Timeline of key discoveries in myotonic dystrophy research since DM was first described in 1909. Click on the corresponding timeline entry for links to research abstracts or reviews.
Abstracts not available for: Greenfield and Fleischer, 1911/1918; Bell, 1947; Vanier, 1960.
Maurice Swanson, Ph.D., Professor of Molecular Genetics and Microbiology at University of Florida, Gainesville, and a team of researchers have found that the muscleblind-like 2 (MBNL2) protein in the central nervous system (CNS) may be responsible for the neurological impacts of myotonic dystrophy (DM), providing hope for new treatments. Muscleblind is a type of protein that plays an important role in switching proteins typically found only in babies to proteins found in adults. If this switch isn’t made, an imbalance exists that leads to myotonic dystrophy.
Dr. Swanson states that the team’s work seeks to understand what causes myotonic dystrophy beyond the mutations in the DM1 and DM2 genes.
Dr. Swanson examined which genes were affected by loss of MBNL2 in the brain and found more than 800 affected genes. Many of them had one thing in common: the encoded protein could be made in both fetal and adult forms and MBNL2 appeared to regulate which version was created, according to an article in Neurology Today. One persistent concern that people living with DM1 and DM2 have is the effects of this disease on the brain. “People who don’t have DM usually feel refreshed after a night’s sleep. Myotonic dystrophy patients do not routinely achieve a normal sleep pattern; instead, they have an interrupted series of sleep-wake patterns that do not allow for deep, restful sleep cycles”.
Dr. Swanson created a mouse that lacks the MBNL2 protein as an animal model for DM effects on the CNS. These mice showed normal skeletal muscle structure and function. However, the mice did have DM-related sleep issues, such as a higher number of REM sleep episodes and more REM sleep in general, leading to less restful sleep. In mice lacking MBNL1, another member of the MBNL protein family, the skeletal muscle effects were similar to what is seen in DM. But the central nervous system was not affected, according to Dr. Swanson.
“What we would like to do now is identify the specific cellular events that are abnormal in the DM brain and see if there is something we can do to treat these disease manifestations with focused therapy development. We would also like to understand the heart and muscle problems in DM. We have developed mice with DM-associated problems and we want to use these mouse models to develop effective drug treatments. Also, we want to understand what is so different about the congenital form of DM. Why does it manifest in babies and children? If we can develop animal models for congenital DM, then we can begin to address the important question of what goes wrong during fetal life,” explains Dr. Swanson.
Recently, therapy development for DM has accelerated and treatments based on anti-sense oligonucleotides will hopefully enter clinical trials in the near future. These new studies focused on the roles of MBNL proteins in CNS function should lead to alternative therapeutic strategies designed to reverse effects caused by expression of the mutant DM1 and DM2 genes.
04/16/2013
Dr. Darren Monckton describes anticipation, the process by which the disease increases in severity as it is passed from generation to generation, a unique feature of myotonic dystrophy.
The path to a myotonic dystrophy (DM) diagnosis can be long and complex. Medical professionals meet patients with DM infrequently and are often not familiar with DM. Symptoms of DM can also mimic more common diseases, which can lead to months – or even years – of medical testing to rule out other potential causes. This can be especially true for those who were the first in their family to be diagnosed. On average, people living with DM1 spend more than six years searching before they are correctly diagnosed, while those living with DM2 spend an average of over 10 years! Once the disorder is suspected, the next step is to confirm the diagnosis with genetic testing.
Your doctor will ask about your symptoms, and possible symptoms and signs of DM in other family members. Your doctor will also perform a physical examination of you. Sometimes, your doctor can suspect the diagnosis of myotonic dystrophy just based on your symptoms and this physical examination. If there is another family member, who was already diagnosed with DM, it will be easier for your doctor to consider DM. If your doctor suspects DM, the next step is to get genetic confirmation with a blood test.
