Research

New Findings on Quality of Life in DM2

Published on Tue, 06/07/2016

There has been relatively little research on quality of life for DM2 patients, and DM2 is often considered “less severe” than DM1. However, a new study identified a subset of DM2 patients who are impacted as severely as those with DM1.

Dr. Dusanka Savic-Pavicevic and colleagues recently published a comparison of genetically confirmed DM2 and DM1 patients using a variety of quality of life measures.

The research team found no differences between DM2 and DM1 in the overall and physical composite scores of the survey.

Emotional and mental composite scores were typically better in DM2 patients, as were independence and body image scores. Disease impact on cognition, strength, heart function, breathing and cataracts were also less severe in DM2.

The DM2 patients who reported worse scores were typically older, weaker, and had higher fatigue levels than the DM2 patients who scored better on certain segments of the surveys. Lower quality of life scores were also associated with lower cognitive achievement, memory impairment and lower educational levels.

A deeper understanding of the correlation of age, strength, and fatigue with quality of life in DM2 is needed to facilitate better patient outcomes. More DM2 studies like this will pave the way for higher quality care.

Reference:

Quality of life in patients with myotonic dystrophy type 2.
Rakocevic Stojanovic V, Peric S, Paunic T, Pesovic J, Vujnic M, Peric M, Nikolic A, Lavrnic D, Savic Pavicevic D.
J Neurol Sci. 2016 Jun 15. 

Applying Gene Editing Technology to RNA Diseases

Published on Wed, 05/18/2016

“CRISPR-Cas9" (pronounced "crisper") is an acronym for the full name of a new cutting edge, gene-editing technology: “Clustered Regularly Interspaced Short Palindromic Repeat - Cas9". 

CRISPR-Cas9 has garnered wide research interest for its capacity to target and correct disease-causing mutations. A naturally occurring gene editing technology, it was first identified in bacteria, which use it to protect against invasive viruses. 

CRISPR and DM 

DM is a disease of RNA processing, and understanding RNA binding proteins is at the core of understanding DM. It is the reduced availability of the RNA binding proteins muscleblind and CUGBP1 that cause the alterations in RNA splicing leading to many, if not all, of the signs and symptoms of DM.  

New Breakthroughs in Targeting RNA from University of California

Dr. Gene Yeo’s lab at University of California, San Diego focuses on how gene expression is controlled at the level of RNA, the intermediary step in the DNA to RNA to protein pathway by which genes produce proteins. 

His lab is specifically interested in RNA processing, RNA binding proteins, and how defects in RNA binding proteins cause neurological and neuromuscular diseases like DM.

In a recent publication in Cell and a more detailed commentary on technology development in Bioessays, Yeo and colleagues show that incorporating a fluorescent tag into the CRISPR-Cas9 system allows them to target and track the movements of RNA within individual living cells.  

Importantly, the binding of the CRISPR-Cas9 tracker did not appear to influence the level of RNA or its function, letting it function as an inert tracking tool. We know that proper RNA localization and movement within the cell is essential to faithfully transmit the genetic code into protein synthesis.  

This latest publication offers an opportunity to better understand the disease mechanisms in DM (through precise tracking of intracellular movement of RNA), an essential step in therapy development. 

CRISPR for DM Mouse Models 

Another important use of CRISPR-Cas9 technology is in the development of better DM mouse models to support studies of disease mechanisms and developing therapies. 

This novel gene editing approach allows triplet repeat expansions to be precisely inserted into the mouse DMPK and ZNF9 genes in the same locations the expansions occur in the human genes. MDF is currently working with researchers to improve DM models, including mouse models, and make them available to our research community through this strategy.

The Future of CRISPR

Although there are considerable hurdles to overcome, we will likely see CRISPR-Cas9 technology in clinical trials in the next several years as a novel, potentially disease-mitigating approach.  

Since editing of the genome is involved, unintended consequences could be severe, so the first uses of CRISPR-Cas9 in humans will draw considerable attention from national regulatory authorities like the Food and Drug Administration (FDA) in the US, and the European Medicines Agency (EMA) in Europe.

We look forward to gene editing progress on the use of CRISPR-Cas9 to treat disease, and learning more about the potential for this approach to edit the CTG and CTTG expansions in DM1 and DM2. 

