The 8th International Myotonic Dystrophy Consortium Meeting (IDMC-8), was an exciting mix of the latest scientific developments and clinical research in types 1 and 2 myotonic dystrophy (MMD1 and MMD1, also known as DM1 and DM2).
The meeting, sponsored in part by MDA, was held in Clearwater, Fla., Nov. 30-Dec. 3, 2011, and drew speakers and attendees from around the world. Some 200 researchers, physicians and students attended; about half the speakers were current or former MDA research grantees and many presenters were physicians associated with MDA clinics.
A separate meeting, EMPOWER 2011, for MMD-affected families, was held at an overlapping time, with a joint session for professionals and families conducted Saturday afternoon, Dec. 3. This session featured research updates, a question-and-answer session, and talks by people with MMD and their relatives.
This joint session was live-streamed on the Internet by MDA, and local MDA offices hosted "viewing parties" around the country for those who wanted to watch together. An archived version of the joint session is available for viewing on MDA's website.
Several presentations examined the molecular mechanisms underlying MMD1 and MMD2.
In MMD1, it's been known since the early 1990s that the underlying genetic defect is an expanded section of repeated DNA sequences called CTG repeats on chromosome 19 in a gene called DMPK. However, the steps between this phenomenon and the many manifestations of MMD1 are still being studied, with an eye to interrupting them to slow or stop the disease.
In MMD2, it's been known since the early 2000s that the underlying defect is an expanded section of repeated DNA sequences called CCTG repeats on chromosome 3 in a gene called ZNF9. Even less is known about the steps between this repeat expansion and the symptoms of MMD2, which are similar but generally milder than MMD1. The secrets of this disease are likewise becoming clearer, though mysteries remain.
Much of the meeting was spent discussing molecular mechanisms underlying MMD1 and MMD2. The theme might be summarized as "it's not just about splicing anymore." For several years, it's been known that the repeat expansions on chromosome 19 in MMD1 and on chromosome 3 in MMD2 affect how several proteins, including insulin receptors, chloride channels and others, are spliced (constructed from their genetic instructions at the RNA level).
But now, new information shows that it's not just splicing but the levels of a protein and localization of a protein that can be affected by repeat expansions. And some new evidence shows that even which proteins are produced may be affected by the repeats.
Tao Zu, in the laboratory of Laura Ranum at the University of Florida in Gainesville, presented new and exciting evidence showing that abnormal protein translation (production of proteins from genetic instructions) appears to be taking place in MMD1 and MMD2 as a result of the repeat expansions in cells. (The Ranum lab has received MDA support.)
Normally, the process of translating genetic instructions into a protein takes place only when a molecular "start signal" tells the cell to begin this process. However, the presence of the repeats on chromosomes 19 and 3 apparently allows protein translation to take place even when a start signal isn't in the code, which could result in production of proteins that are toxic to the cell.
Some time was devoted to discussion of various animal models of MMD. These are mostly mice, but also include fly, worm and zebrafish models of this disease.
These models can be used to understand MMD at the molecular, cellular, tissue and functional levels, and to assess the impact of various therapeutic strategies. Zebrafish are relatively inexpensive to maintain and are very good for screening potential drug treatments for MMD, it was noted.
Chris Chamberlain (from Laura Ranum's lab) gave a particularly exciting lecture on the effects of overexpressing MBNL1 in a mouse model of MMD1. MBNL1 is a protein that's sequestered by the RNA repeat expansion and therefore can't do its normal job (which includes regulating splicing of other proteins) in cells. Treatments based on raising MBNL1 levels and thereby compensating for the loss of MBNL1 are one possibility for treating MMD1.
MMD1 mice with excess MBNL1 showed improvement in splicing, as well as in their myotonia (delayed muscle relaxation) and other skeletal muscle pathology. However, a cautionary note was sounded when Chamberlain explained that overexpressing MBNL1 in the mice apparently caused some central nervous system abnormalities, such as reduced signaling via the corpus callosum, the structure that connects the left and right sides of the brain.
Almost all of the therapeutic avenues now being explored are aimed at either disrupting the interaction between the expanded RNA repeats and various proteins, particularly MBNL; or triggering cellular processes that degrade the repeat expansions.
Antisense, RNA interference, peptides and small molecules all are being tried in preclinical (laboratory) studies. Biotech companies Isis, Prosensa and Genzyme are working with academic investigators to develop therapies for MMD. (For more on antisense and RNA interference, see Defensive Action: Can toxic genes be blocked to treat disease?, Quest, Jan. 1, 2007; and The Future of Antisense: FDA, NIH Talk It Out, Quest, Oct. 1, 2010.)
Not all sessions were focused strictly on RNA and DNA. Many were devoted to the many clinical aspects associated with MMD1 and MMD2.
Chad Heatwole from the University of Rochester (N.Y.) reported on his MDA-supported research into the disease aspects that people with MMD1 say have the greatest impact on their lives.
Heatwole found that the 278 people with MMD1 who participated in the study identified the most troublesome aspects of their disease as (in order): fatigue, limitations in mobility, inability to do specific activities, hand or arm problems, and impaired sleep.
William Groh, an MDA research grantee at Indiana University, and Denis Duboc from the Pierre and Marie Curie University in Paris, each summarized their separate research on the cardiac aspects of MMD1.
