As a proximate mediator of the splicopathy that characterizes DM1, DMPK RNA carrying the toxic expanded CUG repeat sequence represents a potentially important target for therapy development. A candidate therapeutic with drug-like properties, including the ability to access the many affected target tissues in DM1, that specifically targets expanded repeat RNA, would represent an important compound for evaluation in interventional clinical trials. A new study has taken steps to establish preclinical proof of concept for such an agent.

Initial Development of Cugamycin

Ms. Alicia Angelbello (PhD graduate student) and Dr. Matt Disney at The Scripps Research Institute, Florida and their colleagues (at University of Florida and Iowa State) have developed a small molecule compound capable of cleaving DMPK expanded repeat RNA, as evidenced by data from studies in DM1 patient-derived myotubes and a DM1 mouse model (Angelbello et al., 2019). The candidate therapeutic has been named Cugamycin, because of its specificity/affinity for expanded, but not sub-disease threshold, CUG repeats.

The research team explored the idea that bringing specificity to a known RNA cleaving compound, bleomycin A5, represents a rationale path toward a DM1 therapeutic. By attaching bleomycin A5 to an RNA-binding molecule, the team could achieve a critical level of specificity and thereby advance both bioactivity/efficacy and safety of the resulting compound—Cugamycin. Target recognition and cleavage specificity of Cugamycin was established through studies showing in vitro binding and efficient cleavage of CUG^exp, but not DNA repeat hairpins.

Cell- and Animal-Based Support for Further Development of Cugamycin

In vitro analyses using DM1 patient-derived and control myotubes showed that Cugamycin was cell-permeable (overcoming a hurdle seen in large molecule development for DM1 muscle) and tracks to the nucleus. DMPK RNA cleavage efficiency in this model was 40%, with an EC₂₅ in high nanomolar range—notably, wild type DMPK RNA was spared. The research team also established that Cugamycin reduced nuclear foci and rescued defects in the splicing events tested in the cell model. Direct comparison of Cugamycin and antisense oligonucleotides (AONs) targeted to DMPK expanded repeat RNA showed higher specificity for the small molecule drug (AON sequence/chemistry used here failed to distinguish between expanded and subthreshold DMPK RNA).

Findings of subsequent in vivo evaluations of drug metabolism and pharmacokinetics (the other DMPK) of Cugamycin supported a move to mouse efficacy testing. Short-term dosing of 10 mg/kg ip every other day in adult HSA^LR mice was well tolerated and without side effects linked to the base bleomycin A5 compound. Short-term dosing also produced a 40% reduction in toxic DMPK RNA and reversal of splicing defects tested in hindlimb muscles, confirming systemic drug bioavailability and target engagement and modulation. Treated HSA^LR mice showed restoration of Clcn1 protein levels and reductions in myotonia. The high selectivity of the candidate therapeutic was confirmed in RNA-seq analyses of skeletal muscle samples from untreated wild type and vehicle only and Cugamycin treated HSA^LR mice.

The authors conclude that, as a preclinical candidate molecule, Cugamycin has limited liabilities, but do note the opportunities for further chemical analoging around its scaffold to continue to optimize and arrive at a development candidate for IND-enabling studies and entry into clinical trials.

Path Forward

Taken together, this new study provides a compelling case that small molecules can be developed to safely and effectively target toxic RNA cleavage in DM1. At the time of this writing, yet another reminder became available that efficacy in a mouse model may or may not translate into an effective drug in patients (Chakradhar, 2019 and justsaysinmice). Thus, while current findings are encouraging, they are in a model organism that cannot actually “have” the human disease—we look forward to further testing of Cugamycin and its analogs, and pursuit of all strategies for the development and regulatory approval of safe and effective drugs for patients living with DM.

References:

Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model.
Angelbello AJ, Rzuczek SG, Mckee KK, Chen JL, Olafson H, Cameron MD, Moss WN, Wang ET, Disney MD.
Proc Natl Acad Sci U S A. 2019 Mar 29. pii: 201901484. doi: 10.1073/pnas.1901484116. [Epub ahead of print]

It’s just in mice! This scientist is calling out hype in science reporting.
Chakradhar, S.
STAT. April 15, 2019
 

The muscular dystrophy field provides case studies of how flawed assumptions about the mechanistic understanding of a disease can lead therapeutic discovery and development efforts astray. One should never assume that we “already know” all key aspects of disease pathogenesis and thus have identified all feasible targets for therapeutics.