Sometimes your doctor may order additional tests, such as an electromyography (EMG), to evaluate for electrical myotonia (abnormal muscle activity when a small needle is inserted into the muscle). This test can be particularly helpful for patients being evaluated for DM2.
A genetic test, also referred to as DNA testing, is required to definitively confirm a diagnosis of DM1 or DM2. The genetic test involves collecting DNA through a blood or saliva sample. The DNA - the genetic material in the nucleus of cells - is then analyzed to determine whether or not you carry the DM1 or DM2 mutation.
Role of a Genetic Counselor: Often times, it is ideal to reach out to a genetic counselor (GC) as early as possible in your journey to a DM diagnosis. The role of a GC encompasses more than genetic test logistics and insurance. The genetic counselor helps you and your family make several important decisions about testing and diagnosis. Conversations with your genetic counselor may cover:
In general, the genetic counselor works with a doctor to order a genetic test. However, this may differ from state to state based on the licensure laws to order the genetic tests.
Types of genetic tests: Genetic testing for DM1 and/or DM2 uses standard DNA diagnostic protocols:
Costs of these tests are variable and are often dictated by insurance coverage. Generally, commercially available southern blot tests are more expensive than PCR tests. List prices vary from lab to lab, ranging from $250 to $2,000. Your genetic counselor may be able to help navigate pricing of these tests, and may work with your insurance company to try to obtain authorization for testing. Usually, a PCR test is able to provide a yes or no answer regarding a diagnosis of DM1 or DM2, but may not provide an exact repeat number. Your doctor and genetic counselor can inform your decision and recommend the test that is best for you based on your background, family history, and insurance coverage.
Time considerations: The total time from the first visit to a healthcare provider, to the confirmation of the diagnosis via genetic test results, depends on insurance authorization and test turn-around times. Typically, once a sample is sent out for testing, a result is received within 3-4 weeks. The individual can then consult their doctor or genetic counselor to review the results of the test.
Interpreting results: Depending on the test methodology, your report may or may not include an approximate repeat number in the CNBP and/or DMPK gene. Usually, a test will come back with a positive or negative result. In rare scenarios, you may obtain a result with a repeat number in an uncertain or “premutation” range. Your genetic counselor will discuss these results with you upon receipt of the report.
Retesting for DM once a genetic diagnosis is established is not recommended and is unlikely to be covered by insurance.
A confirmed diagnosis using a genetic test can eliminate the need for additional medical tests and may provide a definitive explanation for many of your symptoms. If you have no symptoms of DM, but other family members carry a diagnosis of DM, genetic testing can help establish whether you carry the DM mutation and therefore are at risk of developing symptoms later in life, or passing DM on to your children.
If you are experiencing symptoms and wonder whether you should seek evaluation for a diagnosis of DM, please consider the following situations in which a diagnosis may help guide or improve your care:
In DM1, the causal mutation is on chromosome 19, where the genetic code (CTG) on a gene called DMPK is expanded. People affected by DM1 have more than 50 CTG repeats, but the number of repeats can range from 50 to more than a thousand when measured in blood.
In DM2, the causal mutation is on chromosome 3, where a genetic code (CCTG) on a gene called CNBP is expanded. People with DM2 have more than 75 CCTG repeats, but usually many thousand repeats in blood cells.
In DM1, generally speaking, people who have a low number of CTG repeats (between 50-100), develop symptoms later in life, while those with >1000 repeats may develop symptoms in childhood or may have symptoms at birth. However, in between, above 100 and below 1000 CTG repeats, this connection between number of repeats and symptoms is less clear. For example, if one person has more repeats than another, it does not mean their disease will be more severe.
In DM2, there is no known relationship between CCTG repeat size and symptoms.
For more information on the significance of CTG repeats, watch Dr. Darren Monckton's presentation, Everything You Wanted to Know About CTG Repeats.