Cardiac rhythm abnormalities (arrhythmias) are common in this disease because of degeneration of the conduction system of the heart. Sudden death is not a rare occurrence in MMD1 because of the arrhythmias. Treatments for arrhythmias include pacemakers, which can correct bradycardia (a heart rate that’s too slow), and implantablecardioverter-defibrillators (ICDS), which can act as pacemakers and also can deliver strong shocks in an attempt to correct dangerous tachycardias (fast heart rates).
Groh, who has received MDA funding for his surveillance of cardiac problems in MMD1, suspects that ICDs may be superior to pacemakers in treating this aspect of the disease and would like to conduct a clinical trial to see if this can be confirmed.
Duboc presented his group’s findings, which showed that improved survival and a lower rate of sudden death can be brought about by an invasive cardiac evaluation and monitoring strategy, coupled with prophylactic pacing if signal conduction through the heart is assessed as too slow.
Shahinaz Gadalla from the National Institutes of Health presented findings showing that having either type 1 or type 2 MMD appears to increase the risk of developing cancer, particularly of the colon, brain, endometrium (uterine lining) and ovary.
The study was done by examining records of 1,683 people with MMD (the type was not specified) in Sweden and Denmark.
Maya Das from the University of Maryland presented her group’s data on 911 MMD patients, 86 percent of whom had type 1 MMD. Being female and having MMD1 rather than MMD2 were associated with an increased risk of tumor development in this study.
A number of investigators presented various findings on changes in brain structure and in some aspects of cognition in people with MMD. (For more on this topic, see The Brain in MMD, Quest, Sept. 1, 2008.)
John Day from Stanford University noted that the term central nervous system degeneration, long used to describe brain abnormalities in MMD, actually may be a misnomer. New imaging techniques have revealed that there isn’t much actual loss of neurons in the brain and that the problem may be that neurotransmission (communication of signals among nerve cells) is faulty. If true, this might be a good thing, he noted, as it is potentially more amenable to treatment than degeneration of brain tissue would be.
Stefan Winblad from Gothenburg University in Sweden presented his team’s study of 37 people with MMD1 who underwent comprehensive neuropsychological testing and retesting five years later. A significant decline in test scores was found in 24 of the 37 study participants (65 percent). However, 13 (35 percent) did not decline over the five-year period.
Areas in which test scores declined were attention, verbal memory and visual-spatial construction ability. There was no correlation between decline in cognition, CTG repeat size or other clinical data.
Jeffrey Wozniak from the University of Minnesota presented his group's findings that widespread "white matter" abnormalities occur in the brains of young people with congenital-onset and juvenile-onset MMD1 and that these abnormalities seem to be related to the neurocognitive impairment seen in these individuals. (White matter refers to nerve fibers coated with myelin, which appears pinkish white to the naked eye.)
Nathalie Angeard from Hôpital de la Pitié Salpêtrière in Paris presented some intriguing findings from a literature review of neurocognitive impairment in childhood-onset (not congenital-onset) MMD1. Experts in this field no longer think of childhood-onset MMD1 as associated with global cognitive impairment, Aneard said.
Recent research suggests instead that there is a specific pattern of deficits involving certain types of memory, visual-spatial skills, processing speed and attention. This pattern, Angeard said, could implicate an abnormality of neural circuitry in the frontal (front) and parietal (side) lobes of the brain.
On Dec. 3, the family-centered EMPOWER 2011 meeting, sponsored by the Myotonic Dystrophy Foundation, and the professional-centered IDMC-8 briefly merged. Valerie Cwik, executive vice president-research and medical director at MDA, co-chaired this session, which was live-streamed on the Internet and now is archived on MDA's site at mda.org/IDMC8. Approximately 7,500 people from 30 countries viewed the live stream.
Several people who have MMD or have family members with the disease gave frank and informative talks about their experiences. A call for more understanding of the cognitive and psychosocial aspects of MMD was a theme that surfaced in more than one presentation. Another theme was reducing the time and effort involved in the “diagnostic odyssey” that so many families experience, through better education of physicians and other health care professionals who do not specialize in neuromuscular disease and often don’t recognize MMD when they see it.
Clinicians and researchers answered several questions submitted by families at the conference and via the Web. Clinicians admitted that research on nutrition and exercise in MMD is scant but needed. A balance should be struck, it was noted, between too much exercise, which can be a problem in MMD because of impaired muscle regenerative capacity, and too little exercise, which can lead to disuse atrophy (muscle loss because of lack of use of the muscles).
There seemed to be a consensus that maintaining one’s general health is important, as well as monitoring specific problems associated with MMD, such as cardiac abnormalities and cataracts.
It was noted that, in the United States, the high cost of genetic testing can be a significant barrier to obtaining it for many individuals.
Registry participation urged
People with MMD1 or MMD2, as well as unaffected family members, were urged to join the National Registry of Myotonic Dystrophy & Facioscapulohumeral Muscular Dystrophy Patients and Family Members.
This national registry, funded by the U.S. National Institutes of Health (NIH), is housed at the University of Rochester (N.Y.) Medical Center, and is described as a "match-making" service for people interested in joining research studies and investigators who are looking for subjects to participate in such studies.
For more information, including how to join, see the website, or call (888) 925-4302 or (585) 276-0004.