While the DM field certainly has developed a strong disease understanding, including of molecular targets that are tractable for drug and biologic development, there are many nagging questions remaining, such as the role of RAN translation in DM1 and DM2 and that of the epigenetic modifications upstream of the DMPK locus in CDM. In addition to these known unknowns, there likely are unknown unknowns in DM biology to worry about. Therapeutic efforts certainly need to go forward for rationale targets. But, as the NINDS concluded several years ago, there will always be a need for the novel findings that originate only from continuing basic and mechanistic research.

Might RNAi Machinery Play a Role in DM1?

A new article (Qawasmi et al., 2019) from Drs. Susana Garcia (University of Helsinki), Yuval Tabach (The Hebrew University of Jerusalem), and colleagues explores an alternative gain-of-function mechanism, that expanded CUG repeats in the DMPK transcript serve as templates for gene silencing via RNA interference (RNAi). This work utilized a novel C. elegans model of DM1.

The research team used the worm model they had developed previously, expressing 123 CUG repeats in the 3’UTR of a GFP transcript driven by a skeletal muscle promoter. Phenotypically, this model is characterized by motility and heat shock survival response defects.

To show that RNAi could be activated by expanded CUG repeats independent of other RNA mechanisms known to be operative in DM1, wild type worms were fed plasmid expressing RNA with 50 CTG repeats—this RNA is known to be cleaved and the resulting short CUG fragments activate RNAi. Data showed the development of motility defects similar to that of their 123 CUG DM1 model and a heat shock survival defect.

Consistent with findings in wild type worms fed expanded CUG plasmid, the 123 CUG repeat DM1 model showed, over time, a decay of the exogenous CUG repeat transcript and its protein product. By silencing RNAi pathway genes, the team showed that gene silencing was responsible for disappearance of the 123 CUG repeat. In the next series of experiments, they tested whether CUG repeats in their DM1 model were similarly processed and act as non-coding RNAs to silence expression of other endogenous CUG-bearing genes via RNAi. In these studies, expression of endogenous genes bearing at least 4 repeats was reduced by 1.6-fold. This suggests that expanded CUG repeat transcripts activate RNA silencing followed by the downregulation of endogenous CUG-bearing transcripts. Using RNA-seq of entire worms, a total of 982 genes were found to be downregulated by ≥ 1.5x; because some of the knocked down genes are not expressed in muscle, the overall effect apparently involves non-cell-autonomous RNA silencing in adjacent tissues. Finally, knocking down genes comprising the RNAi machinery rescued expression of genes that were otherwise affected in the 123 CUG repeat model.

Connecting the Dots

Collectively, these studies support the conclusion that expression of CUG expanded repeats triggers an RNAi-mediated repression of multiple endogenous genes that normally contain CUG repeats in their transcript. Thus, RNAi pathways may contribute towards the pathogenesis of DM1 and thus may represent a potential target for therapeutic intervention in the disease. Future studies should evaluate the potential operation of RNAi driven pathology in mammalian models of DM1 and determine its relative contribution to disease.

Reference:

Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans.
Qawasmi L, Braun M, Guberman I, Cohen E, Naddaf L, Mellul A, Matilainen O, Roitenberg N, Share D, Stupp D, Chahine H, Cohen E, Garcia SMDA, Tabach Y.
J Mol Biol. 2019 Mar 14. pii: S0022-2836(19)30121-4. doi: 10.1016/j.jmb.2019.03.003. [Epub ahead of print]

First Grant in $1M DM Cure Development Project Awarded

MDF community members likely remember that in late 2017 very generous donors committed $1M to MDF to launch a gene editing development project to find a cure for myotonic dystrophy. MDF conducted a comprehensive scoping and discovery workshop, followed by a Request for Applications in mid-2018. We are delighted to announce that Dr. Vincent Dion was awarded the first grant for that project.

Dr. Dion's Approach

Dr. Dion was trying to understand why the size of the repeating piece of genetic code in the gene that causes myotonic dystrophy varied from cell to cell in patients with the condition and in so doing, he may have stumbled on a novel treatment for the disease.

MDF has awarded Dion a two-year grant totaling $250,000 to support his research to determine the feasibility of a gene editing treatment for DM. He will be helped by Drs. Geneviève Gourdon at the Imagine Institute in Paris, and Jack Puymirat at Université Laval.