Myotonic dystrophy can cause symptoms affecting multiple organ systems beyond the muscle, e.g. the GI system, eyes, and the heart. You may have seen several different specialists for disparate symptoms, such as an ophthalmologist for blurred vision, a gastroenterologist for stomach pain, diarrhea or constipation, and a cardiologist for an abnormal heartbeat. These individual physicians may not be aware of your full range of problems and therefore may not have put the pieces together for a uniform explanation of your symptoms - myotonic dystrophy.
The severity of symptoms can also vary greatly, even within the same family. People with DM1 can develop symptoms at any point in their lives. Some people with DM1 may have mild symptoms or not show any signs until an older age. Due to this variability, many people may not seek medical attention which can cause their DM to go unrecognized until another family member is diagnosed. DM2 usually affects people later in life, and does not have a congenital form (symptoms at birth).
Some people opt against genetic testing when they have no symptoms. Problems that may arise from a definitive diagnosis of DM include:
For more information on the pros and cons of testing, read our interview with Carly Siskind, MS, LCGC, senior genetic counselor on the Stanford University Neuromuscular Disorders Team.
I cannot get evaluated, what can I do? If symptoms of DM and/or a family history of DM exist, but for various reasons it is not possible to get evaluated, the following steps can be taken:
Individuals pursuing a diagnosis are discouraged from relying on consumer companies focused on ancestry data and genetics for diagnostic results. The sequencing technology used by such companies and their third-party affiliates typically does not have the capacity to produce accurate repeat expansion mutation readings.
There are a number of labs that conduct testing for DM, including academic or commercial laboratories. Clinical (non-research) genetic testing must be ordered by an authorized provider, which can include a doctor, genetic counselor, or both. Work with your care team to discuss lab and testing options that fit your needs. Ask your doctor and/or genetic counselor whether insurance authorization is necessary and what your anticipated cost for testing will be, and whether you may qualify for financial aid or a patient assistance program. Genetic counselors will often take care of any insurance/billing logistics needed prior to testing. However, if you are not working with a genetic counselor you may want to call your insurance company ahead of testing to get an idea of whether the testing will be considered a covered service or not.
Antisense oligonucleotides – short segments of genetic material designed to target specific areas of a gene or chromosome – that activate an enzyme to “chew up” toxic RNA (ribonucleic acid) could point the way to a treatment for a degenerative muscle disease called myotonic dystrophy, said researchers from Baylor College of Medicine and Isis Pharmaceuticals, Inc., in a report in the journal Proceedings of the National Academy of Sciences (www.pnas.org) .
“This is a proof-of-principle therapy that is very effective in cell culture and mice,” said Dr. Thomas A. Cooper, professor of pathology and immunology and molecular and cellular biology at BCM and the report’s corresponding author. “The treatment will have to be refined to deliver systemically in people with myotonic dystrophy.”
Myotonic dystrophy is the most common muscular disease in adults, affecting mainly the skeletal muscles, heart and central nervous system. It occurs because of a mutation that causes numerous repeats of three letters of the genetic code (CTG) in a gene called DMPK. RNA is made as a step in the cell’s production of the protein associated with the gene. The messenger RNA (the chemical blueprint for making a protein) that is produced from the mutated gene also contains the abnormal long repeats that cause the RNA to accumulate in the cell’s nucleus. There it sequesters and blocks the function of a protein called Muscleblind-like 1 and activates another protein called CELF1. These proteins antagonize one another and the result is abnormal expression of proteins from many other genes in adult tissues, resulting in disease.
To counteract this, Cooper and his colleagues created antisense oligonucleotides called gapmers, which are simply strands of genetic material that seek out portions of the abnormal RNA repeats and target an enzyme called RNase H to the toxic RNA causing its degradation. They also showed that combining the gapmers with other antisense oligonucleotides that help released the sequestered Muscleblind-like1 can enhance the effect.
“It worked in cultures of cells with the expanded repeats and in mice that model myotonic dystrophy,” said Cooper. “We did it in skeletal muscle first because we can inject the material directly into the muscle.”
Later, he plans to determine if the material also works in the animals’ hearts.
