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.

References:

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]

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.

References:

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.

Clinical Trials Targeting GSK3β

AMO Pharma is in clinical development with AMO-2 (tideglusib), an inhibitor of GSK3β signaling, for congenital myotonic dystrophy (CDM). A single blind, phase 2 trial has been initiated at Newcastle University to evaluate drug safety and efficacy in adolescent and adult patients with congenital and juvenile-onset DM1 (see https://clinicaltrials.gov/ct2/show/NCT02858908).

Studies from Dr. Lubov Timchenko and colleagues provided the initial preclinical rationale for the GSK3β target in a mouse model of DM1 (Jones et al., 2012). AMO’s clinical development of the GSK3β inhibitor, tideglusib, was, in part, based on these preclinical data. The GSK3β—cyclin D3—CUGBP1 pathway is of particular interest for CDM because of the potential role CUGBP1 plays in myogenesis. Now, additional studies have been undertaken to validate this novel target for drug development in CDM.

Evaluation of a GSK3β Inhibitor in Young HSALR Mice

Dr. Timchenko and colleagues at Cincinnati Children’s Hospital, Baylor College of Medicine, Centre Hospitalier–Université Laval Research Center, and Mount Sinai Hospital (Toronto) conducted evaluations of the validity of the GSK3β inhibition strategy in young (1.5 month old) HSALR mice. Two GSK3β inhibitors (6-bromoindirubin-39-oxime (BIO) and indirubin) were administered to mice, ip every 48 hours for 6 weeks. The group reported that early correction of GSK3β signaling was important for differentiation and long-term integrity of HSALR mouse skeletal muscle. Their data showed that correction of GSK3β—cyclin D3—CUGBP1 pathway activity was instrumental in the structural and functional changes in skeletal muscle. Using a Celf1 knockout model, the research team further established the connection between CUGBP1 levels and skeletal muscle development.

Relevance for Clinical Trials with Tideglusib

This latest study focuses on the validity of the GSK3β target for DM, as measured by changes in muscle histopathology and functional grip strength. These preclinical data show that the GSK3β target may be capable of modulating the progression and severity of the disease. However, differences in the drug employed and delivery regimen in this mouse study mean that it did not evaluate the efficacy of the tideglusib drug as a candidate therapeutic for DM. Rigorously-designed studies of tideglusib will be important to support the case for DM1 therapy development.

References:

Correction of GSK3β at young age prevents muscle pathology in mice with myotonic dystrophy type 1.
Wei C, Stock L, Valanejad L, Zalewski ZA, Karns R, Puymirat J, Nelson D, Witte D, Woodgett J, Timchenko NA, Timchenko L.
FASEB J. 2017 Dec 4. pii: fj.201700700R. doi: 10.1096/fj.201700700R. [Epub ahead of print]

GSK3β mediates muscle pathology in myotonic dystrophy.
Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian J, Timchenko NA, Timchenko LT.
J Clin Invest. 2012 Dec;122(12):4461-72. doi: 10.1172/JCI64081. Epub 2012 Nov 19.

The Genesis of Drug Screening Assays

Early stage drug development programs are often predicated on the development of biochemical or cell-based assays that allow identification of candidate therapeutics that engage and modulate targets deemed to be potentially disease mitigating. To be efficient and effective such screening assays must meet accepted pharmaceutical industry criteria—guidance in development of acceptable assays has been provided as part of a preclinical research toolbox by the National Center for Advancing Translational Sciences (https://ncats.nih.gov/files/agm-factsheet.pdf).

Screening assays frequently arise from academic groups focused on both mechanistic and translational goals. While not typically in compliance with industry standards for high throughput screening of libraries that can exceed 1M compounds, such assays may provide important first steps in that direction.

A Novel Effort Towards a DM1 Drug Screening Assay

Dr. Krzysztof Sobczak and colleagues at Adam Mickiewicz University have developed a minigene-based assay to assess critical RNA binding protein sites/splicing regulatory regions in pre-mRNA that may have implications as a drug screening assay for DM1. Dr. Łukasz Sznajder, currently an MDF fellow at the University of Florida, was part of the team.

