Dystonia DYT1 Gene FAQ

Summary of Nature Genetics article. Edited: June 3, 1999 (JEB)

In the September 1997 issue of Nature Genetics, scientists announced the discovery of the gene responsible for most cases of early-onset dystonia, the most common form of hereditary dystonia. This type of dystonia, also known as generalized dystonia or idiopathic torsion dystonia (ITD), is a neurologic movement disorder characterized by twisting or turning movements and abnormal postures. The gene, called DYT1, encodes for a protein known as torsinA. The exact function of torsinA is not known.

Frequently Asked Questions about the Discovery of the Early-onset Dystonia Gene. (These questions were answered by Dr. Mitchell F. Brin, Director Movement Disorder Center, Mount Sinai Medical Center, New York, NY, US)

I am affected by dystonia, as are other members of my family. What does the discovery of the DYT1 gene mean to me?
The discovery that the DYT1 gene encodes for torsinA has several important implications for those affected by early-onset dystonia. You and other members of your family may now be able to receive an accurate, direct genetic test to determine if you are a carrier of this gene. Such a test may benefit individuals who have symptoms associated with dystonia as well as those who do not have symptoms but have a relative with dystonia. For those individuals with symptoms, a positive test for the DYT1 gene may assist their neurologist in confirming the diagnosis. For relatives of affected individuals, this genetic test may provide important information as to whether or not they are also carriers of the DYT1 gene. This may help to establish their risk for developing symptoms associated with dystonia.

The tendency or "predisposition" for developing any of the various types of dystonia is controlled or regulated by the interaction of many genes. Therefore, negative test results do not necessarily mean that individuals do not have another gene that may contribute to the development of dystonia. The discovery of the DYT1 gene will accelerate research into the causes of early-onset dystonia. When scientists understand more fully how defective genes work and interact to cause the symptoms of dystonia, they may be able to design treatments that directly address these problems. It is important to remember that finding the gene for a condition is only the first step in the long process of developing better treatments. However, with this information in hand, the logical direction for research into treatments becomes clearer.

What is a genetic test?
A genetic test is a particular kind of laboratory test, usually done on cells from the blood of the person being tested. The goal of the test is to determine the presence or absence of particular changes in the genes of the person being tested; aid in the diagnosis of a disease; or determine if a person is a carrier of a particular disease gene. A direct test looks for change(s) in the actual gene in question. This type of testing is more accurate than the linkage test, which tests for chromosome differences usually close in location to the disease gene. Until now, the only genetic test for early-onset dystonia was a linkage test. A direct test is now possible for one form of early-onset dystonia associated with the DYT1 gene.

What are genes?
Genes are long molecules composed of the chemical DNA and are found in the nucleus of each cell. Genes perform two important functions. Firstly, each gene is the recipe, blueprint, or code for building a particular protein within the cell. Because proteins do all their work inside a cell, a mistake in the blueprint for any one of these proteins may have serious consequences for the functioning of that cell. Early-onset dystonia is caused by a mistake in the gene that contains the code for the protein called torsinA. The exact role of torsinA in brain cells is not known. Secondly, genes are the material of inheritance–copied and passed from parent to child–they ensure that offspring arise from a combined set of blueprints from the parents. Genes are linked together to form even longer structures known as chromosomes. Almost every human cell contains exactly 46 chromosomes or 23 pairs. Each chromosome comprises hundreds or thousands of genes strung together. The DYT1 gene is located on the long arm of chromosome 9 (9q34).

What is a genetic disorder?
A genetic disorder is a condition that occurs as the result of mistakes or changes in the code or of a gene. These changes, called new mutations, occur before conception during sperm or egg production. When this mutation occurs, the parent is not affected by the disorder; however, the child who receives the genes in that sperm or egg may be affected. As the developing fetus grows, the mutated or altered gene is usually copied exactly (i.e., in its mutated or changed form). Therefore, each cell in the body carries the mutated gene. This includes the sperm or egg cells produced by this individual. This means that this individual may pass on the gene to his or her children. A disorder that occurs as the result of a mutated gene that can be "transmitted" is occasionally called a heritable disorder. Early-onset dystonia is one type of heritable dystonia.

