Regulation of MBNL1 Localization and Function in the CNS

Published on Mon, 04/09/2018

Role of Muscleblind Proteins in Health and Disease

Muscleblind (MBNL) proteins play a central role in the pathogenesis of myotonic dystrophy (DM), as MBNL depletion below a threshold level triggers a range of mRNA splicing, polyadenylation, localization, and processing defects and, thereby, the production of temporally inappropriate protein isoforms. This compromise of function for a wide range of proteins, in turn, leads to the multi-organ system phenotypes that characterize DM. To understand MBNL’s roles in normal development and function, and dysfunction in DM, it is essential to elucidate mechanisms underlying its spatial and temporal localization and steps necessary for its functional activation/inactivation.

Dissecting the Role of MBNL in the CNS

Understanding the regulation and functional roles of MBNL proteins in the CNS represents a critically important problem in determining pathogenic mechanisms underlying the nervous system phenotype in DM. Dr. Guey-Shin Wang at National Yang-Ming University and Academia Sinica (Taiwan) have published an article in Cell Reports that MBNL1 localized to the cytoplasm, but not that retained in the nucleus, plays a key role in neurite morphogenesis and show that this role is disrupted in DM1.

Using FLAG-tagged isoforms of MBNL1 (with and without exon 5) expressed in hippocampal neuron cultures, Dr. Wang and colleagues demonstrated that MBNL1 that included exon 5 was retained in the nucleus and had no impact on neuronal development, while exon 5-deleted MBNL1, which translocates to the cytoplasm, enhanced dendrite and axon morphogenesis.

Consistent with this role for MBNL1 in regulating neurite differentiation and the differentiation failure in DM1, the research team showed that either MBNL1 knockdown or overexpression of 960-repeat DMPK mRNA (DMPK-CUG960) resulted in delayed neurite maturation. Moreover, the cytoplasmic (exon 5 deleted) MBNL1 isoform, but not the nuclear-localized isoform, was found to rescue maturation defects in neurons expressing DMPK-CUG960 in a dose-dependent manner.

Mechanisms Regulating Neuronal Subcellular Distribution of MBNL1

Analysis of the developmental distribution of the two MBNL1 isoforms led to the puzzling finding that nuclear or cytoplasmic localization was independent of exon 5 inclusion/exclusion, suggesting that another factor regulated MBNL1 localization in the developing brain. The research team then demonstrated that Lys 63-linked ubiquitination of MBNL1 and neuronal activity level regulated its cellular localization. Finally, it was shown that deubiquitination caused by expanded repeat mRNA resulted in a cytoplasmic-to-nuclear translocation of MBNL1 and corresponding alterations in neurite morphogenesis—these consequences were prevented by deubiquitination inhibitors.

Taken together, Dr. Wang and colleagues have shown that MBNL1 plays a key role in neuronal differentiation and that disruption of its cellular localization alters functionally significant steps in neuronal structure and function that likely underlie the CNS consequences of DM. Moreover, their identification of the regulatory role that the ubiquitination/deubiquitination status plays in the cytoplasmic localization of MBNL1 suggests a novel potential target for therapeutic development in DM1.


Ubiquitination of MBNL1 Is Required for Its Cytoplasmic Localization and Function in Promoting Neurite Outgrowth.
Wang PY, Chang KT, Lin YM, Kuo TY, Wang GS.
Cell Rep. 2018 Feb 27;22(9):2294-2306. doi: 10.1016/j.celrep.2018.02.025.

NHGRI Genomic Medicine Research Initiative

Published on Mon, 04/09/2018

The National Human Genome Research Institute (NHGRI) has issued two new Funding Opportunity Announcements in support of research to utilize a patient’s own genomic information to inform clinical care and health outcomes. These Announcements represent a potential opportunity to apply an understanding of the genomics of those living with myotonic dystrophy (DM) to clinical management and treatment settings.

