Tackling DM from Basic Research through Clinical Care

Tetsuo Ashizawa, MD, better known as "Tee" to colleagues and patients, has focused his career on the search for treatments for myotonic dystrophy (DM). As one of seven primary investigators who will participate in the first clinical trial of a potential treatment for DM1, Dr. Ashizawa may be closer than ever to achieving that goal. Yet in addition to pursuing research with dedication and tenacity, he has also been committed to providing the best possible care to people living with DM. Dr. Ashizawa's engagement in myotonic dystrophy spans basic research, translational science, patient-oriented research and clinical care.

Originally trained in neuromuscular diseases, Dr. Ashizawa first became involved in DM as a basic researcher, working with a team at Baylor College of Medicine to hunt for the DM gene. "There were actually several teams working internationally to find the gene," said Dr. Ashizawa. "Interestingly, in 1992 the various research teams all had the same finding, which was identification of DMPK, the genetic mutation responsible for myotonic dystrophy type 1. It was an exciting time, and that was the beginning of our journey to find treatments and a cure."

Patients Play a Key Role with Researchers

In 1998, as Dr. Ashizawa was expanding his research efforts, he received an email that would broaden his perspective. Shannon Lord, the mother of two boys with juvenile-onset DM1, wanted to make a donation to advance DM research. She provided a grant to Dr. Ashizawa through the Hunter Fund, an account named after her older son and established by Shannon and her husband Larry to support DM research projects. The grant was the start of a long-term friendship between Dr. Ashizawa, Shannon and Larry Lord, and ultimately led to a DM scientific meeting organized by Dr. Ashizawa and including the Lord family. "It was so powerful," said Dr. Ashizawa. "Before this meeting, many in the scientific community only saw DM through a microscope. Now investigators could see and understand the human face of the disease. It was a real morale booster for everyone and provided a great deal of momentum to move our work forward."

By then Dr. Ashizawa had also co-founded the International Myotonic Dystrophy Consortium (IDMC) to bring together scientists and clinicians focusing on DM. Shannon Lord attended the third biennial IDMC meeting in Kyoto in 2001, serving in the role of patient advocate and introducing patient advocacy to the IDMC research community. By the fourth meeting, about one hundred patients and families attended, and the participation of a large number of patients at these international meetings has since become routine. Today, IDMC meetings provide a unique opportunity for global researchers, clinicians and patients to come together; IDMC 10 will be held next June in Paris, France. "Without patient involvement, we wouldn't be able to push forward on the research frontier," Dr. Ashizawa said.

Research Moves Out of the Lab

By 2011, DM science had progressed significantly in the development of potential treatments for DM1. Seven research and clinical institutions around the country are currently preparing to launch the first clinical trial in affected patients to test the efficacy of an antisense oligonucleotide (ASO) therapy, DMPKrx, in people affected by DM1. The University of Florida (UF) will serve as one of these sites, with Dr. Ashizawa as the Primary Investigator for the institution.

Dr. Ashizawa has recently started a project looking at DM1 patient-derived, induced pluripotent stem cells (iPSCs), which can be developed into different cell types needed for research, e.g. muscle, heart, or even brain cells. These cells can help researchers understand how DM affects different body systems and causes disease symptoms. While the clinical use of these cells may be a long way off, iPSCs have a more immediate and critical function as a platform for the screening of compounds to find drugs that have therapeutic potential in DM1. "It's a very exciting time in DM research," Dr. Ashizawa says.

Providing Multidisciplinary Care in the Clinic

In addition to his research projects, Dr. Ashizawa oversees the clinical program at the University of Florida. Patients benefit from a multidisciplinary team of doctors that includes cardiologists, anesthesiologists and geneticists. "We help patients access any clinical trials for which they may be eligible," he says. "And when new treatments become available we are committed to helping our patients access them as soon as possible."