References:

For more information on CRISPR, see a recent New Yorker article, The Gene Hackers.

Programmable RNA Tracking in Live Cells with CRISPR/Cas9.
Nelles DA, Fang MY, O'Connell MR, Xu JL, Markmiller SJ, Doudna JA, Yeo GW.
Cell. 2016 Apr 7. Epub 2016 Mar 17.

Applications of Cas9 as an RNA-programmed RNA-binding protein.
Nelles DA, Fang MY, Aigner S, Yeo GW.
Bioessays. 2015 Jul. Epub 2015 Apr 16.

Rare Chemistry: Matt Disney Advances Development of Small Molecule Therapeutics for DM

Published on Wed, 05/11/2016

Dr. Matt Disney brings an unusual and increasingly valuable skill to therapy development for DM—he’s a chemist. 

Dr. Disney’s background, position and interests give him the flexibility to do exploratory work that leverages the latest advances in RNA biology in order to target the unique disease mechanisms of DM. By focusing on small molecules, his work has the potential to target all organ systems affected by DM and move toward practical applications in treating DM.

Medicinal chemists working on rare diseases at universities or non-profit research organizations, like his home base at The Scripps Research Institute, Florida, are rare, as they usually are based in the Pharma/Biotech sector.  

The NIH has recently awarded two research grants in support of Dr. Disney’s research.  

The first grant is an NIH Director’s Pioneer Award— a program that the NIH describes as supporting “individual scientists of exceptional creativity, who propose pioneering and transforming approaches to major challenges in biomedical and behavioral research.” 

The Pioneer program is extremely competitive, with only 13 Pioneer Awards issued by NIH in 2015. This five-year, $960,000/year award seeks to utilize the defective gene as a catalyst for the synthesis of highly selective therapeutic compounds directly in the affected cells. The approach ensures that the drug will be available in precisely the cells where it is needed, thereby entirely avoiding issues encountered by traditional drug development and delivery strategies.

The second grant award is a renewal of Dr. Disney’s current NIH funding, providing an additional 5 years and $2.5M of support. In this work, he is trying to overcome the limitations of oligonucleotide therapeutics traditionally used to target RNA through the design, synthesis, and evaluation of small drug-like compounds with potent RNA binding capacity. Dr. Disney and colleagues have recently described this novel platform in an article in Bioorganic & Medicinal Chemistry Letters.

Reference:

Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA.
Costales MG, Rzuczek SG, and Disney MD.
Bioorg Med Chem Lett. 2016 Jun 1. Epub 2016 Apr 11.

Gender Matters in DM1

Published on Wed, 05/11/2016

While it has been widely recognized by clinicians treating DM that gender plays an important role in determining disease heterogeneity and progression, there is little hard data to support differential response of males and females to DM.

Dr. Guillaume Bassez and a large team in France and Canada have recently published an analysis of gender as a modifying factor of the DM1 phenotype. In the study, they evaluated 1,409 adult DM1 patients in the French DM-Scope registry. Importantly, findings were validated using additional cohorts from the AFM-Telethon DM1 survey and the French National Health Service Database.

The research team identified clear differences in symptoms detected by gender. Adult males were much more likely to present with “traditional” DM1 signs and symptoms, including muscle weakness and myotonia, cognitive impairment, and cardiac and respiratory involvement. By contrast, adult females had symptoms that were less suggestive of “traditional” DM1, instead showing predominance of cataracts, obesity, thyroid signs, and GI symptoms.  

The differing constellation of symptoms in the two sexes led the research team to conclude that women were often less symptomatic of DM1 and thus often undiagnosed, although this was potentially offset by the finding that women appeared to more often seek specialist care for DM1 symptoms.

Gender matters in DM1. The biologic mechanisms underlying the gender differences that the French group has documented for DM1 are unknown. To improve diagnosis and management of DM1, as well as to better plan for inclusion of both genders in clinical trials, it will be important to understand the factors responsible for the very different onset and progression of DM1 in males and females.

The heterogeneity (variability) that characterizes the clinical manifestations of myotonic dystrophy type 1 (DM1) has been well recognized by physicians, patients, and family members. Although the length of CTG expansions in the DMPK gene correlates with age of onset and severity of DM1, knowledge of other factors that impact progression of DM1 currently is rather limited.  

