of the CTG repeat can change from generation to generation. While the long CTG repeat can come from either parent, there is a tendency for the number of repeats to increase when it is inherited from the mother and to decrease when inherited from the father. This is different than the other SCAs. When the expanded SCA8 "gene comes from the mother, the number of repeats will often grow into a size that causes ataxia. In contrast, inheriting the abnormal SCA8 gene from the father means that the number of repeats is likely to shrink, most often into a size range that doesn't cause ataxia, although it may again expand in future generations. This means that most people who develop SCA8 ataxia symptoms have inherited a long CTG repeat from their mother.

Because a person needs only one copy of the long CTG repeat in SCA8 to have ataxia, we initially expected to see a clear pattern of dominant inheritance for SCA8 families. A dominant family tree would show multiple people in each generation with ataxia and the disease would always be passed on from parent to child (with a 50% chance that each child would inherit the abnormal gene and have the disease). The SCA8 family in Figure 1 shows some of the trends of dominant inheritance and some trends specific to SCA8.

[Figure 1 ILLUSTRATION OMITTED]

It shows that the disease can be passed from generation to generation and that it is present in both males and females. But it also shows the tendency of the CTG repeats to increase in length when passed on from the mother and to decrease in length when passed on from the father. This difference in inheritance; which leads to some people inheriting the abnormal SCA8 gene, but not developing the disease, would not usually be expected in a dominant family tree.

All SCA8 families do not have a clear pattern of dominant inheritance of the disease -- figures 2 and 3 show that while the inheritance of the SCA8 gene is always dominant, it can be hidden because not everyone with a long CTG repeat will develop ataxia. The family in Figure 2 provides an example of how SCA8 can appear to be recessive. In this family, a brother and sister both have ataxia. Although neither parent shows any signs of ataxia, we can use the genetic test for SCA8 to see that the father carries a large repeat size of 250 CTG repeats. We can also see how the repeat size decreased in length when it was passed from the father to his children. In this situation, we do not yet understand why the father would not have ataxia -- we think that maybe a repeat of this size is too large to cause the disease. Hopefully, further study of SCA8 families will help to answer this question.

[Figures 2-3 ILLUSTRATION OMITTED]

The family in Figure 3 shows an example of a person who appears to have no family history of ataxia (i.e. sporadic ataxia). Because this woman has no other siblings or any other relatives with ataxia, there would be no reason to think that her ataxia is inherited. However, genetic testing for SCA8 in her family reveals that her mother is actually a carrier for SCA8. The CTG repeat carried by the mother is not large enough to cause ataxia, but the number of repeats grew when passed to her daughter and increased to a size that does cause ataxia. If the affected woman in Figure 3 also had a brother or sister with ataxia, the family tree would look recessive if there were two affected siblings and healthy parents rather than sporadic with only one person in the family affected. While the inheritance pattern of SCA8 can appear to be dominant, recessive, or sporadic; the disease itself is relatively rare.

Differences between SCA8 and other spino-cerebellar ataxias

As we have mentioned before, the genetic cause of SCA8 is different from other SCAs. Five of the SCAs are caused by extra CAG repeats within DNA that codes for proteins (SCA1, SCA2, SCA3, SCA6, and SCA7). SCA8 is different not only because it is caused by too many CTG repeats (instead of CAG repeats), but also because the repeats occur in a "silent" area of DNA that does not code for a protein. Myotonic dystrophy is the only other disease known to be caused by CTG repeats in a "silent" area of DNA. Myotonic dystrophy, the most common form of muscular dystrophy in adults, causes symptoms completely unlike those of ataxia (muscle weakness and stiffness, cataracts, and abnormal heart rhythms). While the clinical features of myotonic dystrophy differ from those of SCA8, we hope that clarifying the genetic similarities of these disorders will help us identify the causes and treatments for both diseases.

Spinocerebellar ataxia type 5

Ironically, we originally developed RAPID cloning to identify the gene that causes SCA5, another form of dominantly inherited ataxia that we have been studying. While the RAPID method was successful in finding SCA8, it has not worked for SCA5. Just as SCA8 provides us with a new twist on ataxia, we believe that finding the SCA5 gene will also lead us to something else that is new. It is possible that SCA5 is not caused by a CAG or CTG repeat expansion, or that SCA5 is caused by an expansion that is too short to be identified by the RAPID method. Because SCA5 is clinically milder than other SCAs (it primarily affects the cerebellum and not the brainstem) identifying the genetic cause of SCA5 will be tremendously important in understanding how different DNA changes affect different groups of nerve cells to cause ataxia. Once again we are focusing on traditional approaches involving as many family members as possible to pinpoint precisely where in the haystack the SCA5 gene is located. The help and participation of as many family members as possible has been, and will continue to be, crucial to finding the SCA5 gene.

What you can do to help ...

We are extremely grateful to all of the individuals and family members who have made this research possible. There remain a large number of individuals with genetically undefined ataxias in whom novel causes could be identified with RAPID cloning. If you are interested in helping with any of our ataxia research, please contact Amy Durand or Dr. Laura Ranum at [phone] to learn more about what you can do to help. Ataxia research is a team effort and we would not be able to do it without your support.

What can be done to help you ...

Although cures for most types of ataxia have not been identified, designated Ataxia Clinics can help individuals and families cope with these disorders. At the University of Minnesota, the Ataxia Clinic provides comprehensive evaluation and therapy for the respiratory, nutritional, communication, and mobility concerns that are common in ataxia patients. Additionally, the genetic testing and genetic counseling needs of individuals and families with ataxia are thoroughly addressed. Clinic patients are routinely informed about recent research findings and ongoing research opportunities. As they have done with SCA5 and SCA8 families, Dr. John Day (the newly appointed Ataxia Clinic Director at the University of Minnesota) and Dr. Lawrence Schut, (clinic Co-Director, and Medical Director of the NAF), are working with the entire clinic staff to bring the latest research findings to ataxia patients and their families.

RELATED ARTICLE: About Family Trees 

In genetics, almost all family trees are drawn the same. Circles are used to represent females and squares to represent males. Horizontal lines connect parents and their children are shown below them.

Affected individuals are shown with a filled-in symbol and people with a long CTG repeat but no disease are shown with a small black circle within their symbol. The numbers listed below each symbol represent the number al long CTG repeats present; CTG repeats in the normal range are not shown.

These family trees and the CTG repeat sizes are not based on a real family. The information shown is an illustration of the type of data we've seen in our study.

RELATED ARTICLE: SCA8 Summary

CTG Repeat Sizes   Affected Status

16-50 Repeats      Normal
51-109 Repeats     Unknown (may have increased risk)
110-249 Repeats    Likely to cause ataxia
250+ Repeats       Unknown (may not cause ataxia)

SCA8 is caused by a CTG repeat expansion. The repeat length usually increases when passed on from the mother, and decreases when passed on from the father.

Amy Durand, M.S. University of Minnesota, Minneapolis, MN3