Dr. Ashizawa has published over 190 research papers and 35 book chapters. He is currently Executive Director at the McKnight Brain Institute at UF and Professor and Chair of the Department of Neurology at the UF College of Medicine, and he serves on MDF's Scientific Advisory Committee. With Drs. Maurice Swanson and S.H. Subramony, he has recruited Dr. Laura Ranum to UF and is in the process of recruiting a handful of other key DM investigators to build one of the strongest DM research teams in the world. "We are very hopeful about the research and treatment possibilities on the horizon. We have a distance to go and there are many questions to answer, but we won't stop working," says Dr. Ashizawa. "We are dedicated to our patients and to collaborating with them to find a cure."

12/09/2014

Dahlqvist et al
European Journal of Neurology

Dr. John Vissing and his colleagues at the University of Copenhagen recently tracked a group of 68 adults with myotonic dystrophy type 1 (DM1), measuring their endocrine function change over 8 years.  The authors examined bloodwork for many endocrine dysfunctions including diabetes (HbA1c blood test), hyperparathyroidism (PTH blood test), and androgen insufficiency (testosterone blood test in men), and found that these dysfunctions became more common over time in people with DM1.  The authors recommend that doctors treating people with DM1 should screen for endocrine functions regularly, as the dysfunctions occurs more frequently in DM1 than the general population.

Click here to read the abstract for this study.

Click here for a PDF of this paper.

10/16/2014

A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor

Researchers from Dr. Matthew Disney's lab at the Scripps Research Institute of Florida, including Suzanne Rzuczek, PhD, a 2013 MDF Fund-a-Fellow grant recipient, recently published an article describing a new chemical they designed to inhibit the unhealthy repeat-containing RNA molecule seen in myotonic dystrophy type 2. This project was supported by a postdoctoral fellowship awarded by MDF. The study describes the design of a pair of molecules that seek out the unhealthy repeat RNA and attach to it. When both of the molecules attach near each other on the RNA, they join together and permanently attach to each other, forming a strong inhibitor of the RNA. The authors state that they are "using the cell as a reaction vessel and a disease-causing RNA as a catalyst." By this they mean that only cells that have the large DM2 repeat-containing RNA will create their own chemical to inhibit the negative effects of the DM2 RNA. They were able to show that their chemicals reduced the number of unhealthy RNA clumps found in DM2 cells, and were able to partially reverse the improper processing that normally occurs in those with DM2 as a result of the unhealthy RNA.

Click here to read the full article. You can also view a presentation from the 2014 MDF Annual Conference by Dr. Rzuczek where she discusses this research.

09/25/2014

Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, has prepared the following summary of the recently published study, "Parental Age Effects, But No Evidence for an Intrauterine Effect in the Transmission of Myotonic Dystrophy Type 1" in the Journal of Human Genetics. 

Researchers from the laboratories of Fernando Morales from the University of Costa Rica, and Darren Monckton from the University of Glasgow collaborated in a recent study examining how the DNA mutation causing myotonic dystrophy type 1 (DM1) worsens from one generation to the next. Previous studies have shown that the DM1 mutation behaves differently depending on whether it is passed on from the father or mother. However, there has been conflicting information regarding whether the age of the parent’s symptom onset or parent’s age at conception of their affected child can change the degree to which the child is affected by DM1.

The conflict in research findings is likely the result of using different methods to assess the size of the DM1 mutation, and failing to account for the age of the parent at the time the blood was collected, since the mutation grows throughout their lifetime. This study uses a newer technique called "small pool PCR" to assess the mutation size, and a complex statistical analysis to predict what the original size of the repeat was at birth. This method clarified the relationship between parent and child with regard to CTG repeat size and symptom onset, confirming that children born with DM1 have an inherited repeat that is larger than their parent’s repeat about 95% of the time, and symptom onset comes earlier in the child than their affected parent around 86% of the time. Furthermore, the parent’s age of onset is correlated with the child’s age of onset, but the correlation is much stronger in affected mothers than fathers.