The stated objective of the NHGRI program is to “stimulate innovation and advance our understanding of when, where and how best to implement the use of genomic information and technologies in clinical care in all populations.” The program utilizes both R01 (PAR-18-735) and R21 (PAR-18-736) grant mechanisms. R01 applications are limited to $500,000 direct costs/year and 4 years; R21 applications to $275,000 total direct costs over 2 years. The PAR designation implies that applications will be assigned to a dedicated study section (Special Emphasis Panel or other) for review; there are no set-aside funds designated for this initiative.

Eligible activities include, but are not limited to, research studies on genome sequencing for disease diagnosis, treatment, or healthcare utilization. Interested applicants should see the Program Announcements referenced above and are strongly encouraged to discuss plans for applications with the Program Director identified in the Announcements.

Tissue-Specific Sensitivities to DM1 Repeat Expansion

Published on Wed, 11/20/2019

Understanding Tissue Specificity in Repeat Expansion Disorders

The instability of short tandem repeats and consequent somatic expansion underlies an entire class of neurological disorders. In DM1, the interaction between expanded repeat transcripts and the RNA binding protein/splicing regulator MBNL determines subsequent pathogenic events. Although the inherited (progenitor) repeat length is independent of cell/tissue type, tissue specificity in somatic expansion defines both the timing and severity of organ systems impacted by DM1. Questions of the spatial and temporal patterns of disease pathophysiology are difficult to ask and answer in studies of patients. Yet, most model organisms used to study DM1 to date are not capable of interrogating mechanisms that underlie such cell type- and tissue-specific effects.

New Mouse Models to DM1 Study Tissue Specificity

New technologies, rolling circle amplification and CRISPR/Cas9 genome editing, have been used by Dr Maury Swanson (University of Florida) and colleagues to develop novel Dmpk 3’UTR CTGexp knock-in mouse models of DM1. Mice expressing 170 (Dmpk170/170) and 480 (Dmpk480/480) repeats were selected. These new models enable study of repeat expansion, MBNL sequestration, mis-splicing, and pathophysiology on specific cell and tissue type levels. Dr. Curtis Nutter, recipient of a 2018 MDF Fellowship, was lead author on this work.

Dmpkexp mice exhibited nuclear foci and reduced Dmpk mRNA and protein levels, but disrupted splicing regulation was not observed and downstream muscle phenotypic changes (myotonia, central nuclei) were absent. Similar reductions in Dmpk mRNA and protein were seen in cultured myoblasts and myotubes. In contrast to absent splicing changes in adult mice, MBNL sequestration and mis-splicing were seen in Dmpk480/480 but not in Dmpk170/170 mouse myotubes. To reconcile their findings, the authors found that MBNL activity might be more effectively damped in myoblasts/myotubes than in mature muscle—reinforcing the notion that pathology reflects both tissue and developmental stage specificity due to interactions of relative repeat load (expansion length and gene expression level) with MBNL protein levels. Crosses resulting in Dmpk480/480 mice haploinsufficient for MBNL supported this idea.

Given the severity of the CNS phenotype in DM1, the research team also evaluated choroid plexus (a CNS tissue expressing high Dmpk levels) in the Dmpkexp mice. Nuclear foci were prominent and DM1-related splicing anomalies detected in choroid plexus of these mice.

Insights into Cell Type Specificity and Pathogenesis of DM1

 The Dmpkexp mice have not, to date, shown evidence of repeat instability—in keeping with the absence of an in vivo phenotype. Larger repeat loads may be necessary to trigger mouse phenotypes. Perhaps more importantly, these data help establish a link between DMPK CTGexp length and the cell/tissue patterns of pathology in DM1. That choroid plexus may be affected earlier (i.e., at lower repeat load) than skeletal muscle helps solidify understanding of the spatial and temporal patterning of DM1. It’s now highly likely that the repeat load in other cell/tissue types can be more directly linked to their disease phenotype. Finally, these results also make it clear that there is a need to explore potential involvement of affected choroid plexus function (CSF production) in the CNS consequences of DM1.