The research team first evaluated functional protein (MBNL)/RNA interactions, taking into account RNA primary and secondary structure in a design that allowed assessment by CLIP-seq or other means of transcriptome analysis. In an evaluation of the potential to assess splicing regulation, antisense oligonucleotides on two backbone chemistries (2’OMe and LNA) targeted to MBNL binding regions of Atp2a1 were able to inhibit exon 22 inclusion in the Atp2a1 transcript. The approach was validated using other transcripts regulated by MBNL.

They also designed hybrid Atp2a1 mini genes containing functional MBNL-binding motifs in introns and exons. These were used to establish that inclusion or exclusion of the MBNL motifs had the predicted effect on exon 22 splicing; results were confirmed in transfected HeLa cells. Taken together, they showed that MBNL-binding regulatory regions could be transferred from their original genetic context into a different mini gene transcript and still regulate alternative splicing.

In an initial proof of concept, the research team showed that the Atp2a1 mini gene could feasibly discern the potency of various interventions to disrupt MBNL binding. Inclusion of a reporter gene in the minigene construct may provide an effective assay for drug discovery via high-throughput screening.

References:

Hybrid splicing minigene and antisense oligonucleotides as efficient tools to determine functional protein/RNA interactions.
Cywoniuk P, Taylor K, Sznajder ŁJ, Sobczak K.
Sci Rep. 2017 Dec 14;7(1):17587. doi: 10.1038/s41598-017-17816-x

Insulin Resistance and Diabetes in DM are the Product of INSR Mis-Splicing, Right?

Insulin resistance, impaired glucose utilization by multiple tissues (particularly in skeletal muscle), and multi-systemic consequences of type 2 diabetes mellitus represent impactful metabolic alterations that contribute to morbidity and mortality in DM1 and DM2. Understanding the molecular mechanisms behind insulin resistance will foster better treatments for patients living with DM. It is easy to conclude that we already understand the basis of insulin resistance in DM1—that it is a direct consequence of an already well-established mis-splicing and predominance of the fetal insulin receptor (INSR) transcript. Yet, that assumption has not been directly tested.

The Real Story Appears to be More Complex

An MDF Fellow, Laura Renna, and her colleagues in Milan have recently published a study that provides new insights into the pathogenesis of insulin resistance and diabetes in DM1 and DM2. This research team took the novel approach of evaluating INSR transcript and protein, and the status of downstream insulin signaling pathway components, in DM patient muscle biopsies and myotubes differentiated ex vivo in order to better understand the molecular causes of the metabolic phenotype that characterizes DM.

Despite observation of mis-spliced INSR in all DM1 (65% fetal isoform) and DM2 (50% fetal isoform) muscle biopsies, levels of INSR protein were not reduced when compared with controls. However, basal phosphorylation levels of Akt/PKB, p70S6K, GSK3β and ERK1/2 were altered, indicating potential compromise of signaling pathways downstream of the INSR. In keeping with DM1 pathophysiology, distal muscles (tibialis anterior) exhibited greater signaling pathway impairment than proximal (biceps brachii). 

To facilitate studies aimed at a better understanding of events downstream of INSR protein, the research team utilized DM patient-derived myotubes. In patient myotubes, no differences in INSR protein levels were detected between DM1, DM2, and controls.  But, analyses of glucose uptake showed reduced insulin-mediated stimulation in DM myotubes. Moreover, activation of both IRS1-Akt/PKB and Ras ERK pathways was impaired. Thus, deficits in insulin signaling in DM may not be the sole consequence of INSR mis-splicing, but rather may be due to dysfunction in downstream signaling pathways.