What really stood out in this paper was a completely new finding that the age of the affected parent at conception correlates with the repeat size in their child. In other words, as people with DM1 age, the size of the repeat in their eggs or sperm grows larger. Basic genetic principles dictate that there is a 50% chance of an affected parent passing on the mutation to their child.

This paper found that if the child inherits the mutation from their mother and gets DM1, there is a 64% risk of the child’s DM1 being congenital if the mother’s repeat size is above 164 CTGs. There are very few cases of an affected father having a congenitally affected child, and none were found in this study. Unfortunately, current procedures for diagnosing DM1 do not use the same experimental method as in this paper and do not predict what the individual’s repeat was at birth. Therefore this predicted risk cannot be applied to mothers whose repeat was sized using conventional methods for diagnosis.

The authors estimate that the diagnostic test most women get to determine the size of their repeat would also predict that if their offspring inherit the expanded repeat, they would be congenitally affected 64% of the time when the mother's repeat length is over 284 CTGs.

Genetic counseling for families with DM1 can be very complicated, as many factors such as the repeat size and sex of the DM1-affected parent can alter any predictions as to how severely a child may be affected. Overall, this study clarifies how the growing repeat size in adults with DM1 can affect their children, and brings to light a new factor to be considered by genetic counselors when advising families of the risks of transmitting DM1.

Click here to view the article abstract. Click here for an interview on genetic counseling with Carly Siskind of Stanford University Hospital and Clinics.

08/20/2014

A team of researchers at the University of Illinois at Urbana-Champaign recently published the results of a study in which they designed small molecules to combat myotonic dystrophy type 2 (DM2). Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, provided MDF with the summary below. The study was published in ChemMedChem. 

Previous studies have suggested that the main problem in the cells of people with DM2 is an expansion of a CCTG DNA repeat sequence in the ZNF9 gene. This DNA mutation is transcribed into RNA, where it forms abnormal structures that pull other proteins into clumps and prevent them from performing their normal activities.

In this study, researchers redesigned a small molecule that disrupted the improper interaction of repeat-containing RNA with other proteins, but was highly toxic to cells. Their new molecule still disrupted the desired RNA-protein interaction, but was less toxic and was able to enter cells with greater ease.

Future studies will take the small molecules and test them in fruit flies and mice to see if the molecules will be safe in organisms while continuing to disrupt the RNA-protein interaction associated with DM2. Click here to access the abstract and article.

07/23/2014

Expanding the Scope of DM Research

A little over three years ago, MDF awarded a grant to support the establishment of the first-ever Myotonic Dystrophy Clinical Research Network (DMCRN). Based on input from university researchers and pharmaceutical companies, MDF felt it was critically important to expand the scope of DM research and prepare for upcoming trials of potential treatments.

Developing Targeted DM Treatments

A targeted treatment is one that is tailor-made and specifically designed for a particular disease. Targeted treatment development is a lengthy process that involves at least nine different steps. The targeted treatment development process for myotonic dystrophy was started when the DM1 genetic mutation was discovered in 1992, and continued with the identification of the DM2 mutation in 2001. The pace of scientific discovery has accelerated significantly in recent years. Isis Pharmaceuticals is scheduled to begin testing the first targeted treatment in DM patients later this year, with more options from other industry members to follow in the future. While it is likely that progress in treating DM will come in several steps rather than one giant leap, and the best treatment approach may involve a combination of drugs to best meet individual patient needs, this accelerated progress has been very encouraging.

Why We Need the Network

Testing a new drug involves a series of studies, called clinical trials, that are designed to answer several key questions:

• Does the drug have a beneficial effect? If not, why not?
• What benefits can the drug provide and what are the potential side effects?
• If the drug is effective, what is the best dose? How long does it last? When should it be started?

To answer these questions we need reliable testing procedures with proven accuracy, and a group of research sites to monitor the treatment and carry out the measurements. The testing procedures must be carefully selected and standardized, and the teams at each site should have extensive experience using the procedures to ensure that test results are consistent. The Clinical Research Network is focused on making this happen.