Cell-type-specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy.
Nutter CA, Bubenik JL, Oliveira R, Ivankovic F, Sznajder ŁJ, Kidd BM, Pinto BS, Otero BA, Carter HA, Vitriol EA, Wang ET, Swanson MS.
Genes Dev. 2019 Oct 17. doi: 10.1101/gad.328963.119. [Epub ahead of print]

Toward a Cardiac Biomarker for DM1?

Published on Wed, 11/20/2019

Cardiac Biomarkers and DM

Cardiac rhythm disturbances represent a cardinal feature and a leading cause of death in DM. To elevate the level of patient cardiac care, consensus-based care recommendations are now available for DM1, children with CDM or DM1, and DM2. The molecular basis of cardiac dysfunction in DM, however, has been difficult to discern. It has been suggested that serum levels of high-sensitive cardiac troponin T and N-terminal pro B-type natriuretic peptide may be predictive of cardiac risk and potentially useful for stratification (Valaperta et al., 2016 and 2017), but these have not yet shown promise as efficacy biomarkers for interventional clinical trials. Similarly, mis-splicing of SCN5A has been implicated in DM cardiac conduction defects (Freyermuth et al., 2016; Pang et al., 2018), but its value as a clinical trial tool has not been determined. Thus, specific biomarkers for cardiac involvement in DM have not yet been established and their absence represents an important gap in the ability to assess candidate therapeutics for a key phenotype in this patient group.

Assessing Mis-Splicing of Cardiac-Relevant Transcripts

Drs. Rosanna Cardani and Giovanni Meola (IRCCS-Policlinico San Donato and University of Milan) and colleagues initiated a study of alternative splicing of several genes that could be used to follow the cardiac phenotype in DM1 or DM2 patients. Analyses were performed in patients with and without cardiac involvement; molecular analyses focused on TNNT2 expression, in part because it is mis-spliced in both skeletal and cardiac muscle in DM.  Dr. Laura Valentina Renna, a former MDF fellow, contributed to this work.

The research team evaluated skeletal muscle biopsies in 24 DM1, 9 DM2 patients, and 10 age-matched controls; subjects also underwent muscle strength evaluations (MRC scale), staging of DM1 (MIRS), ECG, and Holter tests. Their study also included a range of histologic and immunocytochemical markers to establish correlations between observed splicopathies and skeletal muscle status.

TNNT2 encodes cardiac troponin T (cTnT). The research team showed that TNNT2 mis-splicing was more evident in skeletal muscle biopsies from DM1 subjects (where the fetal isoform was > 50% of total transcript) versus DM2. The authors suggest that greater mis-splicing in DM1 may relate not only to the more severe myopathy, but to the general disease severity, including cardiac involvement, in DM1. Finally, the level of TNNT2 mis-splicing strongly correlated with QRS duration abnormalities in DM1 (but not DM2), suggesting that alternative splicing of TNNT2 may have value as a cardiac biomarker.

TNNT2 as a Biomarker of DM1 Severity?

Overall, the authors cannot conclude that TNNT2 mis-splicing is a specific biomarker of cardiac involvement in DM, only that data are suggestive that it may be when further data are acquired. They do argue that TNNT2 mis-splicing may function as a biomarker of disease severity in DM1, the potential of which should be explored in natural history studies and interventional clinical trials.


High-sensitive cardiac troponin T (hs-cTnT) assay as serum biomarker to predict cardiac risk in myotonic dystrophy: A case-control study.
Valaperta R, Gaeta M, Cardani R, Lombardi F, Rampoldi B, De Siena C, Mori F, Fossati B, Gaia P, Ferraro OE, Villani S, Iachettini S, Piccoli M, Cirillo F, Pusineri E, Meola G, Costa E.
Clin Chim Acta. 2016 Dec 1;463:122-128. doi: 10.1016/j.cca.2016.10.026. Epub 2016 Oct 22.

Cardiac involvement in myotonic dystrophy: The role of troponins and N-terminal pro B-type natriuretic peptide.
Valaperta R, De Siena C, Cardani R, Lombardia F, Cenko E, Rampoldi B, Fossati B, Brigonzi E, Rigolini R, Gaia P, Meola G, Costa E, Bugiardini R.
Atherosclerosis. 2017 Dec;267:110-115. doi: 10.1016/j.atherosclerosis.2017.10.020. Epub 2017 Oct 21.

Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, Kino Y, Arandel L, Jollet A, Thibault C, Philipps M, Vicaire S, Jost B, Udd B, Day JW, Duboc D, Wahbi K, Matsumura T, Fujimura H, Mochizuki H, Deryckere F, Kimura T, Nukina N, Ishiura S, Lacroix V, Campan-Fournier A, Navratil V, Chautard E, Auboeuf D, Horie M, Imoto K, Lee KY, Swanson MS, de Munain AL, Inada S, Itoh H, Nakazawa K, Ashihara T, Wang E, Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N.
Nat Commun. 2016 Apr 11;7:11067. doi: 10.1038/ncomms11067.

CRISPR -Mediated Expression of the Fetal Scn5a Isoform in Adult Mice Causes Conduction Defects and Arrhythmias.
Pang PD, Alsina KM, Cao S, Koushik AB, Wehrens XHT, Cooper TA.
J Am Heart Assoc. 2018 Oct 2;7(19):e010393. doi: 10.1161/JAHA.118.010393.

TNNT2 Missplicing in Skeletal Muscle as a Cardiac Biomarker in Myotonic Dystrophy Type 1 but Not in Myotonic Dystrophy Type 2.
Bosè F, Renna LV, Fossati B, Arpa G, Labate V, Milani V, Botta A, Micaglio E, Meola G, Cardani R.
Front Neurol. 2019 Sep 27;10:992. doi: 10.3389/fneur.2019.00992. eCollection 2019.

DM and the Canadian Neuromuscular Disease Registry

Published on Fri, 03/09/2018

MDF has strongly supported the inclusion of the patient voice in both care and therapy development for DM. The most recent examples of these efforts are the Patient Focused Drug Development meeting held with FDA, and its subsequent Voice of the Patient report, and the development of DM Care Considerations to drive improved clinical management of patients living with DM. MDF also has long focused on collecting patient- and caregiver-reported data through the Myotonic Dystrophy Family Registry.

To provide the highest level of support to those living with DM, it is important to not only utilize registries for collection of both patient/care provider-reported and clinical data, but to ensure the utilization and sharing of these data to meet the goals of improved care and optimized clinical trials.

The Canadian Neuromuscular Disease Registry (CNDR)

The CNDR is a clinic-based enrollment and data entry registry focused on regular clinical contact with registrants and accurate retrospective data collection from patient charts. Dr. Craig Campbell (University of Western Ontario) and colleagues have recently published information on the CNDR’s efforts to support research into potential therapies for a wide range of neuromuscular diseases, including DM (Wei et al., 2018).

The CNDR’s website reports a current total of 3,440 registrants (; the publication by Dr. Campbell and colleagues reports out on details of the overall registry (including design, consent, data collection and management, and access policies) and data from its pediatric registrants. The CNDR’s pediatric registrants include 249 with dystrophinopathies, 57 with DM, 98 with SMA, and 65 with LGMD. The CNDR houses clinical data obtained from retrospective chart evaluation and data obtained during clinic visits. CNDR data is used to support both research proposal and statistical data requests.

CNDR has supported 30 study requests for pediatric data (20 clinical trials, 5 mail surveys, and 5 other studies). Two of the mail surveys have focused on DM (parent reported burden of disease in CDM and childhood-onset DM1, Johnson et al., 2016; access to technology survey in DM). The ‘other’ studies included a study of CDM and a study of ventilator support use in pediatric patients with DM1. The paper’s authors note that they are exploring post-marketing surveillance models as a potential resource for companies engaging in clinical trials in neuromuscular diseases.

Moving Forward with Registries

The success of individual registries like the CNDR is laudable in fostering improved care and therapy development for rare neuromuscular diseases. As for many neuromuscular diseases, the DM field has harmonized clinical study and registry data collection. Thus, there’s a firm basis for data sharing and meta-analysis of the smaller cohorts that are spread among multiple DM registries. For any rare disease, it is especially important that data not remain siloed, as that’s a hindrance to assembling cohorts that are sufficient to reach meaningful conclusions about disease course and clinical trial endpoints. The DM field will only meet the expectations and trust of the patients who so willingly share their data when cultural changes occur and analysis of internationally shared data is possible (Larkindale and Porter, 2018).