Myotonic dystrophy is known as a trinucleotide repeat disorder because of an expanded repeat of a three-letter piece of genetic code CTG (cytosine, thymine, and guanine) found in the DMPK gene of people with DM1. It’s normal to have several repeats of this code in the DMPK gene, but people who have more than 50 repeats, can develop DM1. The greater the number of repeats, the more severe the disease tends to be.

A Surprising Finding

Dion, a professor at the UK Dementia Research Institute at Cardiff University, knew that the size of repeats in any person with the disease could vary greatly from cell to cell. He wanted to understand why. He was using the gene editing technology CRISPR-Cas9, a bacterial enzyme that allows users to make precisely-targeted cuts in genetic material, to see if he could test a theory that changes in the number of repeats was caused by DNA damage. He wanted to see if disrupting the repeat track by making cuts in a single track of the double-stranded genetic code to expose the repeat would influence whether expansion of the repeat occurred.

In a surprising finding, Dion observed that by making such breaks in the repeat track he had corrected the error. Enzymes that naturally repair damaged DNA healed the cuts to the repeat track. But instead of amplifying the repeat, it reduced its size.

In essence, his work suggested gene editing might prove to be a way to correct the toxic repeat and possibly arrest the mechanism of the disease.

“We stumbled upon this by chance,” said Dion, who earned his Ph.D. in molecular biology at Baylor College of Medicine in Houston and then completed a postdoctoral fellowship at the Friedrich Miescher Institute in Basel. “The question we were asking was completely different and we ended up using CRISPR to correct the mutation in human cells, and then we went from there.”

Accelerating Research with MDF

The MDF grant will allow Dion to continue his work, exploring the gene editing approach in a DM mouse model to see if it corrects the mutation.

The grant will also be used to see how precise the approach will be within a living organism and to make sure that the CRISPR cuts the expanded repeat in the DMPK gene as intended, and not elsewhere, which could lead to severe off-target effects.

Dion does have some tricks to ensure the CRISPR targets the genetic material correctly at the desired point. He uses RNA to target the repeat track he wants it to cut. That’s not without its challenges, as he needs to package the CRISPR and RNA into a viral vector to carry it into the cell.

The other issue any gene editing therapy will face is the need to deliver it into the central nervous system (the brain) to address the neurological effects of the condition. That would likely require some means of direct delivery. In the mouse model, Dion will be injecting directly into the brain. If all of that works, Dion then hopes to move the gene editing work to a larger DM animal model.

For now, Dion hopes to demonstrate that the approach works. Even if he is successful with the experiments he'll be conducting over the next two years, he believes it would still be several years before the approach could advance to human testing.

“The hope is that we'll know whether it works. We'll know whether it's specific enough for the repeat track and whether it might cause other mutations,” said Dion. “If those questions are answered successfully, then I think we're looking at another five years or so after that to do a clinical trial.”

A Core Issue for Understanding DM—How MBNL Interacts with RNA

Given the disease mechanisms that are operative in DM, an understanding of how the RNA-binding protein, Muscleblind (MBNL), interacts with pre-mRNA to regulate alternative splicing is essential. Recent studies have shown that MBNL exhibits differential dose-response relationships across the various gene translation events that it regulates in health and disease. It is as yet unclear precisely how the structure of the pre-mRNA itself contributes to patterning of MBNL-dependent alternative splicing.

RNA Structural Properties May Impact MBNL Binding and Functionality

MBNL’s normal function in alternative splicing, and perturbations of those functions in DM, is governed in part by the tissue-specific distribution and expression levels of its three isoforms (MBNL1, MBNL2, and MBNL3) during pre- and post-natal development. Yet, the structural properties of the pre-mRNAs that MBNL regulates may, themselves, play critical roles in the binding affinity and efficiency of MBNL-directed alternative splicing. A new publication looks at the MBNL—pre-mRNA interactions with the goal of understanding how transcript properties influence alternative splicing.

While the nature of MBNL-binding motifs has been well-characterized previously, Dr. Krzysztof Sobczak’s group (Adam Mickiewicz University—Poland) and their colleagues at the University of Florida show here the structural organization of the RNA regulatory elements in target pre-mRNA may play a more important role. An MDF fellow, Lukasz Sznajder, contributed to this work.

The team demonstrated the importance of target RNA structure in showing that both MBNL binding and splicing activity are regulated by the number and structural arrangement of UGCU motifs, but, while splicing regulation is affected by the distance between UGCU motifs, that outcome is not a function of differences in binding efficiency. MBNL binding patterns are altered, however, when the MBNL binding sites are included in an RNA hairpin. Furthermore, modifications of target RNA secondary structure showed that structuring the same RNA binding site differently leads to altered MBNL1 binding and splicing regulation activity. In tissues expressing multiple MBNL paralogs, the team detected competitive interactions that influenced splicing events.