Intensive analysis of large cohorts of DM1 and DM2 patients are underway to identify both genetic modifiers, gene variants that can speed or slow disease onset or progression, and biomarkers, measurable indicators in blood or other tissues that can be critical for studies of disease progression and clinical trials. 

MDF is partnering with the research community to identify biomarkers and move them toward qualification by the regulatory authorities as drug development tools.

Understanding of the biological factors behind heterogeneity of DM1 is critical to help patients better understand their disease, as well as to help drug developers design successful clinical trials. The studies necessary to identify the underlying factors require large cohorts of affected individuals—for this reason, it is essential that patients become involved in research efforts that build the requisite databases, such as the Myotonic Dystrophy Family Registry

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, and Bassez G.
PLoS One. 2016 Feb.

Molecular Changes Lead to Cardiac Dysfunction in DM

Published on Tue, 04/19/2016

Heart dysfunction is the second leading cause of death for DM patients and affects 80% of the population; yet very little is known about the molecular changes that alter the cardiac conduction system. A multi-disciplinary, international team, representing 25 different academic institutions, recently undertook a massive messenger RNA sequencing project to learn more about this. Their findings provide an important understanding of the molecular basis of cardiac dysfunction in DM and may have immediate implications for how DM patients are treated.

Using biopsy or post mortem samples from DM1 and DM2 patients, the team assessed the identity of mis-spliced genes and correlated the pattern of changes with the cardiac dysfunction seen in these patients. Considerable progress has been made in understanding the molecular events behind the skeletal muscle changes in myotonic dystrophy (DM). The CTG or CCTG expansions (“triplet repeat”) in the DNA of patients with DM1 or DM2, respectively, produce aberrant messenger RNAs that alter the expression of two proteins that regulate gene splicing, muscleblind and CUG-binding protein 1. These changes in splicing regulatory proteins, in turn, cause the mis-splicing of key skeletal muscle genes that, in turn, produce myotonia and muscle wasting.

Until now, we have had very little knowledge of these molecular level events regarding the DM heart. The altered synchronization of the heartbeat (arrhythmias) and altered heart rate (ventricular tachycardia) seen in DM are likely the result of alterations in sodium and potassium ion flux. The propagation of electrical impulses across the specialized heart muscle cells that comprise the heart’s conduction system is dependent upon the flux of sodium and potassium ions across the cardiac cell membrane. Among the DM-related splicing changes in the heart, the research team discovered that a sodium channel gene, SCN5A, was mis-spliced. Specifically, there was a switch from SCN5A messenger RNA containing the normal, adult 6B exon to the fetal 6A exon.

This finding was of particular interest since the 6A exon-containing SCN5A is known to exhibit reduced excitability when compared to the normal adult SCN5A. To establish a connection between the molecular event, the DM-related switch from adult to fetal SCN5A isoform, to cardiac dysfunction, the research team developed a mouse model expressing the fetal, rather than the adult, SCN5A isoform. Notably, these mice exhibited similar cardiac conduction system delays and arrhythmias to those characteristic of DM, thereby providing support for a causal relationship between mis-splicing of SCN5A and cardiac dysfunction.

The mis-splicing of SCN5A explains some important changes in the hearts of DM patients. Mutations in SCN5A have been linked to other cardiac diseases, and there is the potential for repurposing the therapeutic and management strategies used in those diseases to DM. Knowledge of the downstream molecular changes that are responsible for changes in heart function will yield important insights into development of novel therapies for myotonic dystrophy.

It should be recognized that this study would not have been possible without the partnership of DM patients and a large scientific team of investigators. The sharing of expertise and resources that lies behind the success of this study needs to be our continuing model for future progress in understanding and treating DM. For information on other scientific studies currently recruiting, please see the Study and Trial Resource Center.

Reference:

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, Lopez de Munain A, 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.

The Genetics of DM1 Repeat Size

Published on Sat, 04/02/2016

Since its discovery almost 25 years ago, researchers have been working to try to understand the DNA mutation causing myotonic dystrophy type 1 (DM1).