Goals of the DMCRN

1. To develop research teams at each site, with team members who are committed to myotonic dystrophy and experience with the research procedures.
2. To learn more about DM - there is still much we don't know. For example, researchers do not have a detailed understanding of why myotonic dystrophy is so variable from person to person, what controls the size of the repeat expansion, or what exactly leads to the muscle weakness, gastrointestinal symptoms, or central nervous system effects.  Answering these questions will help researchers undestand how people respond to therapies and may lead to the design of new targeted treatments.
3. To collect additional data needed for clinical trials, including:

• ​Outcome measures (how the success of a trial will be measured)
• Disease progression (how and why DM becomes more severe over time)
• Biomarkers (something in a cell or body tissue that can help indicate the presence of a disease like DM, and help measure changes in that disease due to the effects of a drug)
• Endpoints (outcomes of drug treatment that demonstrate whether a drug is effective, e.g. improved strength, interrupted disease progression, etc.)

A major focus in setting up the DMCRN was making sure that all researchers in the Network would have free and unrestricted access to the data collected through DMCRN studies, and that they would all be able to publish the results of these studies. In addition, DMCRN stakeholders committed to making access to study results available to researchers across the US and the world, in both the academic sector and in industry. The objective with these Network design decisions was to help lower barriers to advancing DM science and research, and continue the remarkably collaborative and friendly research environment that has been a hallmark of the DM research community to date.

DMCRN Members

The DMCRN is comprised of eight medical centers with significant proficiency in myotonic dystrophy clinical care and research. The current DMCRN sites are:

1. University of Florida McKnight Brain Institute - Dr. S. Subramony,  Primary Investigator
2. University of Kansas Medical Center Research Institute - Dr. Richard Barohn, Primary Investigator
3. Ohio State University Medical Center, Dr. John Kissel - Primary Investigator
4. Stanford University School of Medicine, Dr. John Day - Primary Investigator
5. University of Rochester - Drs. Richard Moxley and Charles Thornton, DMCRN Primary Investigator
6. National Institutes of Health - Dr. Ami Mankodi, Primary Investigator
7. University of Utah - Dr. Nicholas E. Johnson - Primary Investigator
8. Houston Methodist - Dr. Tetsuo Ashizawa - Primary Investigator

The University of Rochester is the lead DMCRN site, with Dr. Charles Thornton as the DMCRN PI. Data from the DMCRN studies are processed in the Data Management Center at Rochester, as is analysis of tissue and blood samples from the current DMCRN study. While Dr. Thornton and the University of Rochester initiated the current DMCRN research study, future studies may originate from any of the sites. Other DMCRN sites may be added in the future.

DMCRN Funding

DMCRN financial support has come from a broad consortium of stakeholders in the DM community. These include MDF, along with other patient advocacy organizations such as the Marigold Foundation and the Muscular Dystrophy Association; the National Institutes of Health (NIH) through their support of the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center in Rochester; and industry, through support from pharmaceutical company Biogen Idec.

DMCRN Activities and Progress

Since the Network's launch last year, DMCRN researchers have initiated a number of projects to achieve the goals described above. Standardized equipment to measure myotonia and muscle strength is now in place at all DMCRN sites, and training sessions for research coordinators and evaluators have been carried out. Research teams at each site now have experience with specialized measurements of muscle strength and myotonia and the procedures used to obtain biopsy samples of muscle tissue. A study of biomarkers was completed and published in December 2013 and a study to select biomarkers for use in clinical trials is currently underway. The Network has launched a longitudinal (long-term) study to track the progression of DM over time in 100 patients.

