An MDF community member and mother describes the medical team she has assembled for her daughter, Kate.

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/

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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/

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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.

Originally presented on April 15th, 2022.

Do you have questions about brain-fog and the cognitive issues associated with DM1? Join DM expert Benjamin Gallais, PhD, of the the Center for the Study of Living Conditions and the Needs of the Population (ECOBES) for an “Ask-the-Expert” session on Key Neuropsychological Features of DM1.

View the open access article, Instrumental activities of daily living in adults with the DM1 childhood phenotype: going beyond motor impairments, referenced during the presentation.

Doctor Benjamin Gallais obtained his doctorate in clinical psychology from the University of Paris 8 in 2010 and received an MDF Research Fellowship in 2016. A clinical psychologist in France, his country of origin, he then completed a postdoctoral internship with the Interdisciplinary Research Group on Neuromuscular Diseases (GRIMN ) in the Saguenay, in order to deepen his knowledge of myotonic dystrophy type 1. Today, his expertise in this neuromuscular disease is recognized internationally. Specialized in health psychology and neuropsychology, Dr. Gallais is interested in the characterization of personality and damage to cognitive functions in neuromuscular diseases, their evolution and their impact on autonomy and social participation. In addition, his work focuses on the consequences of damage to the central nervous system, such as fatigue and motivational disorders. Dr. Gallais joined the ÉCOBES team in 2018.

Click here to find all our upcoming “Ask-the-Expert” question sessions!

Speech disorders (dysarthria) in CDM and childhood-onset DM1 have long been recognized and surveillance by speech and language therapists is an important aspect of patient care. Facial weakness and myotonia, and involvement of oral cavity, palatopharyngeal and respiratory muscles, are known to contribute to speech impairment.

The Three Major Contributors to Speech Disorders 

In a recent review of speech disorders in DM1 (Lopes Cardos and Baptista, 2017), three major contributors to speech disorders were identified—myotonia as a hindrance to the initiation of speech, muscle weakness leading to reductions of lip force, and atrophy of tongue muscles. The authors note that few studies have evaluated the effectiveness of various speech therapies. There is no consensus on whether oral muscle exercises can improve lip strength. Other reports have shown that warming up reduced myotonia and led to increased speech rate and decreased variability in speech, but there were some concerns that this strategy could increase fatigue and thereby be counterproductive. Finally, increasing lip strength through exercising with an oral screen has been reported to increase lip force, but had no apparent effect on lip articulation. The authors concluded that strategies of warming up facial muscles and lip exercises can help, but used alone are insufficient to correct speech disorders in DM1 and therefore speech therapy is advised.

In this context, a new study has characterized the characteristics of speech in 50 subjects with CDM and childhood-onset DM1 (Sjőgreen et al., 2018). All subjects with CDM showed impairments of the intelligibility of their speech and nearly 80% of those with childhood DM1 were similarly impaired. The authors further characterized key speech components, identifying deficits in producing sounds: (1) that require coordinated function of both lips (bilabial consonants), (2) that require placing the tip of the tongue between the teeth (interdental consonants), and (3) that are due to increased airflow through the nose during speech (hypernasal speech). They also established a correlation between maximum lip force (as an indicator of how oral and facial muscles are affected in DM patients) and the intelligibility of speech. Some patients employed a variety of compensatory strategies to improve speech, including placing their tongue between their lips or biting the lower lip, to produce appropriate speech sounds—in some these strategies were very effective, but still did not reduce poor intelligibility in others.

The Connection Between DM and Speech Disorders

The researchers conclude that most children with CDM or childhood-onset DM1 will need speech therapy starting at a young age and that the most those with the severe manifestations will require training in alternative means of communication. Taken together, they show that weakness of oral and facial muscles is the primary cause of disordered speech in congenital and early-onset DM1. These findings suggest that therapies under development to improve muscle function in DM may also have positive effects on speech disorders. Finally, the research team reaffirmed conclusions of prior studies in that this patient group will require speech therapy from an early age.

References:

Myotonic dystrophy type 1 (DM1) and speech problems.
Lopes Cardoso I, Baptista H.
JSM Communication Dis. 1(1): 1003.
https://www.jscimedcentral.com/CommunicationDisorders/communicationdiso…

Speech characteristics in the congenital and childhood-onset forms of myotonic dystrophy type 1.
Sjögreen L, Mårtensson Å, Ekström AB.
Int J Lang Commun Disord. 2018 Jan 12. doi: 10.1111/1460-6984.12370. [Epub ahead of print]

Clinical Trials Require Infrastructure and Information

To develop new therapies for patients living with myotonic dystrophy (DM), specific infrastructure and information needs to be in place to make clinical trials feasible. It is essential, for example, to understand how a disease manifests and progresses in a cohort of patients that is sufficiently large and representative to provide confidence in the findings. This understanding enables the design and validation of outcome measures that are sufficiently sensitive, reliable, valid and responsive to show whether a candidate therapy is effective or not.