The mutation is known by many names, including “CTG repeat,” “triplet repeat,” “trinucleotide repeat,” “expansion mutation” and many more. Over the years researchers have determined that the mutation is unstable, and most often grows larger in size. Not only does the repeat usually get larger each time it is passed on to children, it can also get larger inside an individual person. 

For example, a common blood test for DM1 taken from the same person several times over many years reveals that the repeat grows slowly over time. It is important to note that a repeat size reported on a genetic test most often reflects an average size, or the most commonly found size of the repeat, it does not represent the size found in every single blood cell. 

Furthermore, the repeat size in the muscles of an individual with DM1 will often be many times bigger than the repeat size found in their blood, making the study of DM1 repeat size a very complicated research field. 

Researchers have puzzled over why the repeat is so unstable, and what drives the repeat to expand so much in some types of cells, and in some people more than others. In order to understand this better, researchers from the University of Costa Rica and the University of Glasgow teamed up to examine the DNA from 199 individuals with DM1 in order to determine what might be driving the repeat to grow. 

This team had previously developed a way to mathematically predict the original repeat size found in an embryo at the time of fertilization, and determined that this predicted repeat size could more accurately predict the age someone with DM1 would first experience any symptoms. In fact, this predicted repeat size was calculated to be responsible for 89% of the variability seen in blood over time. However the remaining forces driving repeat instability were unknown. 

In this recent publication, the same team explored whether there were other genetic factors aside from the repeat that might be inherited, and driving instability. They found that one variation in the genome, inside a gene called MSH3, was strongly connected to an increased amount of instability. 

This gene has previously been connected to the instability of DNA repeats, however this is the first time a naturally occurring variation has been connected to driving instability in people with DM1. Researchers call this variation a “modifier,” because it modifies how the DNA repeat behaves over time. 

Since larger DNA repeats have been previously associated with more severe symptoms, it is possible that future research might show that symptoms can be worse or better depending on which of the two variations of the MSH3 gene you inherit from each of your parents.  

However, that type of study would likely require many more patient samples than this preliminary study of 199 individuals. Interestingly, a study on cancer risk found that this same variation was linked with an altered predisposition to cancer, but the variant that had negative consequences when it came to cancer risk was the variant that saw less instability in DM1. Therefore, this variant can have both positive and negative consequences in humans.

Reference:

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.
Morales F, Vasquez M, Santamaria C, Cuenca P, Monckton DG.
DNA Repair (Amst). 2016 Mar 8.

MDF Research Fellow Profile: Dr. Melissa Dixon

Published on Sat, 04/02/2016

MDF is pleased to announce that Dr. Melissa (“Missy”) Dixon, a Research Associate in the Deptartment of Neurology at the University of Utah, has been awarded a 2016-2017 postdoctoral fellowship.

Dr. Dixon’s research proposal is titled “Evaluation of Functional Connectivity as a Brain Biomarker in Congenital Myotonic Dystrophy.” In this study, she and her colleagues will use magnetic resonance imaging (MRI) to evaluate connectivity networks in the brains of children with congenital-onset myotonic dystrophy (CDM) to see if they differ from those of children without CDM, whether they change over a one-year time period, and whether the MRI results correlate with data from neuropsychological testing.

Dr. Dixon has an extensive background in clinical psychology, neuropsychological testing and clinical trial coordination. She received her doctorate in counseling psychology from the University of Utah in December 2015. We recently talked with Dr. Dixon to learn more.

MDF: There was a time when most children with CDM didn’t survive very long. Do they have a better prognosis now?

MD: Oh, absolutely. I would say that kids with this disorder have a better prognosis than they did a decade ago. We now know that respiratory and feeding problems can be life-threatening, and we’re better equipped to work with those issues from the start.

MDF: What is known so far about the neuropsychology and the brain abnormalities in children with congenital-onset myotonic dystrophy?

MD: Networks in the brain are kind of like a highway system. You can get from Illinois to Colorado by taking Interstate 80, but if there’s a block in that road or a piece of the road that’s missing, you have to take a different route to go around it. 

I don’t know if there are fewer “interstates” in the brains of children with CDM compared to those of children without CDM, but it may be that they’re using more roundabout pathways for getting from one place to another. I think the networks are different [from those in unaffected children.]  