The Canadian Neuromuscular Disease Registry: Connecting patients to national and international research opportunities.
Wei Y, McCormick A, MacKenzie A, O'Ferrall E, Venance S, Mah JK, Selby K, McMillan HJ, Smith G, Oskoui M, Hogan G, McAdam L, Mabaya G, Hodgkinson V, Lounsberry J, Korngut L, Campbell C.
Paediatr Child Health. 2018 Feb;23(1):20-26. doi: 10.1093/pch/pxx125. Epub 2017 Dec 8.

Parent-reported multi-national study of the impact of congenital and childhood onset myotonic dystrophy.
Johnson NE, Ekstrom AB, Campbell C, Hung M, Adams HR, Chen W, Luebbe E, Hilbert J, Moxley RT 3rd, Heatwole CR.
Dev Med Child Neurol. 2016 Jul;58(7):698-705. doi: 10.1111/dmcn.12948. Epub 2015 Oct 28.

Seeking a better landscape for therapy development in neuromuscular disorders.
Larkindale J, Porter JD.
Muscle Nerve. 2018 Jan;57(1):16-19. doi: 10.1002/mus.25961. Epub 2017 Sep 23.

Predictors of DM1 Patient Survival

Published on Fri, 03/09/2018

Analysis of phenotypic variability in the presentation of DM1 has led to the conclusion that disease types based upon age of onset represent a continuum, but that there are recognizable patterns in symptom onset and progression (De Antonio et al., 2016) that impact prognosis. Gender is also a major modifier of symptomatology and, ultimately, of mortality rates (Dogan et al., 2016). Understanding these risk factors and how they contribute toward the clinical spectrum and stages of DM1 is critically important for appropriate management of patient care and for the design of clinical trials.

Implementation of the care considerations developed by the MDF in partnership with an international group of physicians represents a critically important step in improving the quality of life for those living with myotonic dystrophy. Development of a means to quantitatively assess the risk factors of and long-term prognosis for this multi-systemic disease at the individual patient level would provide an important tool for patient management.

Towards a Prognostic System for DM1 Patient Survival

To determine whether a clinical scoring model might predict long-term survival, Dr. Karim Wahbi (Cochin Hospital, Sorbonne Paris Cité University) and colleagues assessed a cohort of 1296 consecutive adult patients with molecular confirmation of DM1 and included in the French DM1 Heart Registry (Wahbi et al., 2018). 1066 patients were used in a derivation cohort to identify and assign weighting of variables that would comprise a survival index, while the remainder of patients, all from two other clinics, served as a validation cohort. The primary study endpoint was survival and ten variables collected in the DM1 Heart Registry were evaluated for inclusion in a prognostic index.

The commonly available variables of age, diabetes, need for support when walking, heart rate, systolic blood pressure, first-degree atrioventricular block, bundle-branch block, and lung vital capacity were associated with death. These factors were associated with survival by multiple variable Cox modeling and found to contribute to a prognostic model. CTG length, atrial fibrillation, left ventricular dysfunction, and dysphagia did not add to the predictive value of the scoring system and were excluded. Scores ranging from 1 or less to 15 or more were associated with 10-year survival probabilities from 98.1% to 22.5%, respectively. Thus, the model exhibited a wide dynamic range in predicting survival. Survivors and non-survivors were similarly well discriminated in the validation cohort.

A Simplified Tool for Patient Management and Clinical Trial Design

The research team emphasized the value of the DM1 survival score by noting that just eight common patient traits typically collected in clinical examinations are needed to determine a score. Moreover, the reliability and long-term prognostic capability may make this system an essential tool in the management of care in a multi-disciplinary setting.


Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.
De Antonio M, Dogan C, Hamroun D, Mati M, Zerrouki S, Eymard B, Katsahian S, Bassez G; French Myotonic Dystrophy Clinical Network.
Rev Neurol (Paris). 2016 Oct;172(10):572-580. doi: 10.1016/j.neurol.2016.08.003. Epub 2016 Sep 21. Review.

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.
Dogan C, De Antonio M, Hamroun D, Varet H, Fabbro M, Rougier F, Amarof K, Arne Bes MC, Bedat-Millet AL, Behin A, Bellance R, Bouhour F, Boutte C, Boyer F, Campana-Salort E, Chapon F, Cintas P, Desnuelle C, Deschamps R, Drouin-Garraud V, Ferrer X, Gervais-Bernard H, Ghorab K, Laforet P, Magot A, Magy L, Menard D, Minot MC, Nadaj-Pakleza A, Pellieux S, Pereon Y, Preudhomme M, Pouget J, Sacconi S, Sole G, Stojkovich T, Tiffreau V, Urtizberea A, Vial C, Zagnoli F, Caranhac G, Bourlier C, Riviere G, Geille A, Gherardi RK, Eymard B, Puymirat J, Katsahian S, Bassez G.
PLoS One. 2016 Feb 5;11(2):e0148264. doi: 10.1371/journal.pone.0148264. eCollection 2016.

Development and Validation of a New Scoring System to Predict Survival in Patients With Myotonic Dystrophy Type 1.
Wahbi K, Porcher R, Laforêt P, Fayssoil A, Bécane HM, Lazarus A, Sochala M, Stojkovic T, Béhin A, Leonard-Louis S, Arnaud P, Furling D, Probst V, Babuty D, Pellieux S, Clementy N, Bassez G, Péréon Y, Eymard B, Duboc D.
JAMA Neurol. 2018 Feb 5. doi: 10.1001/jamaneurol.2017.4778. [Epub ahead of print]

Thanks Dr. John Porter, Welcome Dr. Lisa Ackermann!

Published on Tue, 03/06/2018
Dr. John Porter

MDF is bidding a very fond farewell to John Porter, PhD, as MDF’s Chief Science Officer, and bidding a very warm hello to Elizabeth (Lisa) Ackermann, PhD.

John Porter, PhD

Since 2016 John Porter has done an exemplary job of leading the research and drug development acceleration programs at MDF in his role as Chief Science Officer. He spearheaded the implementation of key recent initiatives including the development of the MDF cell line library, initiation of MDF’s BAC transgenic mouse model, known at MDF as the Mega Mouse and, in partnership with CEO Molly White, helped significantly expand the number of industry members considering myotonic dystrophy as a drug development candidate via countless presentations to biotech and pharma companies internationally. John also identified and wrote the content for the monthly DM Research News, the first and only DM-only research newsletter for the professional community. John brought significant expertise to MDF drawn from his roles as a Program Director at the National Institute of Neuromuscular Disorders and Stroke (NINDS), as CEO at Parent Project Muscular Dystrophy and via his roles as professor of neurology and neuroscience, and academic researcher, at Case Western Reserve University. The good news is that while John is retiring from the CSO role at MDF, he will continue to support the foundation as a consultant on key programs.



Elizabeth (Lisa) Ackermann, PhD

MDF is thrilled to announce that Dr. Lisa Ackermann has joined MDF as our new Chief Science Officer. Lisa has over 20 years of pharmaceutical drug discovery and development experience, most recently as Vice President of Clinical Development at Ionis Pharmaceuticals. During her extensive career she has led both preclinical and clinical teams in the areas of rare genetic disorders and Alzheimer’s Disease, and at Ionis Pharmaceuticals served as Project Team Leader for the inotersen development program (a novel therapy to treat Transthyretin Amyloidosis, a rare and severe disease). Lisa is a seasoned senior scientist and drug development professional, and we look forward to continuing and amplifying the good work John carried out under her leadership.

Please join us in thanking John and wishing him well in his retirement, and in extending a very enthusiastic and appreciative welcome to Lisa!

Speech Disorders in Congenital and Childhood DM1

Published on Tue, 03/06/2018

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.