Taken together, the cellular/molecular mechanisms underlying reduced insulin sensitivity in DM may be more complex that has been appreciated. The Milan research team assessed insulin signaling pathways and concluded that perturbations of post-INSR signaling may well be a key factor in development of insulin resistance in DM, irrespective of any changes in INSR transcript splicing. The pathophysiological mechanisms underlying these alterations in post-receptor signaling proteins are currently unknown.

Reference:

Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle.
Renna LV, Bosè F, Iachettini S, Fossati B, Saraceno L, Milani V, Colombo R, Meola G, Cardani R.
PLoS One. 2017 Sep 15;12(9):e0184987. doi: 10.1371/journal.pone.0184987.

Control of RNA Gain-of-Function Versus Toxic RAN Protein Mechanisms

Since the discovery of Repeat-Associated Non-AUG (RAN) translation, the pathogenesis of any disorder that is the consequence of microsatellite expansions must consider two distinct mechanisms—RNA gain-of-function (i.e., toxicity of expanded repeat RNA), toxicity of RAN proteins, or a combination of both mechanisms. For myotonic dystrophy (DM), the toxic RNA mechanism has predominated thus far, as there are only limited reports of the detection of RAN proteins in affected tissues. How these two potential pathogenic pathways in DM are regulated, and whether they may be in any way co-regulated, are currently open questions.

Muscleblind (MBNL) Plays a Key Regulatory Role Over RAN Translation

Dr. Laura Ranum (University of Florida) and colleagues have recently published studies that provide new insights into the regulation of molecular pathogenic pathways in DM2. Through assessments of expanded sense (CCTG) and antisense (CAGG) transcripts in DM2 autopsy brains and in vitro, they demonstrated the occurrence of bidirectional transcription. The research team also showed that transcripts containing a threshold repeat length produce the corresponding poly(LPAC) and poly(QAGR) RAN proteins, with protein production positively correlated with repeat length.  Cytoplasmic poly(LPAC) protein was localized to gray matter (neurons and glia), while poly(QAGR) was found in white matter, primarily in oligodendrocyte nuclei (but also in pathologic regions containing activated microglia). Using in vitro expression studies, the research team showed that both RAN proteins are toxic in neurons by mechanisms unrelated to RNA gain-of-function.

The production of poly(LPAC) protein was reduced or blocked by nuclear foci formation and retention of CCUG expansion RNA by MBNL1 binding. By contrast, CAGG transcripts do not bind MBNL1 and form nuclear foci, but rather are translocated to the cytoplasm, resulting in elevated poly(QAGR) RAN protein (CLIP experiments showed that poly(QAGR) protein does bind hnRNP A1).

A Model for Regulation of RAN Translation in DM2

Taken together, nuclear MBNL1 levels control the relative degree to which mis-splicing and RAN translation products contribute toward the pathogenesis of DM2. If free MBNL1 levels remain sufficient, expanded CCUG transcripts are retained in the nucleus, CCUG-mediated RAN translation is blocked, and disruption of splicing may not reach a level where functional consequences are observed. Depletion of MBNL results in mis-splicing, translocation of CCUG toxic RNA to the cytoplasm, and production of the poly(LPAC) RAN protein and its corresponding pathogenic contributions to DM2. By contrast, the poly(QAGR) RAN protein is not regulated by MBNL1 and it plays a role at least in the brain in DM2. The data supporting linkage of RNA gain-of-function and RAN protein-mediated pathology, and the differential localization of sense and antisense strand products within the brain, provide new insights into understanding the mechanisms underlying the neurologic components of DM2. These findings also support an RNA sequestration failure model as the mechanism for the action of toxic RAN proteins in the brain of patients with DM2.

Reference:

RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2.
Zu T, Cleary JD, Liu Y, Bañez-Coronel M, Bubenik JL, Ayhan F, Ashizawa T, Xia G, Clark HB, Yachnis AT, Swanson MS, Ranum LPW.
Neuron. 2017 Sep 13;95(6):1292-1305.e5. doi: 10.1016/j.neuron.2017.08.039.