What is the DYT1 mutation and how did it arise?
The DYT1 mutation that causes early-onset dystonia is a deletion of three nucleotides, called GAG. Nucleotides are the molecular building blocks of DNA. This relatively minute change in the torsinA blueprint apparently causes critical changes in the function of the protein, and in some cases, ultimately leads to the symptoms of dystonia. Therefore, individuals who have this mutation are carriers of the DYT1 GAG deletion.

Most cases of early-onset dystonia are not due to new mutations, but rather to accurate or "faithful" copying and inheritance of a gene mutation that occurred many generations in the past. Many cases of this type of dystonia are found among the Ashkenazi Jewish population (Jews who trace their ancestry back to Central and Eastern Europe). In addition, non-Ashkenazic individuals with the disorder carry the same mutation. This mutation is also seen in non-Ashkenazic Caucasians, African Americans, Asians, and other populations.

What are the other types of heritable dystonia?
There are other types of heritable dystonia, each of which is distinguished by the gene responsible for the disorder. For example, the gene for dopa-responsive dystonia (DRD) has been identified and well characterized. The gene locations for several other dystonias have also been determined, including that for X-linked parkinsonism on the X chromosome. Another disease gene located on chromosome 8 codes for a type of dystonia observed predominantly in the Amish and Mennonite populations. Other genetic forms of dystonia are summarized in the table Dystonia: Molecular Classification. If a gene test is negative, it is possible that another genetic form is present but not the one tested.

Do both parents need to pass on the gene mutation in order for a child to develop dystonia?
No, not usually. Early-onset dystonia is known as a dominant disorder. This means that only one copy of the abnormal gene is needed in order for an individual to inherit the potential to show symptoms. Some other genetic disorders, but not heritable dystonias (except for rare cases of DRD) are termed recessive. This means that two abnormal copies of the abnormal gene are needed before a person develops the disorder. Early-onset dystonia is also an autosomal disorder, meaning the gene is not carried on the chromosomes that determine an individual gender or sex (i.e., the X or Y chromosomes). Consequently, individuals of both sexes may develop the disorder and either parent may pass on the gene to their offspring. In contrast, an X-linked recessive gene is more likely to be expressed in males. X-linked dominant genes are usually lethal in males.

If I have a mutation in my DYT1 gene, does that mean that I will get dystonia?
It is possible that you will get dystonia, but not necessarily. For reasons scientists do not yet understand, only 30 to 40% of those with the abnormal DYT1 gene develop dystonia. There is no way yet to predict whether a person with the abnormal gene will develop symptoms of the disorder.

Should I be tested for the dystonia gene?
The decision to get a genetic test is a personal decision and one that should not be made lightly. You may want to consider these factors while making your decision:

Do you have symptoms of dystonia?
Individuals who already have symptoms of dystonia, but who have not yet been definitively diagnosed, may benefit from genetic testing. A positive result may allow their physician to make a definitive diagnosis and allow individuals with dystonia to finally identify a cause of their symptoms. A negative test result does not mean that you do not have an inherited form of dystonia. It simply means that you do not carry the DYT1 gene abnormality.

Does a family member have early-onset dystonia?
If another member of your family has early-onset dystonia, you have probably asked yourself whether you will also develop symptoms. Your test results may provide you with the additional knowledge. A positive result only means that you may develop symptoms and most individuals who have the gene do not develop the symptoms of dystonia. Moreover, a negative result does not necessarily mean that you are "dystonia free." There are other forms of inherited dystonia.

Are there professionals who can help me understand the issues that are involved in genetic testing?
A genetic counselor is a person trained in both the science and the psychological issues involved in genetic testing. A genetic counselor can help you explore the benefits and downsides of getting tested, as well as help you understand what the results mean and do not mean. If you are thinking of undergoing a genetic test, you should plan to talk with a genetic counselor. In fact, most centers that do genetic testing require consultation with a genetic counselor before the test is performed. These centers have genetic counselors who are available for appointments.

Where can I get a genetic test if I want one?
Genetic testing is available at a number of laboratories. The Movement Disorders Program at Mount Sinai Medical Center in New York City sends its patients blood samples to the Massachusetts General Neurogenetics DNA Diagnostic Laboratory in Boston, MA. The telephone number for the laboratory is (617) 726-5721.

For a listing of genetic counselors in your area, contact:
National Society of Genetic Counselors (NSGC)
www.nsgc.org

For additional information on a variety of genetic issues, contact:
The Genetic Alliance
www.geneticalliance.org

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