Modeling Regulation of Alternative Splicing by MBNL

The modeling of MBNL regulation of alternative splicing now has at least two components. Component 1—it has already been clear that the spectrum of MBNL-modulated alternative splicing events are differentially sensitive to free MBNL levels. Component 2—these latest findings extend understanding of regulatory control by showing that structural properties of the pre-mRNA targets also represent a key determinant of splicing event sensitivity to free MBNL. Moreover, tissue specificity in alternative splicing is now seen to derive from the MBNL paralogs that are expressed and interactions among those paralogs. An understanding of MBNL protein interactions and of how pre-mRNA structure impacts binding and functional activity of the MBNL paralogs may be critical in efforts to design effective therapeutic strategies for DM.

Reference:

MBNL splicing activity depends on RNA binding site structural context.
Taylor K, Sznajder LJ, Cywoniuk P, Thomas JD, Swanson MS, Sobczak K.
Nucleic Acids Res. 2018 Jun 28. doi: 10.1093/nar/gky565. [Epub ahead of print]

An Ophthalmological Perspective on DM1

When considering the spectrum of organ system involvement in DM1, the list of ophthalmological considerations is usually short—cataracts being the major concern, but also ophthalmoplegia (including ptosis) and extraocular muscle myotonia (see MDF’s website for a review of ocular issues in DM). Some reports have suggested the co-occurrence of DM1 and Fuchs’ endothelial corneal dystrophy (FECD), a disease, like DM1, that is linked to an expanded CTG repeat (in TCF4 rather than DMPK) and MBNL sequestration along with expanded CUG RNA in nuclear foci. Identification of this pathophysiologic mechanism link between the two diseases suggests that the RNA gain-of-function in DMPK that produces DM1 may also put these patients at risk for FECD.

A Prospective Study of DM1 Patients for FECD

Due to the mechanistic similarities between DM1 and FECD—that both are RNA gain-of-function diseases resulting from MBNL sequestration by expanded trinucleotide repeats—Dr. Keith Baratz (Mayo Clinic) and colleagues prospectively evaluated 26 subjects from 14 DM1 families for phenotypic FECD and expanded repeats in DMPK and TCF4.

The research team identified five genotypically and phenotypically DM1 probands with phenotypic FECD (36%), a prevalence that greatly exceeded the prevalence of FECD in the at-risk age group in the general population (5%). Genotypic evaluation of samples available from 4 probands failed to show expanded CTG repeats in TCF4—thus each was phenotypically FECD without the normally associated genotype—but each had repeat expansions in DMPK. Co-segregation of DM1 and FECD was found in 12 additional family members; none of the affected individuals had expanded repeats in TCF4. Finally, RNASeq evaluation of RNA samples from the corneal epithelia of a FECD-affected and an unaffected subject confirmed target tissue expression of both DMPK and TCF4.

Monitor DM1 Patients for Development of FECD

These data suggest that DM1 patients are at risk for phenotypic FECD even though they lack the disease-causing expanded repeat in TCF4. Sequestration of MBNL and disruptions to alternative splicing patterns appear to be the commonality to the two diseases. Chromsomal location of the MBNL-sequestering pathogenic expanded repeat sequence then may not be essential in causation of either disease. The research group did not find an association between clinical/genetic traits of DM1 and the presence/severity of FECD—but they acknowledge that such analyses would likely require a considerably larger cohort. Finally, since TCF4 is broadly expressed (including a putative role in CNS development and linkage to the neurodevelopmental disorder, Pitt-Hopkins Syndrome), the converse might be true—that FECD patients are at risk for DM1—but there does not appear to be any available information addressing that hypothesis, perhaps due to tissue expression levels of TCF4.

Reference:

Fuchs' Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy, Type 1.
Winkler NS, Milone M, Martinez-Thompson JM, Raja H, Aleff RA, Patel SV, Fautsch MP, Wieben ED, Baratz KH.
Invest Ophthalmol Vis Sci. 2018 Jun 1;59(7):3053-3057. doi: 10.1167/iovs.17-23160.