AMO Pharma has been conducting a Phase 2a clinical trial of Tideglusib (also known as AMO-02) for adolescents and adults with congenital myotonic dystrophy. Tideglusib is an antagonist for GSK3β, a cell signaling molecule thought to play a role in the pathogenesis of myotonic dystrophy. The AMO clinical trial is a single-blind study of 400 mg and 1000 mg doses of Tideglusib; single-blind means that those conducting the trial know the dose that each patient received and there was no placebo control included in the study. The study is being conducted at Newcastle University.

AMO recently reported interim data from the first cohort of 8 patients who received the 1000 mg dose of Tideglusib. Small, Phase 2a studies such as this are informative as to whether the candidate therapeutic is safe and well-tolerated. AMO reported that no trial subjects withdrew from the study as a result of adverse events or other issues.

Phase 2a studies also are used as a pilot to determine proof of the scientific concept as well as how various study endpoints perform in a particular patient group. Since there have been no prior clinical trials using novel drugs targeted to the brain in congenital myotonic dystrophy (CDM), multiple endpoint measures were explored to help in selection of endpoints for subsequent, definitive trials. AMO reported that data analysis was still ongoing, but that multiple endpoint measures indicated improvements that were statistically significant. With AMO’s focus on developing a drug to address brain manifestations of CDM, some of the endpoints showing improvement included central nervous system symptoms, autistic features and activities of daily living.

AMO Pharma is scheduled to present findings at the upcoming American Neurological Association meeting in San Diego in October. More complete information may be available after that presentation. Based upon these early stage results, AMO intends to launch a larger, multi-site study of Tideglusib in adolescents and children with CMD.

MDF is pleased to see candidate therapeutics moving forward for myotonic dystrophy and appreciates AMO Pharma’s efforts. To date, their results suggest that the drug does not have safety concerns and the positive data from the exploratory endpoints examined here suggest that it could prove effective for CDM. We await the launch and completion of a definitive, multi-site, placebo-controlled controlled trial, the gold standard for the regulatory authorities, for Tideglusib.

GI Symptoms Are an Important Component of DM Disease Burden

The involvement of gastrointestinal functions in all types of myotonic dystrophy is well documented (see MDF’s summary). Common GI symptoms include difficulties in chewing or swallowing, GI reflux, abdominal or chest pain, gallstones, constipation, diarrhea, impaired/painful bowel movements, and incontinence. GI manifestations have been treated by repurposing existing drugs (e.g., mexiletine, metoclopramide, cholestyramine) or behavioral modifications. Awareness of the types and breadth of GI manifestations from appropriately powered studies is vital to inform patient management.

Report on GI Manifestations from a Registry-based Study

James Hilbert and colleagues have reported findings of the frequency, progression and management of GI manifestations using data from the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members. The investigators evaluated Gi manifestations in a cohort of adult patients (913 DM1 and 180 DM2) enrolled in a patient-reported registry, analyzing data collected between 2002 and 2016, with annual updates on registrants.

GI Manifestations Represent a Substantial Factor in the Burden of Disease.

GI involvement was already prevalent among registrants at initial data entry, as 79% of DM1 and 77% of DM2 registrants reported one or more manifestations. Less than 2% of DM1 and none of the DM2 patients reported GI involvement as the first sign of their disease. In order of descending frequency, trouble swallowing, acid reflux, and constipation were most commonly reported for DM1, while constipation, acid reflux, and trouble swallowing were most commonly reported for DM2. Abnormal liver problems were in sufficient numbers (6-8% of DM1 and DM2) to potentially be a factor for clinical trials. As in prior reports of gender differences, female sex was associated with a higher frequency of GI manifestations in both DM1 and DM2 (constipation and gallbladder problems in this study)Analysis of management practices for GI manifestations included 59 medications used in DM1 and 28 medications in DM2. 