What's Next

The DMCRN is moving forward quickly, and meeting the interim goals established for the first 3-5 years. Equally hopeful, the drug development pipeline continues to grow with additional pharmaceutical companies engaging in DM treatment development. The establishment of the DMCRN and other infrastructure projects like the Myotonic Dystrophy Family Registry, the University of Rochester FSHD and DM Registry, and DM biobanks are demonstrating to pharmaceutical and biotech companies that myotonic dystrophy is a good bet for drug development. Overall, DMCRN members are very pleased with the progress they have achieved with the Network. In the words of DMCRN Primary Investigator Dr. Charles Thornton, "The pieces are falling into place, and we hope that the DMCRN will prove to be a historic partnership of industry, advocacy groups, academic researchers and government to develop a truly effective treatment for myotonic dystrophy."

07/23/2014

Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.) announced today that it has launched a Phase 1 clinical trial for IONIS-DMPKRX. Ionis earned a $14 million milestone payment from Biogen Idec associated with this achievement. IONIS-DMPKRX is designed to reduce the production of toxic dystrophia myotonic-protein kinase (DMPK) RNA in cells, including muscle cells, for the treatment of Myotonic Dystrophy Type 1 (DM1).

"[IONIS]-DMPKRX is an example of the broad applicability of our antisense technology to develop novel drugs to treat patients with severe and rare disease. IONIS-DMPKRX is the first drug to enter our pipeline that is designed to target a toxic RNA, the first systemically administered drug to enter development from our Biogen Idec partnership and the second generation 2.5 drug to enter clinical development," said C. Frank Bennett, Ph.D., senior vice president of research at Isis.  "Myotonic dystrophy represents an ideal opportunity for antisense as the disease-causing gene produces a toxic RNA, which is not accessible by traditional therapeutic approaches but is uniquely accessible with our antisense technology. We look forward to rapidly advancing the development of IONIS-DMPKRX."

"Our collaboration with Biogen Idec has been very productive. [IONIS]-DMPKRX has rapidly advanced to the clinic, and we continue to make progress across the board in our drug discovery programs with Biogen Idec. All of these successes advance our neuromuscular disease franchise and translate into the potential for significant revenue as our drugs and programs progress," said B. Lynne Parshall, chief operating officer at Isis.

DM1 is a rare genetic neuromuscular disease characterized by progressive muscle atrophy, weakness and muscle spasms. DM1, the most common form of muscular dystrophy in adults, affects approximately 150,000 patients in the US, Europe and Japan. Patients with DM1 have a genetic defect in their DMPK gene in which a sequence of three nucleotides repeats extensively, creating an abnormally long toxic RNA, which accumulates in the nucleus of cells and prevents the production of proteins needed for normal cellular function. The number of triplet repeats increases from one generation to the next, resulting in the possibility of more severe disease in each subsequent generation. There are currently no disease-modifying therapies that address more than one symptom of the disease. IONIS-DMPKRX is designed to improve the underlying genetic defect that causes DM1.

"Myotonic dystrophy is a progressive and debilitating disease that affects thousands of patients for whom there are no direct therapeutic options. The innovative science behind IONIS-DMPKRX is compelling and targets the underlying genetic defect that causes myotonic dystrophy," said Molly White, executive director of MDF. "IONIS-DMPKRX has a chance to fill the therapeutic void for DM1 patients and transform the hopes and futures of thousands of patients and families."

07/09/2014

A recently released study identifies the gene that may be responsible for increased side effects in DM2 patients taking statins to lower cholesterol. Katharine Hagerman, PhD, Research Associate at Stanford University Neuromuscular Division and Clinics, provides MDF with a summary of the study conducted at the University of Helsinki in Finland.

Abnormal Splicing of NEDD4 in Myotonic Dystrophy Type 2: A Possible Link to Statin Adverse Reactions
Screen M, Jonson PH, Raheem O, Palmio J, Laaksonen R, Lehtimäki T, Sirito M, Krahe R, Hackman P, Udd B.(June 4, 2014).
American Journal of Pathology. e-publication ahead of printing.

