Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, affects the eyes, heart, hormonal systems, and blood, in addition to causing muscular dystrophy and involuntary muscle stiffness (myotonia). Prior to this research, most cases of myotonic dystrophy were thought to be the more severe form, myotonic dystrophy type 1 (DM1), which occurs in about one of every 7,000 people worldwide. Earlier estimates that DM2 occurs at 2 percent of the rate for DM1 have now been significantly revised; the frequency of DM2 may equal that of DM1 in some populations.
"Until now, myotonic dystrophy type 2 has been difficult to diagnose," said John W. Day, M.D., Ph.D., professor, Department of Neurology and the Institute of Human Genetics. "The DNA alteration that causes DM2 is extremely unstable, and dramatically varies in size within blood of an affected individual. Because of this marked range of sizes in each affected individual, the genetic change has been very difficult to detect." The new diagnostic method amplifies a portion of the mutation in DNA from a patient's blood, and then uses a second step to verify that it truly is a DM2 mutation.
"Oftentimes, people with DM2 are not correctly diagnosed with the disease," said Laura P. W. Ranum, Ph.D., associate professor, Department of Genetics, Cell Biology and Development and the Institute of Human Genetics. "They see different doctors about separate symptoms, without either patient or physician knowing the underlying cause. Being able to diagnose these patients means we hope to stay a step ahead with their treatment."
Ranum, Day, and their colleagues evaluated the genetic features of 379 individuals from 133 DM2 families, demonstrating that. DM2 occurs in many families of Northern European ancestry. Clinically, DM2 resembles adult-onset DM1, with myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, and cardiac conduction defects. An important distinction with DM1 is the lack of a severe congenital form of DM2.
In earlier research, Day and Ranum located the genetic cause of DM2 on chromosome 3 in 1998 (Nature Genetics 19:196), and collaborated with investigators in Germany and Texas to find in 2001 that DM2 is caused by repetition of the genetic code "CCTG" over and over again within intron 1 of the zinc finger protein 9 (ZNF9) gene (Science 293:864-867, 2001). These earlier findings indicated that a novel disease mechanism involving abnormal RNA causes both DM1 and DM2. "RNA is the messenger molecule that translates the DNA code into proteins," said Ranum. "Identification of the unusual genetic cause of DM2 led to the realization that RNA itself can cause disease."
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Journal
Neurology