Some MDF community members may have watched the news show, 60 Minutes, on April 29th. The show featured a segment titled: "CRISPR: The Gene-Editing Tool Revolutionizing Biomedical Research" (if you missed it, the transcript is available here). 60 Minutes took a thoughtful approach in choosing the words " tool" and "research" for its segment title. Understanding those two words is the key to parsing hope from the hype in genome-editing technology.

Evaluating Genome-Editing Technology

MDF received a generous donation in late 2017 to help evaluate whether genome-editing technologies, like CRISPR, have the potential to translate into a safe and effective therapy for DM1. Both the donors and MDF are on the same page in understanding what Dr. Eric Lander (President and Founding Director, Broad Institute of MIT and Harvard) said so clearly about CRISPR on 60 Minutes: “I [want to] always balance hope versus hype here. While it's not [going to] affect somebody who might be dying of a disease today, this is [going to] have a real effect over the course of the next decade and couple of decades. And for the next generation, I think it'll be transformative.”

Genome editing includes a range of technologies—CRISPR is just one of several with the potential to address inherited human diseases. For this technology to achieve its promise for patients, genome-editing reagents have to be delivered to the correct body tissues and, once there, edit the affected genes in efficient and safe ways. All three parts of that equation—delivery, efficient editing, and safety in avoiding unintended damage to other genes—must be optimized. It’s important to remember that CRISPR is a natural defense mechanism used by bacteria to kill invading viruses. Drug developers need to ensure that a technology designed to kill must be transformed into one that very selectively edits defective human genes in a highly controlled manner.

Strategies for Research

Because genome-editing technology must continue to evolve before this research tool is transformed into effective therapies, MDF organized an expert workshop to understand the current state of the science and identify opportunities and barriers to moving forward. On April 17, MDF convened a day-long panel of 14 experts from universities, companies and Federal agencies (NIH and FDA), along with MDF staff and the donors, as a first step toward understanding how to foster research that evaluates and optimizes genome-editing strategies to the specific needs of DM1.

Workshop participants discussed how to optimize genome-editing strategies, how to best deliver genome-editing reagents to the body tissues where they need to act, how to evaluate the efficacy and safety of genome-editing tools in patient cell and animal models, and, finally, how to best implement the evaluation and development of genome-editing in the context of the unique genetics of and patient needs in DM1. The small group atmosphere and tightly-focused discussions at the workshop led to a wealth of information for MDF to use in the design of a request for proposals (RFP) soliciting research grant applications, evaluation of those applications and guidance of the funded research project(s).

Moving Forward

CRISPR and the other genome-editing technologies have considerable potential as an effective therapeutic for the approximately 7,000 inherited diseases that are known today. The hope for DM1 lies in the potential to remove the expanded repeat from the DMPK gene and thereby mitigate or eliminate many of the disease symptoms. But potential is not a drug. It’s important to foster hope while knowing that any excessive hype is not realistic at the current stage of research. MDF is launching this research program from a very informed perspective and will continue to relay advances from the program to the patient, family and research communities.

Questions? Contact MDF at info@myotonic.org

Dr. Darren Monckton describes anticipation in myotonic dystrophy, the process by which the disease increases in severity as it is passed from generation to generation.

Watch Part 2 of this series

The Myotonic Dystrophy Foundation is excited to introduce Understanding Myotonic Dystrophy, a new series of short educational animations designed to educate people living with myotonic dystrophy (DM) and their healthcare providers!

Our second animation “Understanding Myotonic Dystrophy – Inheritance of Myotonic Dystrophy Type 1 (DM1)”, explains how DM1 is passed down from generation to generation and highlights the importance of genetic testing. This animation is a valuable resource for individuals and families living with DM1, helping them deepen their understanding of DM, raise awareness within their families, and educate others about myotonic dystrophy.

Stay tuned—our next video on Myotonic Dystrophy Type 2 (DM2) is coming soon!

We are sincerely thankful to all physicians, care providers, and patients for their help providing suggestions, opinions, and input regarding content and design throughout this process. Please let us know what topics you would like us to cover in a future animation. Click here to share your feedback! 

Read the Transcript - Understanding Myotonic Dystrophy: Inheritance of Myotonic Dystrophy Type 1 (DM1)

Dr. Smith: "I have Emma's genetic test results . She has myotonic dystrophy type 1. It is caused by an expanded repeat in a gene. This leads to Emma's symptoms."

Sarah: "How did she get it?"

Dr. Smith: "It is inherited. If one parent has it, there's a 50% chance of passing it to their children with each pregnancy."

Sarah: "Did I give it to Emma or did John?"