A research study headed by Dr. Bjarne Udd at the University of Helsinki recently described biological pathways affected in both myotonic dystrophy type 2 (DM2) and hyperlipidemia (a medical condition most often characterized by high cholesterol or high triglycerides). Previous studies have shown that 63 percent of people with DM2 have high cholesterol, as well as 41 percent of people with DM1. Statins, a class of drugs used to lower cholesterol levels, are commonly prescribed to treat hyperlipidemia, elevated levels of lipid proteins in the blood, as they can block the action of a liver chemical that helps create cholesterol.

One of the side effects of statins is the development of myopathy, including muscle pain, weakness, and cramping. Approximately 5-10 percent of individuals taking statins can develop these symptoms. Individuals with DM have an increased incidence of myopathic side effects when taking statins, and there are many documented cases where statin-induced myopathy is the first muscle symptom experienced in adults eventually diagnosed with DM2.

In order to identify biological pathways that may be affected by both DM2 and statin therapies, these researchers looked at genes that were regulated differently in healthy muscles compared to DM2 muscles and statin-treated muscle cells. They identified a gene, NEDD4, that had increased expression in DM2 (and DM1), and decreased expression in statin-treated individuals with no muscle condition. Furthermore, they showed that the NEDD4 gene was processed differently in DM2 muscles, and made a few different forms of the protein that weren't seen in healthy muscles. The authors suggest that biological pathways involving NEDD4 may be altered in DM, and may be associated with increased statin side effects. According to DM2 research reviews, statins do not have to be avoided. However, if statin treatment produces or amplifies muscle symptoms, there may be other drugs available to combat hyperlipidemia that do not have these side effects in individuals with DM.

07/01/2014

What is the Stanford Biobank?

The Stanford Myotonic Dystrophy Biobank is a collection of biological samples from donors for scientific research. The Biobank stores samples such as blood, muscle, skin, spinal fluid, and other clinical specimens. The Biobank collects tissues from people with myotonic dystrophy, related neurological disorders, and unaffected family members. Samples can be collected with your consent during routine clinic visits, during scheduled surgical procedures, or after death with your family's consent. The Biobank then organizes and stores these samples so that they can be shared with scientists throughout the world for research. These samples are tremendously valuable in helping determine how myotonic dystrophy affects the body, which will in turn help develop meaningful treatments. This resource facilitates the involvement of subjects with myotonic dystrophy to assure researchers have access to necessary samples.

How do I enroll?

Enrollment in the Stanford Myotonic Dystrophy Biobank is relatively easy, and requires you to fill out two forms. The first form is the Intended Donor Information Form containing your personal information, and contact information for your next-of-kin and primary healthcare provider. The second form is the Research Consent Form which allows you to formally state your intent to allow the Stanford Neuromuscular Program to collect your tissue samples for research purposes. Individuals who intend to have their remains donated through an autopsy after their death should include information about their funeral home on the Intended Donor Information Form; the mortician can be very helpful in facilitating an autopsy. The Research Consent Form contains both your signature, and the signature of your next-of-kin, which will help assure your family of your intent. For an autopsy to occur, however, a consent form from the institution performing the autopsy will need to be signed by the next of kin after death. The Biobank recommends that you make several copies of these signed forms and store them in your personal records. You should also give copies to your family, next-of-kin, primary healthcare provider, and designated funeral home. The Biobank team also recommends that you include your Research Consent Form in any medical directive, will or living will. You should mail Stanford the original copies of both forms. If any of the contact information changes, Stanford asks that you update them by emailing or calling the non-emergency contact information below.

How will my donated sample be used?

The donated samples will be stored at Stanford for future research. Qualified researchers who require samples will apply to the Biobank, submitting a description of their research project and proof of institutional approval. Samples given to researchers will have all personal identifying information about the donor removed, and will simply include information about the medical condition of the donor (see privacy question below for more information). Stanford will not be able to provide families with information about where or how individual donor specimens are used, but is happy to provide general information about projects and publications that have used Biobank samples.

What are the benefits of enrolling?