People have used resting-state functional MRI [fMRI] during the resting state [without an attentional focus] to look at brain connectivity in kids who have autism, and they’ve found that it’s sensitive enough to show that there are differences in their connectivity networks. 

Earlier DM studies relied on structural imaging techniques. These can demonstrate a wide range of changes, but they’re not well correlated with clinical outcomes, such as IQ.

We think that by using fMRI we’ll be able to look at connectivity differences in these brain networks and see if they change over time in kids with CDM. 

MDF: Will this study be helpful in telling parents what to expect as their child matures?

MD: We’re hoping to be able to demonstrate changes over time by looking at blood flow in the brain using resting-state fMRI, at baseline and then at a year from baseline.

We’ll be tracking neuropsychological measures, such as executive function and IQ assessment. We’ll also look at adaptive behavior, at how a child is functioning, through a questionnaire that a parent or caregiver will fill out.  At the completion of the study, we would hope to tell parents where a child may have the most learning difficulty, and design interventions to approach those learning difficulties.  

MDF: If you do see abnormalities in connectivity in the brain, what are the possible implications?

MD: We know that cognition is impacted in CDM, but there is not a very sensitive way to see how this changes during the course of a short period of time, like during a drug trial. This technique could become an endpoint for a clinical trial to test the effect of a potential drug or therapy.

MDF: Is it possible that something like, say, DMPKRx, which is being developed by Ionis Pharmaceuticals, could have an effect on the brain, if it could be made to cross the blood-brain barrier?

MD: If not that particular therapeutic, then perhaps another, could potentially slow or halt the progression of the brain changes in this disease as we learn more about them.

MDF: Can you say more about the fMRI study?

MD: We’ll be enrolling 20 participants with CDM, ages 7 to 14, and we already have a control group for comparison. We’re not recruiting yet for the fMRI study; we’re still at the IRB [institutional review board] stage, applying for study approval. We hope to start recruiting in June 2016, and we’ll be posting that on the MDF site when we do. [Studies are listed at the MDF Study and Trial Resource Center under the Current Studies and Trials tab.]

We do, however, have an ongoing study of the natural history of CDM here at the University of Utah, and we hope to recruit some participants for the fMRI study from that group. [The natural history study, which is open, is Health Endpoints and Longitudinal Progression in Congenital Myotonic Dystrophy. Read more about it at the MDF Study and Trial Resource Center under Current Studies and Trials.]

We’ve done neuropsychological testing with the children in the natural history study. The children are all different, and that’s what makes CDM so interesting. The cognitive piece is fascinating. That profile for them is definitely varied, and I think that some of the measures that we’ve been using are just not sensitive enough to understand what’s going on.

I chose 7-year-olds as the lower cut-off age, because they have to stay in the fMRI scanner for 20 to 30 minutes. That can be difficult or scary for any child, and children with CDM sometimes have sensory issues. They’ll have something that’s like a fish tank for them to watch during the scan. It’s not like a movie, where they’d be actively thinking about things, but they’ll be looking at something.

MDF: You have a broad background in clinical psychology. What led you to study children with myotonic dystrophy?

MD: In 2013, when [neuromuscular disease specialist] Dr. Nicholas Johnson came here from the University of Rochester, I became interested in people who have myotonic dystrophy, particularly congenital myotonic dystrophy. I’m interested in understanding the neuropsychological differences in this population. There isn’t a whole lot of known information about congenital myotonic dystrophy and neuropsychological function.

MDF: Did you know that another MDF research fellow, Dr. Ian DeVolder, is doing a study of fMRI in adults with type 1 DM?

MD: Yes, I saw that. That was great to see that someone is doing something very similar in adults. I’m sure our paths will cross as we move forward in our careers. Hopefully, both of our efforts will better define the neuropsychological dysfunction throughout the life spectrum.

Dr. Charles Thornton Wins Prestigious Javits Award

Published on Thu, 03/10/2016

Thornton Receives Prestigious National Science Award

Dr. Charles Thornton, neurologist at the University of Rochester Medical Center and MDF Scientific Advisory Committee member, has been awarded a Javits Neuroscience Investigator Award from the National Institutes of Health (NIH) to further his research on muscular dystrophy. Congress established the Senator Jacob Javits Awards in the Neurosciences in honor of the late Senator Javits (R-NY), who was himself afflicted with amyotrophic lateral sclerosis (ALS).