Dr. Smith: "Emma could have inherited myotonic dystrophy from either of you. Sarah, You mentioned your father had early cataracts and muscle weakness; both could have been symptoms of myotonic dystrophy."

Sarah: "How can we find out?"

Dr. Smith: " You and John should get tested. You may have inherited the expanded gene from your dad and passed it on to Emma. Or John, may have inherited it from his mother or father and passed it on to Emma."

Sarah: "If we don't have any symptoms, why is Emma sick?"

Dr. Smith: "Symptoms can manifest later in life and may worsen from one generation to the next. Doctors call this anticipation. Testing will provide clarity and this will help us understand the risk for your family and future children."

The Myotonic Dystrophy Foundation is excited to release the second video in our Understanding Myotonic Dystrophy series! "Understanding Myotonic Dystrophy – Inheritance of Myotonic Dystrophy Type 1 (DM1)", explains how DM1 is passed down from generation to generation and highlights the importance of genetic testing. This animation is a valuable resource for individuals and families living with DM1, helping them deepen their understanding of DM, raise awareness within their families, and educate others about myotonic dystrophy.

We are sincerely thankful to all physicians, care providers, and patients for their help providing suggestions, opinions, and input regarding content and design throughout this process. Stay tuned—an engaging new video on the inheritance of DM2 is coming soon!

Please let us know what other topics you would like us to cover in a future animation. Click here to share your feedback! 

Learn more about myotonic dystrophy (DM), explore resources, and find support at https://www.myotonic.org/

---------

Dr. Smith: "I have Emma's genetic test results . She has myotonic dystrophy type 1. It is caused by an expanded repeat in a gene. This leads to Emma's symptoms."

Sarah: "How did she get it?"

Dr. Smith: "It is inherited. If one parent has it, there's a 50% chance of passing it to their children with each pregnancy."

Sarah: "Did I give it to Emma or did John?"

Dr. Smith: "Emma could have inherited myotonic dystrophy from either of you. Sarah, You mentioned your father had early cataracts and muscle weakness; both could have been symptoms of myotonic dystrophy."

Sarah: "How can we find out?"

Dr. Smith: " You and John should get tested. You may have inherited the expanded gene from your dad and passed it on to Emma. Or John, may have inherited it from his mother or father and passed it on to Emma."

Sarah: "If we don't have any symptoms, why is Emma sick?"

Dr. Smith: "Symptoms can manifest later in life and may worsen from one generation to the next. Doctors call this anticipation. Testing will provide clarity and this will help us understand the risk for your family and future children."

The Myotonic Dystrophy Foundation is excited to introduce Understanding Myotonic Dystrophy, a new series of short educational animations designed to educate people living with myotonic dystrophy (DM) and their healthcare providers!

Our first animation “Understanding Myotonic Dystrophy – The Basics” is a broad introduction to myotonic dystrophy to help increase awareness and understanding.

We are sincerely thankful to all physicians, care providers, and patients for their help providing suggestions, opinions, and input regarding content and design throughout this process. Please let us know what topics you would like us to cover in a future animation. https://forms.gle/DnF1T46cqa1P1w4ZA

Learn more about myotonic dystrophy (DM), explore resources, and find support at https://www.myotonic.org/

---------

Imagine waking up one day and realising your muscles don’t work quite the way they used to. This could be the first sign of Myotonic Dystrophy, or DM.

Myotonic dystrophy is an inherited disease and a type of muscular dystrophy that frequently causes prolonged muscle contractions and muscle weakness. It can impact everyday activities.

Myotonic dystrophy is caused by an expanded repeat in the DNA that is translated into RNA, which then forms hairpin like structures and traps important proteins.

It comes in two forms: Type 1 and Type 2. Type 1 is the most common. It is caused by an expansion in the DMPK gene. Type 2 is caused by an expansion in the CNBP gene.

The symptoms of myotonic dystrophy can vary a lot. The body systems affected, the severity of symptoms, and the age of onset varies greatly between individuals, even within the same family.

As many as 1 in 2,100 or over 3 million individuals worldwide are affected by the disease. It impacts people of all ages, ethnicities, and backgrounds.

Living with myotonic dystrophy means managing symptoms through a combination of clinical care, medications, and/or lifestyle changes. Your doctor will connect you to specialists and work with you and your care team to develop a personalized treatment plan.

If you or someone you love has been diagnosed with myotonic dystrophy, remember, you are not alone. Support groups and resources are available to provide guidance and community connections.