Myotonic dystrophy is relatively uncommon, so researchers have difficulty procuring the samples they need for investigations. By donating to the Stanford Myotonic Dystrophy Biobank, you will help researchers make scientific discoveries that may ultimately benefit individuals with the condition that affects you and your family. The Biobank research team will take care of all arrangements, and any costs of donation, once you have notified them.

How will my privacy be protected?

All identifying information recorded in the Intended Donor Information Form and Research Consent Form will be stored at Stanford and not released to any other researchers. When samples arrive at the Biobank, they are labeled with a unique identifying number. The Biobank team will ask for specific medical information that will be associated with the specimens, but only Dr. Day and his direct team will have access to the identifying information linked to the unique ID number. Samples shared with researchers will only have the ID number, description of the type of sample/tissue, and characterization of the donor's condition. If at any time you no longer wish to be enrolled in the Biobank, you can contact the Biobank by email or phone and your information and samples will be immediately removed from the Biobank system.

How do I donate?

If you are scheduled for a procedure you believe may produce samples for donation, you can email or phone the non-emergency Biobank contact below to make arrangements for specimen collection. If you are the next-of-kin, primary healthcare provider, or funeral home representing a person enrolled in the Stanford DM Biobank for autopsy donation and you believe death is imminent, contact one of the Biobank staff members listed below. A single phone call is typically all you will need to make; the Biobank team will take care of the rest of the arrangements. After the family member’s death, the next of kin will have to provide consent for the autopsy at the institution providing that service. The autopsy is performed as soon after death as possible, usually within 24 hours. After the autopsy is completed, the remains are returned to the mortician. Care is taken throughout the procedure to preserve normal appearance, so that there is no restriction on the type of memorial service available to the family.

Who can I contact for more information? 

If you have questions, contact the Biobank team using the information below. 

Contact Email: stanfordbiobank@lists.stanford.edu

Biobank enrollment: (650) 497-9807

Dr. Day’s Lab: (650) 723-9574

For urgent matters you may call: 

Katharine Hagerman, PhD
Lab: (650) 723-9574

Shirley Paulose, MS
Office: (650) 724-3792

John W. Day, MD, PhD
Office: (650) 725-7622

 05/16/2014

Interesting Findings Reported in Recent DM Research Studies on Sleep Disturbances

Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, provides a summary of a recent DM2 sleep survey that has drawn criticism from international DM experts in Italy.

Restless Legs Syndrome and Daytime Sleepiness are Prominent in Myotonic Dystrophy Type 2
EM Lam et al; 2013, Neurology 81(2):157-64

A recent study headed by Dr. Margherita Milone from the Mayo Clinic in Minnesota outlining sleep disturbances in those with myotonic dystrophy type 2 (DM2) has drawn criticism from a group of international experts in Italy headed by Dr. Gabriella Silvestri.

Dr. Milone’s study examined the frequency of sleep disturbances by analyzing surveys filled out by 30 people with DM2, and 43 unaffected individuals. Her study found that those with DM2 had more clinically significant reports of daytime sleepiness, fatigue, altered sleep quality, and restless leg syndrome. Surprisingly, the study also found that obstructive sleep apnea was not a frequent sleep disturbance in DM2, going against previous small studies by Dr. Silvestri and others that estimated the prevalence of obstructive sleep apnea to be between 60% and 67% in DM2. 

Though Dr. Milone’s study was able to assess a larger number of affected individuals than other studies, Dr. Silvestri pointed out that it relied on paper-based surveys instead of more reliable clinical measurements from sleep monitoring.  Overall, studies on sleep disturbance in DM2 highlight the need for overnight and daytime sleep studies when individuals have symptoms that may stem from sleep issues, preferably performed in a sleep clinic that is able to differentiate between obstructive and central sleep apnea, along with assessing for sleepiness, fatigue, other forms of hypoventilation, periodic limb movements of sleep, restless leg syndrome, and REM sleep abnormalities.  

For the article abstract click here.