Javits Neuroscience Investigator Award

The Javits Award (R37) is a conditional, seven-year research grant given to scientists for their superior competence and outstanding productivity. Javits Awards provide long-term support to investigators with a history of exceptional talent, imagination and preeminent scientific achievement. The award is initially for a period of four years, after which, based on an administrative review, an additional project period of three years may be awarded.

Investigators may not apply for a Javits Award. Nominations for this award are made by the National Institute of Neurological Disorders and Stroke (NINDS) staff and by members of the National Advisory Neurological Disorders and Stroke (NANDS) Council. These nominations are then reviewed by the Director, NINDS and the NANDS Council.

Particularly Deserving Investigator

MDF reached out to Charles' longtime collaborator, Dr. Richard Moxley, for his thoughts on Charles and the Javits Award. Dr. Moxley noted that his comments about Charles could go on at length. In brief he noted:

"Charles exemplifies the best in superb clinical research. He is a caring physician, a brilliant scientist with innovative insights, a meticulous, thoughtful investigator, and an excellent team builder -- a critically important component of productive translational research."

He also shared the email that he received from Dr. Glen Nuckolls, Program Director of Extramural Research Program at NINDS. Dr. Nuckoll's comments underscore those provided by Dr. Moxley about Charles:

"This is a much deserved award! The NINDS Advisory Council members were universally enthusiastic about [Charles'] scientific accomplishments, service to the research and patient communities and remarkable track record of peer reviewed applications."

MDF's board and staff join many others in extending our very enthusiastic congratulations to Dr. Thornton for this outstanding recognition, and thank him for his transformative work on myotonic dystrophy research.

Read the University of Rochester Medical Center announcement here.

University of Iowa Launches Brain Imaging Study

Published on Thu, 03/10/2016

The University of Iowa’s DM1 Brain Imaging Research Group is excited to announce that its study (previously in a pilot phase of data collection) has been awarded a grant by the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), to fund a 3-year longitudinal study of adults with a family history of DM1. 

This study seeks to identify, measure and track over time common symptoms and changes in the brain that may be happening to individuals living with DM1 and those at risk for DM1. 

The study is looking for adults aged 18 through 65 years old and living in the US who either:

1)    Have been diagnosed with DM1 after the age of 21 OR
2)    Have not been diagnosed with DM1 but have a family history of DM1 (i.e. are “at-risk” for developing DM1)

Research participants will be invited to come to the University of Iowa, located in Iowa City, Iowa, for three yearly study visits, each lasting about 8 hours. Study participants will be compensated for their time and travel.  

Eligible persons interested in participating should contact Stephen Cross, the Research Associate for this study, directly at (319) 384-9391 or email. Learn more about research trials and studies, and read about Dr. Ian DeVolver's study on the brain

Research Fellow Profile: Dr. Ian DeVolder

Published on Fri, 03/04/2016

MDF has awarded a 2016-2017 postdoctoral fellowship to Dr. Ian DeVolder, Ph.D., a Graduate Research Assistant in the Department of Psychiatry at the University of Iowa Carver College of Medicine. 

Dr. DeVolder’s research proposal is titled “Structural and Functional Connectivity in the Brains of Patients with Adult- and Late-Onset Myotonic Dystrophy Type 1 (DM1): A Potential Biomarker for Disease Progression.” In this study, Dr. DeVolder and his colleagues will evaluate brain structure and function in DM1 and correlate these with measures such as neurocognitive functioning and disease duration. The investigators will study 30 patients with classic adult-onset or with late-onset DM1, ages 21 to 65 years old, and compare them to 30 age-matched healthy controls. 

Dr. DeVolder received his doctorate in neuroscience from the University of Iowa in 2015 and is a graduate research assistant in the laboratory of Peg Nopoulos, M.D., at the University of Iowa Carver College of Medicine. His work at Iowa has focused on the structure and function of the brain in children with clefts of the lip or palate and in children at risk for Huntington’s disease.