Adult DM Information Doesn't Necessarily Meet the Requirements for Congenital Trials

Considerable effort has been made to understand the natural history (how the disease presents and progresses) and to develop valid outcome measures for myotonic dystrophy type 1 (DM1). This knowledge has been put to use in clinical trials, including those by Ionis and AMO Pharmaceuticals. MDF is working to further advance understanding of the natural history of DM1 via funding for the Myotonic Dystrophy Clinical Research Network in the U.S. and the PHENO-DM1 study in the United Kingdom. Although congenital myotonic dystrophy (CDM) has genetic similarities to DM1 (both are caused by expanded CTG repeat sequences in DMPK), CDM presents and progresses differently than DM1. Hence there is a clear need for natural history data to better understand the disease and to support the selection of outcome measures that can assess whether a drug is working or not in clinical trials of CDM.

University of Utah Publishes CDM Study to Support Clinical Trial Development

Dr. Nick Johnson (University of Utah) and colleagues have completed a study of the disease burden and potential outcome measures for clinical trials in CDM and recently published their findings in the prestigious journal, Neurology. Their study examined a cohort of 41 children (between 0 and 13 years old) with CDM in comparison to 29 healthy controls, using objective functional measures that could serve as clinical trial outcome measures. The team described the broad traits of children living with CDM, noting impairment of physical and cognitive function and quality of life. Their data suggests that delay of motor function milestones and daytime sleepiness are important, but previously unreported, symptoms in CDM.

They looked at outcome measures that have been used in clinical trials for other neuromuscular diseases to evaluate their feasibility for use in CDM. For the 6-minute walk test, those patients who were able to complete the test walked about 45% less distance than healthy controls. Likewise, grip and pinch strength in children with CDM was about one-third that of controls. Differences in CTG repeat length did not affect walk distance or grip/pinch strength. Children with CDM showed a substantial reduction in lip strength (12% of control value).

Cardiac testing showed cardiac conduction system abnormalities in 5 children (12%) with CDM. The authors note that this finding highlights the importance of regular cardiac monitoring in CDM children of any age. Respiratory function measures, while often compromised in neonates, improved with age in the patient group studied here. Thirty percent of CDM children in the study required use of a gastrointestinal motility agent, suggesting that monitoring GI function in CDM was essential.

Mean IQ of children with CDM was 3 standard deviations below established norms, although IQ did not improve or decline with age and did not correlate with CTG length. Daytime sleepiness increased with both age and CTG repeat length. Having parents complete a standard measure of quality of life showed a decline with age, but quality of life did not show significant differences based on CTG repeat length.

Congenital Clinical Trial Meaures Are Likely to Be Different Than Those for Adult Trials

Children with CDM likely will require different outcome measures than those used in clinical trials of adults with DM1. The researchers did note that the outcome measures studied here showed good ability to discriminate and moderate consistency. More will be learned about the potential for adopting specific outcome measures in their ongoing longitudinal study.

The better understanding of the complexity of CDM that is gained through these studies, and the ability to select appropriate outcome measures, will improve clinical trial readiness and de-risk the disease for biotechnology and pharmaceutical company investments in drug development for CDM. MDF hopes that this will soon lead to more clinical trials directed toward CDM.

Recent studies suggest that the molecular basis of congenital myotonic dystrophy (CDM) differs from that of myotonic dystrophy (DM) type 1 (DM1). Epigenetic changes upstream of the DMPK locus appear to be a co-requirement, along with a threshold repeat expansion length, as a trigger for CDM. Yet, the basis for the considerable phenotypic differences between DM1 and CDM, downstream of genotypes, is poorly understood.

Understanding the divergence of the CDM and DM1 phenotypes may be found in the timing of the critical molecular events—while DM1 is driven by MBNL depletion and reversion to developmentally-regulated alternative splicing events, the severe phenotype of CDM may be linked to disruption of prenatal transitions in alternative splicing essential to normal muscle tissue development. However, little information has been available to support that hypothesis.

Thomas and colleagues (University of Florida and Osaka University Graduate School of Medicine) tested the hypothesis that prenatal depletion of MBNL and disruption of RNA alternative processing pathways critical to myogenesis (and likely other tissue-specific events) explains the severity of CDM. An MDF fellow, Łukasz Sznajder, contributed to this work.

These investigators utilized RNAseq to compare pre-mRNA processing in skeletal muscle biopsies of CDM, DM1, and individuals carrying DM1 pre-mutations. Their data show that alternative splicing events were highly conserved between DM1 and CDM, but consistently showed greater severity in CDM. Similarly, polyAseq identified a pattern of alternative polyadenylation in CDM samples that was similar to DM1, but also more severe.

Working from the model that in utero alternative splicing contributes to the severity of CDM, the team used existing RNAseq data sets to conduct in silico evaluations of RNA processing during in vitro differentiation of human primary myoblasts. They found that RNAs relevant to CDM showed prenatal isoform transitions that were predicted by the models of in utero consequences of expanded CUG repeats.