Myotonic dystrophy type 1 (DM1) and speech problems.
Lopes Cardoso I, Baptista H.
JSM Communication Dis. 1(1): 1003.…

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]

Comorbidity of Childhood DM1 and Autism?

Published on Tue, 02/06/2018

Since a neuropsychological study in 2008 (Ekström et al., 2008), there have been few studies of pediatric cohorts to assess potential links between congenital and childhood-onset DM1 with autism spectrum disorders. The Ekström analysis of 57 children and adolescents with DM1 showed that 53% exhibited autism spectrum or other neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder or Tourette's syndrome). The authors concluded that awareness of potential autism spectrum disorder comorbidity in DM1 was essential to patient care. There has been little literature on this issue since 2008.

A New Cohort Study of Autism and Childhood DM1

Dr. Nathalie Angeard (Paris Descartes University and Institut de Myologie) and colleagues recently published a review of nine studies focused on cognitive disorders in childhood DM1, compromising 175 cases (Angeard et al., 2017).

Emotional and behavioral disorders were prominent among reports in childhood DM1—the earlier study by Ekström and colleagues found that 36% of a cohort containing congenital (CDM) and juvenile-onset DM1 had autism spectrum disorders, although other studies did not report that high a prevalence. Angeard suggests that the association between and difficulties in the differential diagnoses of intellectual disability and autism spectrum might contribute to differences in reports of autism spectrum in CDM and juvenile DM1.

Cognitive function studies in CDM have reported moderate to severe intellectual disability in greater than half of patients studied. Considerable information is available regarding the characterization of specific cognitive function deficits and is reported in this meta-analysis. Patients with autism spectrum comorbidity did not fit a narrow profile, but rather exhibited a range of severity of symptoms, cognitive abilities and functional adaptations. The authors suggest that a considerable gap exists in understanding executive function and social cognition in childhood DM1, making it difficult to compare these patients with those with autism spectrum disorder. Likewise, a dearth of neuroanatomic and brain function studies in childhood DM1 also makes it difficult to compare their profile with that of autism spectrum disorder children. Where comparisons can be made based on available publications, the authors compare and contrast the social/communication, cognitive function and brain abnormality profiles between the two disorders (Table 2 in Angeard et al., 2017).

It’s Not Yet Clear Whether Childhood DM1 and Autism Spectrum Disorders are Comorbid

Overall, Angeard and colleagues note that only the Ekström paper reports high prevalence of autism spectrum disorder in childhood DM1 (36% versus 1% in the general population). Most publications agree, however, upon moderate prevalence of autism spectrum disorders in CDM. An evolving definition of autism spectrum over the time of the publications assessed here complicates any clear conclusion regarding comorbidity. The authors note that the prevalence of intellectual disability among childhood DM1 and autism spectrum may lead to biases in diagnosis. Taken together, they regard the question of comorbidity of childhood DM1 and autism as still open, requiring more careful cross-sectional and longitudinal natural history studies of the cognitive and behavioral phenotype of childhood DM1. For now, earlier attention to the cognitive, developmental, and social/emotional profiles of those at risk for CDM and juvenile-onset DM1 is warranted.


Autism spectrum conditions in myotonic dystrophy type 1: a study on 57 individuals with congenital and childhood forms.
Ekström AB, Hakenäs-Plate L, Samuelsson L, Tulinius M, Wentz E.
Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):918-26. doi: 10.1002/ajmg.b.30698.

Childhood-onset form of myotonic dystrophy type 1 and autism spectrum disorder: Is there comorbidity?
Angeard N, Huerta E, Jacquette A, Cohen D, Xavier J, Gargiulo M, Servais L, Eymard B, Héron D.
Neuromuscul Disord. 2017 Dec 15. pii: S0960-8966(17)31337-8. doi: 10.1016/j.nmd.2017.12.006. [Epub ahead of print]

Toward ‘Responsive’ Outcome Measures for DM1

Published on Sun, 01/07/2018

The Pathway to an Approvable (and Reimbursable) Therapeutic

DM offers many advantages in attracting drug developers, not the least of which is the ability to use changes in alternative splicing as a rapid and quantitative measure of target engagement/modulation and dosing. Beyond such early-stage milestones, a challenge in myotonic dystrophy is finding endpoint measures that: (a) are clinically meaningful to patients and caregivers, (b) show progressive change during the timeframe of a typical clinical trial (6-12 months) and (c) provide sufficient validity, responsiveness and reproducibility as to support acceptance by both regulators and payers.