“If we can know how and when myotonic dystrophy type 1 affects the brain,” DeVolder says, “we can better time treatment so as to have a neuroprotective effect and try to prevent these brain changes from happening in the first place.” We recently talked with Dr. DeVolder to learn more:

MDF: Your previous work was focused mainly on the brain abnormalities that can accompany clefting disorders, such as cleft lip and cleft palate. [See DeVolder, I., et al., Abnormal cerebellar structure is dependent on the phenotype of isolated cleft of the lip and/or palate, The Cerebellum, April 2013.] How did you move from there into myotonic dystrophy?

ID: It’s definitely been a shift in terms of the clinical population that I’ve been working with. Clefting abnormalities and myotonic dystrophy are not directly related. However, in terms of the basic practice, the basic study we did, they’re actually not that far removed. It’s the same type of imaging techniques, the same type of neuropsychological evaluation.

And, even though my thesis work was with the clefting community, I actually have had a large role in a number of different studies in my lab. Importantly, one of those was our study on Huntington’s disease, which can be thought of as a sister disease to myotonic dystrophy. They’re both trinucleotide repeat disorders, and both previously were thought of as primarily neuromuscular diseases. 

The Huntington’s study was focused on children who were at risk for developing HD. These children had either a parent or grandparent who was affected by the disease. We did a full neuropsychological evaluation, MRI and genetic testing. We were comparing children with the expanded repeat, who, in 30 years or so, will likely develop HD, with those who don’t have the expanded repeat. We were looking at Huntington’s from a developmental perspective to see whether, at an early age, there is something being set in motion in terms of neurodevelopmental changes. Results from this study should start being published within the coming year.

It’s been an interesting shift into myotonic dystrophy. We wanted to model our DM1 study after our Huntington’s study, looking at kids who were not yet showing symptoms but who were at risk for DM1. But we underestimated the role of anticipation in DM1. This is a phenomenon that is seen in Huntington’s but not nearly as frequently and not nearly as severely as in myotonic dystrophy.

We discovered that families with DM1 oftentimes don’t know that they have it or that their children are at risk until they have a child that’s born with an extremely expanded repeat and the congenital-onset or childhood-onset form of the disease. So it’s much harder to identify children with pre-DM1 than children with pre-HD. Therefore, we shifted our focus to adult-onset  and late-onset myotonic dystrophy.

There have been some neuroimaging studies in myotonic dystrophy, but they’ve typically focused on the childhood-onset, adult-onset and congenital-onset forms all together in one group.

We really wanted to focus on one type of DM1, because the congenital-onset and childhood-onset forms seem to be so different in terms of the symptoms they show. We wanted to completely remove that confounding factor. We’re looking at a pretty big age range – 21 to 65 – but it’s still adult-onset DM1. We cut off the age for this study at 65 because we didn’t want to introduce aging effects as confounding factors.

We’re combining concepts from a lot of previous neuroimaging studies. We’re using several neuroimaging techniques and we’re combining those with a neuropsychological evaluation. We’re also making it a longitudinal study, where participants will come back once a year for three years. The study is unique in that sense. It’s the first neuroimaging study in DM1 to combine all of these elements.

MDF: What kinds of brain abnormalities are you looking for?

ID: The brain changes in myotonic dystrophy have been primarily found to be white matter-related. We expect to find some of the things that have already been seen, such as increased numbers of white matter hyperintensity lesions. White matter refers to the myelinated fibers that connect different regions of the brain, and there are variants that you can see on an MRI scan. They’re a little bit unclassified, but basically they’re considered to be abnormal white matter.

We’re also using diffusion imaging, which looks even more specifically at white matter structural integrity. Diffusion imaging measures the movement of water molecules in tissues. It’s a way to see if water is moving along the axon versus going out. From that we can get an idea of the actual shape and structure of the white matter. Typically, white matter in the brain forms tight fiber bundles and tracts, so healthier and better-myelinated white matter would lead to an increase in water movement along the axons, rather than out into the brain. This can be measured by diffusion imaging.

There’s been a fair amount of neuroimaging work in myotonic dystrophy, but there’s been hardly any functional neuroimaging. That’s something I’ve worked with in our studies and something I’ve really wanted to focus on for this population as well.

I was really excited and somewhat surprised when I saw the 2014 paper on functional brain connectivity in DM1. [See Serra, L., et al., Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1, JAMA Neurology, May 2014.]

