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Genetics

Myotonic dystrophy is one of the most complex disorders known. In addition to the incredible variability of clinical symptoms, the disease also has unique mechanistic features:

  • True autosomal inheritance. The disease phenotype of patients who are homozygous for myotonic dystrophy is essentially the same as those who are heterozygous.
  • Variable penetrance. Considerable variability is seen between affected individuals, even within the same family. Somatic mosaicism is common, where the genetic defect can be slightly different in various tissues in a single individual and can change over time. 
  • Anticipation. The disease symptoms tend to be more severe and occur earlier in successive generations.
  • Maternal transmission bias for the congenital form. In the most severe form of myotonic dystrophy (congenital myotonic dystrophy: DM1), transmission is nearly always maternal and does not appear to be related to the severity of the disease in the mother. The mutated gene is only very rarely inherited from the father in newborns with myotonic dystrophy.

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Myotonic dystrophy is one of the most complex disorders known. In addition to the incredible variability of clinical symptoms, the disease also has several unique mechanistic features:

  • Autosomal dominant inheritance. The genes for DM1 and DM2 are dominant, meaning that a person can inherit the disease even if only one parent carries the gene. Also, a child has the same risk of inheriting DM regardless of whether it is the father or the mother who carries the gene. 
  • Variable penetrance. This term refers to the fact that the number and severity of DM symptoms varies widely among people with the disease. This is true even among people with the same subtype, and among individuals in the same family. 
  • Somatic mosaicism. A key characteristic of DM is that different cells in different tissue types will show varying numbers of genetic repeats. This is due at least in part to the fact that the number of repeats changes, is different in different cells and increases in number throughout the lifetime of the individual. Thus, the number of repeats reported in a diagnostic test will depend on how old the individual was when sampled, which tissue was tested and then will only measure the average number of repeats. 
  • Anticipation. The number of repeats in the DM genes tends to increase with each affected generation. As a result, the symptoms of DM1 appear earlier in life and are more severe in each successive generation. These changes are often dramatic. For example, a person whose only symptom was cataracts that appeared later in life can have a child with life-threatening symptoms present at birth. This effect indicates that the number of times the gene sequence is repeated has a bearing on the severity of the disease symptoms. Anticipation appears to be less pronounced in DM2. 
  • Transmission of congenital form through mother. The most severe form of myotonic dystrophy (congenital myotonic dystrophy: DM1) is almost always passed to the child from an affected mother. Scientists think that his occurs because the number of repeated sequences expands greatly during the process when the egg cells are created. 

 

Promising Small Molecule Study for DM2

Published on Wed, 07/23/2014

A team of researchers at the University of Illinois at Urbana-Champaign recently published the results of a study in which they designed small molecules to combat myotonic dystrophy type 2 (DM2). Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, provided MDF with the summary below. The study was published in ChemMedChem. 

Previous studies have suggested that the main problem in the cells of people with DM2 is an expansion of a CCTG DNA repeat sequence in the ZNF9 gene. This DNA mutation is transcribed into RNA, where it forms abnormal structures that pull other proteins into clumps and prevent them from performing their normal activities.

In this study, researchers redesigned a small molecule that disrupted the improper interaction of repeat-containing RNA with other proteins, but was highly toxic to cells. Their new molecule still disrupted the desired RNA-protein interaction, but was less toxic and was able to enter cells with greater ease.

Future studies will take the small molecules and test them in fruit flies and mice to see if the molecules will be safe in organisms while continuing to disrupt the RNA-protein interaction associated with DM2. Click here to access the abstract and article.

07/23/2014

DM2 Patients and Statins

Published on Tue, 07/01/2014

A recently released study identifies the gene that may be responsible for increased side effects in DM2 patients taking statins to lower cholesterol. Katharine Hagerman, PhD, Research Associate at Stanford University Neuromuscular Division and Clinics, provides MDF with a summary of the study conducted at the University of Helsinki in Finland.

Abnormal Splicing of NEDD4 in Myotonic Dystrophy Type 2: A Possible Link to Statin Adverse Reactions
Screen M, Jonson PH, Raheem O, Palmio J, Laaksonen R, Lehtimäki T, Sirito M, Krahe R, Hackman P, Udd B.(June 4, 2014).
American Journal of Pathology. e-publication ahead of printing.

A research study headed by Dr. Bjarne Udd at the University of Helsinki recently described biological pathways affected in both myotonic dystrophy type 2 (DM2) and hyperlipidemia (a medical condition most often characterized by high cholesterol or high triglycerides). Previous studies have shown that 63 percent of people with DM2 have high cholesterol, as well as 41 percent of people with DM1. Statins, a class of drugs used to lower cholesterol levels, are commonly prescribed to treat hyperlipidemia, elevated levels of lipid proteins in the blood, as they can block the action of a liver chemical that helps create cholesterol.