An insightful pair of review articles in the NEJM (Pocock and Stone, 2016a, 2016b) discuss interpreting data from clinical trials, pointing out the importance of selection of outcome measures and their underlying methodology: “Trial success may hinge on definitions of the outcomes and on the methods used for their adjudication.” How do we get there for DM?

There is no easy pathway toward adequate, clinically meaningful outcome measures, particularly in a slowly-progressive, multi-system disorder like DM. The necessary ‘grunt work’ involves triaging and implementing a broad battery of putative outcome measures and applying them in sufficiently powered, longitudinal natural history studies. To avoid siloing of small, underpowered datasets, natural history studies in DM should plan, from the beginning, that data sharing will occur in order to achieve broader goals that are un-addressable any other way (Larkindale and Porter, 2017).

‘Responsive’ Outcome Measures for DM1

Drs. Marie Kierkegaard (Karolinska Institute), Cynthia Gagnon (University of Sherbrooke) and colleagues have published the results of a 9-year, longitudinal natural history study assessing function, disabilities and overall health in a cohort of subjects with adult- and late-onset DM1. The responsiveness of a wide battery of functional tests and patient-reported perceptions of changes in relevant functions was evaluated at baseline and 9 years later in 113 subjects seen at the Saguenay Neuromuscular Clinic.

Patient reports of perceived change in specific functions (balance, walking, lower-limb weakness, stair-climbing and hand weakness) correlated with those changes measured by the research team. The highest degree of responsiveness was found for measures of mobility, balance and muscle strength (Timed Up and Go, Berg Balance Scale and Quantitative Muscle Testing). By contrast, outcome measure responsiveness was poorer for manual dexterity and grip strength.

Significantly, some measures -- Timed Up and Go, grip strength, pinch-grip strength and Purdue Pegboard Test -- did not show longitudinal changes that exceeded known measurement errors, raising questions about value for clinical trials.

Criticality of Endpoint Selection for Clinical Trials

Taken together, this study provides important insights into the responsiveness of a range of functionally significant outcome measures that could be selected for interventional clinical trials. Assessment of endpoint measure change was made over a time period considerably longer than any feasible clinical trial (9 years), and DM1-related cognitive decline over the study period likely influenced patient perception abilities, but these data help improve understanding of the relative performance of specific measures. Some measures did not distinguish either clinically important changes from known measurement errors and/or the smallest detectable change for the specific instrument. These findings should be considered, along with data from other studies, when defining suitable outcomes and measurement methodology for DM1 interventional clinical trials. As the authors note, it is essential to assess outcome measure responsiveness over the shorter time period that is feasible for clinical trials.


Responsiveness of performance-based outcome measures for mobility, balance, muscle strength and manual dexterity in adults with myotonic dystrophy type 1.
Kierkegaard M, Petitclerc É, Hébert LJ, Mathieu J, Gagnon C.
J Rehabil Med. 2017 Dec 20. doi: 10.2340/16501977-2304. [Epub ahead of print]

The Primary Outcome Fails - What Next?
Pocock SJ, Stone GW.
N Engl J Med. 2016 Sep 1;375(9):861-70. doi: 10.1056/NEJMra1510064

The Primary Outcome Is Positive - Is That Good Enough?
Pocock SJ, Stone GW.
N Engl J Med. 2016 Sep 8;375(10):971-9. doi: 10.1056/NEJMra1601511.

Seeking a better landscape for therapy development in neuromuscular disorders.
Larkindale J, Porter JD.
Muscle Nerve. 2018 Jan;57(1):16-19. doi: 10.1002/mus.25961. Epub 2017 Sep 23.