Analysis of disease progression in this studied was based on the approximately 50% of DM1 and DM2 registrants with data available at baseline and year 5. For DM1, trouble swallowing (the most frequent symptom at baseline) and acid reflux were the most frequently reported manifestation not previously present at baseline. Likewise, for DM2, manifestations of constipation and swallowing (the first and third most frequent symptoms, respectively, at baseline) were most frequent new reports at year 5.

Better Understanding of Causes, Consequences and Treatment of GI Manifestations Will Require International Collaboration

The research team notes that GI manifestations have complicating consequences for disease management and patient quality of life. Disease duration was associated with GI manifestations, confirming prior findings in DM1. The pathogenic mechanisms and putative biomarkers for many of the GI manifestations are poorly understood—this group noted no association with repeat length—and treatments are symptomatic. Often symptomatic treatments haven’t been systematically studied in DM. Finally, these researchers note the importance of data sharing to assess GI manifestations, and their progression and treatment, across a larger, better powered cohort.

Reference:

High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2.
Hilbert JE, Barohn RJ, Clemens PR, Luebbe EA, Martens WB, McDermott MP, Parkhill AL, Tawil R, Thornton CA, Moxley RT 3rd; National Registry Scientific Advisory Committee/Investigators.
Neurology. 2017 Aug 30. pii: 10.1212/WNL.0000000000004420. doi: 10.1212/WNL.0000000000004420. [Epub ahead of print]

Understanding of the CNS Manifestations Is an Unmet Need in DM

While skeletal muscle biomarkers and clinical endpoints are rightly the current focus of interventional clinical trials in DM1, as they are most likely to inform go/no-go decisions, the CNS burden in DM is considerable and likely requires targeted therapy development programs. Pharmaceutical and biotechnology firms increasingly recognize the need for CNS biomarkers and clinically meaningful endpoint measures, but, likely due to the costs of brain imaging studies, efforts to evaluate brain structural changes with MRI are often modest. A recent review details accomplishments in brain imaging in DM and assesses the path forward to more informative studies.

CNS Imaging Studies May Yield Vital DM1 Clinical Trial Endpoint Measures

Dr. Kees Okkersen and team members at Radboud University Medical Centre and the University of Glasgow have conducted a comprehensive review of published studies that used a variety of imaging methodologies (MRI, functional MRI, MRS, ultrasound, SPECT, PET, and CT) to assess DM1. Their review article in Neurology relies upon a total of 81 cross-sectional and longitudinal studies to draw conclusions about the pattern of changes in the CNS in DM1, to show how they relate to other genetic and clinical parameters, and to provide direction to optimize future studies.

The research team followed a careful search/selection strategy that triaged publications from 1974-2016 in the Embase and MEDLINE databases to include 81 studies, reporting a total of 1,663 DM1 cases, in their analysis. Conclusions were drawn from aggregate analysis of findings from these studies and included comments on the strengths, weaknesses, and overall validity of the various imaging strategies used in DM1. The aggregate data showed widespread structural changes to gray and white matter in cerebral cortex, cerebellum, and basal ganglia, with little evidence of specific regional involvement or sparing; a finding consistent with neuropathologic observations in DM1. Substantial white matter involvement was a consistent feature across studies (with prevalence of 70% in DM1 subjects vs. 6% in controls). Specificity in cortical region involvement was seen across the 7 PET studies that met inclusion criteria; these findings were supported by SPECT studies (n = 5). Findings of fMRI studies supported personality and social cognition patterns seen in DM1.

Overall, the aggregate analysis supported some correlations between findings from brain imaging and genetic/clinical features. If clinical trial endpoints are to be developed, it is essential to understand the natural history of the structural and functional changes in the brain in DM1. The research team, however, observed that only 3 of the 81 studies that qualified for their analysis were longitudinal imaging studies. Such studies were deemed to be particularly important since some of the imaging changes in DM1 are associated with normal aging and it will be important to understand whether DM1 pathophysiology starts within specific brain regions before generalizing. 