One of the side effects of statins is the development of myopathy, including muscle pain, weakness, and cramping. Approximately 5-10 percent of individuals taking statins can develop these symptoms. Individuals with DM have an increased incidence of myopathic side effects when taking statins, and there are many documented cases where statin-induced myopathy is the first muscle symptom experienced in adults eventually diagnosed with DM2.

In order to identify biological pathways that may be affected by both DM2 and statin therapies, these researchers looked at genes that were regulated differently in healthy muscles compared to DM2 muscles and statin-treated muscle cells. They identified a gene, NEDD4, that had increased expression in DM2 (and DM1), and decreased expression in statin-treated individuals with no muscle condition. Furthermore, they showed that the NEDD4 gene was processed differently in DM2 muscles, and made a few different forms of the protein that weren't seen in healthy muscles. The authors suggest that biological pathways involving NEDD4 may be altered in DM, and may be associated with increased statin side effects. According to DM2 research reviews, statins do not have to be avoided. However, if statin treatment produces or amplifies muscle symptoms, there may be other drugs available to combat hyperlipidemia that do not have these side effects in individuals with DM.

07/01/2014

Living with DM2

Dr. Matt Disney and Dr. John Day provide an overview of the DM2 disease mechanism and describe how compounds can be designed as potential therapies for this disease.

Structure of the Myotonic Dystrophy Type 2 RNA

Published on Wed, 01/22/2014

Researchers at important academic labs around the US have recently published exciting new information about advances in DM research. The Matthew Disney Lab at The Scripps Research Institute in Florida announced the results of a study examining RNA toxicity in DM2 patients. Summaries of the studies and results are below, along with links to the PubMed abstracts and complete research publications.

Structure of the Myotonic Dystrophy Type 2 RNA and Designed Small Molecules that Reduce Toxicity Childs-Disney et al (Matthew Disney Lab)

Researchers at Scripps Research Institute in Florida recently examined the structure of the toxic RNA molecule made from the DNA mutation causing myotonic dystrophy type 2 (DM2). Dr. Matthew Disney and his colleagues used a technique called X-ray crystallography to look at the shape of the RNA at the atomic level in order to determine what types of drugs would best attach to it and reduce its toxicity.  

One of the reasons the DM2 RNA is unhealthy in cells is because it changes how other genes are processed and regulated. They showed that their custom-designed drugs were able to reverse the improper processing of a gene known to be affected in DM by varying degrees depending on the design of the drug. This study shows that drugs they previously proposed could bind the toxic RNA are now able to be administered to cells with toxic RNA similar to DM2 and reduce the RNA toxicity.

For more information:

Click here to view a pdf of the full article

Click here to read the abstract

01/22/2014

Key DM Research Discoveries

Published on Fri, 07/26/2013

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.

 


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A New Study Provides Hope for DM Treatments

Published on Tue, 04/16/2013

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

Myotonic Dystrophy Testing & Diagnosis

Myotonic Dystrophy Testing & Diagnosis

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.

What an Initial Evaluation for Myotonic Dystrophy May Look Like

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.

Electromyography (EMG)

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.   

What Genetic Testing for Myotonic Dystrophy Looks Like

 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:

  • Understanding the purpose and procedure of a genetic test.
  • Deciding amongst a wide range of genetic testing options considering their prices and insurance coverage options.
  • Ordering genetic test.
  • Discussion about testing and its implications for individuals and families living with DM.
  • Family planning with DM. 

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:

  1. PCR (Polymerase Chain Reaction) – which copies segments of DNA found in your saliva or blood.  
  2. Southern Blot – a blood test to confirm the presence of the specific genetic sequence for DM in your DNA.  

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.

Benefits of Genetic Testing for Myotonic Dystrophy

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:

  • People living with DM can have trouble with anesthesia. It is helpful for doctors to know about the diagnosis so they can plan ahead accordingly and counsel you better on risks.
  • People living with DM are at risk for cardiac abnormalities, in specific cardiac conduction delays. Knowing the diagnosis of DM can help guide cardiac monitoring and care.  
  • Couples can make family planning decisions. For example, some people with DM may choose to consider in vitro fertilization with pre-implantation diagnostics, which means that embryos are checked for the DM mutation and the embryo without DM is implanted in the women’s uterus. 
  • Expecting mothers living with DM1 usually receive special monitoring and care during pregnancy, so knowing and sharing that you have DM can help your doctors provide appropriate care.  

How Does Repeat Length Relate to the Severity of Myotonic Dystrophy?

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.

Why Does Myotonic Dystrophy Take So Long to Diagnose?

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). 

I Have No Symptoms, Should I Test for Myotonic Dystrophy?

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: 

  • Consider reaching out to family members to inform them about your condition.  
  • Continue to seek regular/annual heart screening and share/follow anesthesia guidelines. 
  • Consider asking your current provider who suspected DM for a referral to, or a remote consultation/satellite care with a neuromuscular specialist. 

Where to Test for Myotonic Dystrophy

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.

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