Cause of Myotonic Dystrophy
Myotonic dystrophy (DM) is a geneticof or pertaining to genes; inherited. --- or inherited --- disease. It occurs when there is a change, called a mutationas used on this web site, a change in the normal chemistry of a gene., in a gene that can be passed on to future generations.
A gene is a stretch of DNA (the genetic material found in the nucleus of nearly every cell) that carries instructions on how proteins should be made and how they should function in the body. In patients with myotonic dystrophy, these instruction are altered and disease symptoms result.
The two forms of myotonic dystrophy are caused by mutations in different genes. Although DM1 and DM2 present with similar symptoms, the two forms have fundamentally different origins. The existence of other forms, caused by mutations at different sites, is currently being investigated.
Myotonic dystrophy is not contagious, nor is it caused by an infectious agent such as a virus or bacteria. A person usually gets the disease by inheriting the mutated gene from one of his or her parents. However, that parent may not have been aware he or she had the mutation because symptoms were not apparent. Such individuals may have a very mild form of myotonic dystrophy or may have a late onset form that will not cause symptoms until later in life.
In theory, a spontaneous - or de novo - mutation can take place in a gene and cause myotonic dystrophy. This type of mutation may explain the presence of myotonic dystrophy in an affected child where there is no family history of the disorder. However, this is extremely rare with only a handful of reports seen for de novo mutations in individuals with DM1 and no reports of de novo mutations seen in DM2.
How is myotonic dystrophy inherited?
An individual has two copies of each gene, one they receive from their mother and one they receive from their father. The mutation seen in myotonic dystrophy is an autosomal dominant mutation, which means one copy of the altered gene --- i.e. one that come from only one parent --- is sufficient to cause the disorder. As a result, affected individuals have a 50% chance of passing the mutated gene on to a child. This means the chances of an affected parent having a child with myotonic dystrophy are the same as the chances of having a child who does not. If neither parent has the mutation, a child cannot inherit the disease.
Once an individual is diagnosed with myotonic dystrophy, other family members may wish to be tested to determine if they also have the mutation. They may have concerns about their own health and risk, as well as that of their children. Questions about family planning may arise. The decision if and when to test for myotonic dystrophy is a complex one, requiring the advice of a genetic counselor familiar with the unique issues involved with myotonic dystrophy.
On very rare occasions, a spontaneous --- or de novo --- mutation takes place in a gene and causes myotonic dystrophy in an individual. However, this phenonemon is not to be confused with patients who inherit the disease from mildly affected patients who are simply unaware they have the disorder. There are no reports of de novo mutations in DM2
How does the mutation cause myotonic dystrophy?
The genetic change that causes the disease is different in each form of myotonic dystrophy:
DM1 The genes responsible for myotonic dystrophy type 1 (DM1) are found on chromosome 19 and contain regions where stretches of DNA are repeated several times. Each chromosome consists of a long chain of nucleotide bases (chemicals that form the units of DNA). Myotonic dystrophy is sometimes referred to as a trinucloetide repeat disease because three of these bases (abbreviated CTG) are repeated many times. In healthy individuals, there are between 5 and 37 repeats of the CTG sequence. People with myotonic dystrophy have expanded repeats, with anywhere from 50 to more than 4,000 repeats of the CTG sequence.
DM2 The genes responsible for myotonic dystrophy type 2 (DM2) are found on chromosome 3 and contain stretches of DNA where four chemicals (abbreviated CCTG) are repeated along the stretch of DNA. These repeated sequences are also expanded in patients, with less than 75 repeats seen in healthy individuals and between 75 and 11,000 repeats seen in patients.
The number of repeats often correlates--- but not always --- with the severity of symptoms seen, particularly in patients with the DM1 form of the disease. In DM1, a lower number of repeats is generally seen in patients with a milder form of the disease, while a higher number can reflect more complicated disease pathology. Also, a higher number is often associated with earlier onset of symptoms. In DM2, the relationship between repeat count and disease state is less direct.
The number of repeats along the DNA tends to increase when the mutation is passed on to children for reasons researchers do not yet fully understand. As a result, symptoms tend to be more severe and occur at a younger age in successive generations within a family. This phenomenon is called anticipation and also occurs in other diseases such as Fragile X Syndrome and Huntington's Disease.
The repeated stretches are unstable, with the number varying between individuals in the same family and even between tissues in the same individual. The number can also change over the lifespan in an individual. In both DM1 and DM2, many other genetic and environmental factors influence disease symptoms. As a result, repeat count should not be considered definitively predictive of an individual's prognosis.
For more information on repeat count and how myotonic dystrophy is inherited print the 'Genetics of Myotonic Dystrophy' fact sheet.