Taken together, this review of brain imaging provides careful selection and analysis of completed studies in DM1. Sufficiently powered longitudinal studies represent a clear need for the field. Given the high costs of such studies, a consortium approach with an agreed upon data collection, sharing, and analysis protocol is likely the best path forward to understanding and developing therapies for CNS manifestations of DM1.

Brain imaging in myotonic dystrophy type 1: A systematic review.
Okkersen K, Monckton DG, Le N, Tuladhar AM, Raaphorst J, van Engelen BGM.
Neurology. 2017 Aug 2. pii: 10.1212/WNL.0000000000004300. doi: 10.1212/WNL.0000000000004300. [Epub ahead of print] Review.

Impact of DM1 on the Brain

DM1 is characterized by involvement of multiple organ systems, raising challenges for understanding disease mechanisms, development of effective disease management strategies, and designing effective and testing therapeutics. The disease burden and unmet need represented by the CNS sequella of DM1 have received insufficient attention to date. Recent efforts by MDF, including the Consensus-based Care Recommendations for Adults with DM1 and the recent session at the 2017 MDF Annual Conference, “Bringing the Patient Voice to CNS-Targeting Drug Development in Myotonic Dystrophy” are important efforts to address this challenge. Given the impact on the brain, a key part of the challenge is understanding how aware are patients of their own disease and to what extent can they assist researchers in improving management and therapy of DM1?

A New Study of Disease Awareness in DM1

Dr. Sigrid Baldanzi and colleagues at the University of Pisa have published results from a cross-sectional study of 65 adult-onset DM1 patients, assessing cognitive function and quality of life. Specifically, the research team was interested in determining how cognitive dysfunction and neuropsychological manifestations of DM1 impacted the patient’s awareness of their own disease—a phenomenon known as anosgnosia or lack of insight.

Anosgnosia, and the consequent reduced patient participation with caregivers, can impact DM1 in multiple ways-- diagnosis can be delayed, lack of awareness and misattribution of the causes of their symptoms can occur, and patient compliance with treatment impacted. To better understand patient awareness in DM1, the research team used a battery of endpoints to assess clinical and neuropsychological status, quality of life, and disease unawareness. The team defined disease unawareness as “an altered ability to recognize the presence or appreciate the severity of deficits in sensory, perceptual, motor, affective, or cognitive functioning.”

The cognitive profile of study subjects was heterogeneous, but executive functions, cognitive flexibility, conceptualization, and visuo-spatial memory tasks ranked below matched control subjects. Assessment of quality of life using INQoL revealed only a mild impact of the patient’s disability. In assessing patient awareness of the impact of their disease, those with mild motor involvement frequently understated their degree of motor impairment in comparison to physician-rated (MIRS) motor abilities. For approximately half of the cohort, discrepancies were noted between patient INQoL ratings and caregivers reports of disease impact. Patients underreported psycho-social difficulties, including their independence and social relationships, when compared to caregiver reports. Patients did not exhibit deficits in awareness of emotional aspects as detected by INQoL.

The research team concluded that DM1 patients did not experience generalized disease unawareness, but rather that unawareness of particular psychosocial and behavioral deficits were present in over half of their cohort. They hypothesize a linkage between anosognosia and brain dysfunction in DM1 and suggest that the terminology “social cognition dysfunction” captures the disease unawareness seen here. Indeed, understanding of the specific features of anosognosia in DM1 may help elucidate its underlying neuroanatomical correlates.  

Finally, the research team noted that analytic tools for anosognisia must be tailored for specific diseases and suggest that patient/caregiver discrepancies in INQoL scores form the basis for such a tool for DM1.

Reference:

Disease awareness in myotonic dystrophy type 1: an observational cross-sectional study.
Baldanzi S, Bevilacqua F, Lorio R, Volpi L, Simoncini C, Petrucci A, Cosottini M, Massimetti G, Tognoni G, Ricci G,Angelini C, Siciliano G.
Orphanet J Rare Dis. 2016 Apr 4;11:34. doi: 10.1186/s13023-016-0417-z.