Using the treatment in people will require more fine-tuning, said Cooper. He would like to be able to give the therapy systemically rather than directly into the muscle. They saw some muscle damage and inflammation in the animals they treated.
Antisense oligonucleotide treatments are being tested in Duchenne muscular dystrophy and another disease called spinal muscular atrophy, said Cooper.
Others who took part in this research include Johanna E. Lee of BCM and C. Frank Bennett of Isis.
Funding for this work came from the National Institutes of Health, the Muscular Dystrophy Association and the Shanna and Andrew Linbeck Family Charitable Fund.
Reposted with permission from Baylor College of Medicine
05/16/2012
While RNA is an appealing drug target, small molecules that can actually affect its function have rarely been found. But now scientists from the Florida campus of The Scripps Research Institute have for the first time designed a series of small molecules that act against an RNA defect directly responsible for the most common form of adult-onset muscular dystrophy.
In two related studies published recently in online-before-print editions of Journal of the American Chemical Society and ACS Chemical Biology, the scientists show that these novel compounds significantly improve a number of biological defects associated with myotonic dystrophy type 1 in both cell culture and animal models.
“Our compounds attack the root cause of the disease and they improve defects in animal models,” said Scripps Research Associate Professor Matthew Disney, PhD. “This represents a significant advance in rational design of compounds targeting RNA. The work not only opens up potential therapies for this type of muscular dystrophy, but also paves the way for RNA-targeted therapeutics in general.”
Myotonic dystrophy type 1 involves a type of RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code. In this case, the repetition of the cytosine-uracil-guanine (CUG) in RNA sequence leads to disease by binding to a particular protein, MBNL1, rendering it inactive. This results in a number of protein splicing abnormalities. Symptoms of this variable disease can include wasting of the muscles and other muscle problems, cataracts, heart defects, and hormone changes.
To find compounds that acted against the problematic RNA in the disease, Disney and his colleagues used information contained in an RNA motif-small molecule database that the group has been developing. By querying the database against the secondary structure of the triplet repeat that causes myotonic dystrophy type 1, a lead compound targeting this RNA was quickly identified. The lead compounds were then custom-assembled to target the expanded repeat or further optimized using computational chemistry. In animal models, one of these compounds improved protein-splicing defects by more than 40 percent.
“There are limitless RNA targets involved in disease; the question is how to find small molecules that bind to them,” Disney said. “We’ve answered that question by rationally designing these compounds that target this RNA. There’s no reason that other bioactive small molecules targeting other RNAs couldn’t be developed using a similar approach.”
The first authors of the JACS study, “Design of a Bioactive Small Molecule that Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif-Ligand Database & Chemical Similarity Searching” (http://pubs.acs.org/doi/abs/10.1021/ja210088v), are Raman Parkesh and Jessica Childs-Disney of Scripps Research. Other authors include Amit Kumar and Tuan Tran also of Scripps Research; Masayuki Nakamori, Jason Hoskins and Charles A. Thornton of the University of Rochester; and Eric Wang, Thomas Wang and David Housman of the Massachusetts Institute of Technology. This study was supported by the National Institutes of Health, Scripps Research, the Camille & Henry Dreyfus Foundation, and the Research Corporation for Science Advancement.
The first author of the ACS Chemical Biology study, “Rationally Designed Small Molecules Targeting the RNA That Causes Myotonic Dystrophy Type 1 Are Potently Bioactive” (http://pubs.acs.org/doi/abs/10.1021/cb200408a) is Jessica L. Childs-Disney of Scripps Research. Other authors include Suzanne G. Rzuczek of Scripps Research and Jason Hoskins and Charles A. Thornton of the University of Rochester. This study was supported by the National Institutes of Health, the Muscular Dystrophy Association, Scripps Research, the Camille & Henry Dreyfus Foundation, and the Research Corporation for Science Advancement.
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see www.scripps.edu.
Reposted with permission from The Scripps Research Institute
Source: http://www.scripps.edu/news/press/2012/20120222disney.html
05/16/2012