To extend their in silico findings, the investigators tested (a) the role MBNL plays in regulating RNA processing during myogenesis and (b) the linkage between RNA processing defects and CDM-like phenotypes using double (Mbnl1, Mbnl2) and triple MBNL (Mbnl1, Mbnl2, Mbnl3) knockout mice. In aggregate, these studies showed that double knockout mice developed a severe splicopathy and congenital myopathy, while data from the triple knockout suggests that Mbnl1 and Mbnl2 loss represents the primary cause of the spliceopathy, but the deletion of Mbnl3 is responsible for more subtle alterations in hundreds of additional splicing events. Both models also showed dramatic changes in gene expression profiles (particularly in stress-related pathways that have been linked to CDM), with, again, greater severity in the triple knockout. 

Taken together, these studies provide important insights into how molecular pathogeneic mechanisms may distinguish CDM and DM1, specifically that the breadth and timing of expanded CUG repeat toxicity and the resulting RNA processing defects contribute to the severity of CDM. Splicing changes in RNAs essential for the development of skeletal muscle were shown to be both MBNL-dependent and to occur in utero, and thus were linked to perturbations of myogenesis and the ensuing congenital myopathy. The novel mouse models developed here provide an important framework for future mechanistic studies to understand the divergence of CDM and DM1 phenotypes and to inform therapy development strategies.

This peer-reviewed research article was accompanied by an editorial by Drs. Jagannathan and Bradley, appearing in the same issue of the journal. This editorial is also referenced below.

References:

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy.
Thomas JD, Sznajder ŁJ, Bardhi O, Aslam FN, Anastasiadis ZP, Scotti MM, Nishino I, Nakamori M, Wang ET, Swanson MS.
Genes Dev. 2017 Jul 11. doi: 10.1101/gad.300590.117. [Epub ahead of print]

Congenital myotonic dystrophy-an RNA-mediated disease across a developmental continuum.
Jagannathan S, Bradley RK.
Genes Dev. 2017 Jun 1;31(11):1067-1068. doi: 10.1101/gad.302893.117.

Inheritance of congenital myotonic dystrophy (CDM) is almost exclusively maternal and, while typically associated with large CTG expansions, is not always genetically differentiated from myotonic dystrophy type 1 (DM1) by repeat tract length. Correlations between CDM/DM1 genotype and phenotype can be improved through evaluation of somatic expansions. Yet it is clear that factors other than germ line repeat length underlie the bias toward maternal inheritance and the heterogeneity of CDM.

The laboratories of Drs. Karen Sermon (Vrije Universiteit Brussel) and Chris Pearson (Hospital for Sick Children) recently collaborated on an epigenetic analysis of the DM1 genetic locus in a cohort of DM1 and CDM patients. Prior reports showed that the DM1 locus resides in a 3.5 kB CpG island with putative CTCF sites, suggesting an epigenetic mechanism for DM1 regulation and disease phenotypes that diverge from CTG length assessments. Earlier reports also established variability in methylation status at that locus in both DM1 patients and DM1 transgenic mice. Drs. Sermon and Pearson hypothesized that CTG expansion might alter CpG methylation status and that a consequent regulatory dysfunction contributes to the severity of the CDM phenotype.

Drs. Sermon and Pearson and team evaluated multiple generations of several families, including 20 individuals with CDM. Results showed nearly an absolute correlation between the methylation status upstream of the expanded CTG repeat and the occurrence of CDM (19/20 cases). By contrast, this pattern of methylation was rarely found among DM1 patients (2/59 cases). The authors suggest that CpG site methylation is an important contributing factor, with the development of CDM not being determined by CTG repeat length alone.

Analysis of human embryonic stem cells (hESC) and chorionic villus samples from the study cohort identified upstream CpG site methylation only in maternally-derived samples; paternal samples never showed methylation upstream of expanded DMPK alleles.

Generational increases in both methylation and CTG expansion length were seen in each CDM family studied. Yet since CTG repeat lengths overlapped in DM1 and CDM, while upstream methylation was almost exclusive to CDM, the authors concluded that methylation status is a stronger indicator of CDM than absolute repeat length. Moreover, they speculate that the maternal inheritance bias of CDM may be a consequence of a failed survival of spermatogonia carrying the pathogenic methylation upstream of DMPK. Importantly, while their data suggests that it is rare, the authors do not exclude paternal inheritance for CDM.

Reference:

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.
Barbé L, Lanni S, López-Castel A, Franck S, Spits C, Keymolen K, Seneca S, Tomé S, Miron I, Letourneau J, Liang M, Choufani S, Weksberg R, Wilson MD, Sedlacek Z, Gagnon C, Musova Z, Chitayat D, Shannon P, Mathieu J, Sermon K, Pearson CE.
Am J Hum Genet. 2017 Mar 2;100(3):488-505. doi: 10.1016/j.ajhg.2017.01.033.