They found that in patients with DM1 there was increased functional connectivity in certain parts of the brain compared to the control group. Specifically, they found increased network connectivity between the left and right posterior cingulate cortex and the left parietal node when the participant was in a resting state – in other words, not engaged in any specific task. They also found that the DM1 group was more likely to show certain personality traits, such as the presence of fixed ideas, rigidity of thought, and an acute sensitivity to anger or hostility in others, than the control group.

In our study, we’re looking at the resting state, and we’re looking at functional connectivity, but we’re also looking at the developmental component, whether these networks are changing over time and with disease duration.

In resting-state functional connectivity analyses, we’re examining low-level changes in blood flow throughout the brain. You can look at the time course of these blood-flow changes at each individual voxel [volume element] in the brain, and then can compare that time course to all other voxels of the brain. From this you can discover areas of the brain that are showing the same levels of blood-flow changes, with the idea being that those areas that are functionally connected to each other would show a more similar type of pattern to each other in terms of blood-flow. With this data we can examine functional networks in the brain, and how they may be changing in DM1.

In some of the questionnaires that we’re administering, we’re also looking for personality traits that may be typical. We’ll see whether or not we capture the same types of findings as the 2014 study.

MDF: If you do find brain abnormalities, are they necessarily the cause of the cognitive and personality differences sometimes seen in DM1? Could it be that focus on certain thoughts or activities could change the brain? Or could it be that respiratory or cardiac impairment associated with DM1 affect the brain?

ID: I think that if there’s a common pattern of brain abnormalities seen in a population, I would argue that it’s more neurobiologically based rather than the other way around. But it’s a hard thing to parse out. 

In another part of your question, you asked about whether what we’re seeing might not be primary but secondary to some of the respiratory or cardiac issues. It’s an issue that we’ve run into, particularly in the clefting studies that I’ve been involved in. 

A fair critique of that study is that some of the changes we measured may actually be secondary, a response to the things these kids experience at really young ages – like anesthesia during reparative surgeries when they’re not even one year old yet. They are facing these environmental insults at this critical developmental time point. It’s a potential caveat to some of our studies.

I think with myotonic dystrophy it won’t be quite as big an issue. In our screening process, we automatically exclude individuals who have a pacemaker installed, because they can’t go into the MRI scanner. As a result, I think those individuals who would be the most severely affected in terms of the cardiorespiratory symptoms are automatically being excluded from the study.

I think it’s going to be more reasonable in this study to really try and parse out the abnormalities that are directly caused by the gene expansion as opposed to other factors.

Also, we do get a pretty extensive medical history from all our study participants, so potentially we could create within the myotonic dystrophy group some separate subgroups, such as those that are most severely affected by arrhythmias, and see whether or not we are getting the same patterns of brain changes.

MDF: Would finding brain abnormalities in study participants with DM1 have therapeutic implications?

ID: We’re focusing on the longitudinal aspect in these studies. What we’re hoping to find is essentially biomarkers for the disease. These do have important therapeutic implications, but they’re not going to be immediately obvious. 

As for the current drug trials that are going on with Ionis, they potentially could have a lot of therapeutic benefit. However, the drug they’re testing cannot cross the blood-brain barrier unless delivered intrathecally -- via spinal infusion. Right now, the potential drug treatments, which are delivered subcutaneously, won’t actually get into the central nervous system. [Ionis Pharmaceuticals is testing its antisense-based drug IONIS-DMPK-2.5Rx, which targets the abnormally expanded RNA from the DMPK gene in DM1.]

The thing is, we don’t have a good idea of the developmental component of the brain abnormalities in terms of the disease progression itself. Before drug discovery can start moving into that area, we have to know what’s actually happening in the brain. If we can get a better idea of when these changes are occurring and what the changes actually are, we can track disease progression much better, potentially having much better timing of when drug delivery should happen. With optimal timing of drug delivery, these drugs could have a neuroprotective effect and ideally prevent these brain changes before they happen.

MDF: Is your study still open to recruitment?

ID: The study is well under way, but yes, it’s still open. We will continue to recruit new participants over the next few years.

Note: For details about this and other DM studies, go to MDF’s Study and Trial Resource Center and select the Current Studies and Trials tab. The study discussed in this article is Brain Structure and Function in Adults with a Family History of DM1.