San Francisco, CA / November 08, 2012
Just two decades ago, the scientific world largely ignored a mysterious disease that causes muscles to weaken throughout the body. Called fascioscapulohumeral muscular dystrophy (FSHD), this disorder literally robs people of their smiles as their facial muscles fail. The shoulder blades jut out like wings and the spine distorts as the supporting muscles degenerate. Patients may lose the use of their arms and legs. Because symptoms can creep up slowly, many doctors regard FSHD as a mild disorder, but patients say it is anything but. “This is a life-shortening disease,” asserts Daniel Perez, President of the FSH Society, the charity he co-founded 21 years ago. Perez, who is in a wheelchair and requires a personal care assistant, saw his mother die earlier this year from respiratory failure, which is common in advanced cases of FSHD.
Thanks to the efforts of Perez and many other patients, FSHD research has come a long way. The evidence was there for all to see at the FSH Society’s 2012 International Research Consortium & Research Planning Meeting, held on November 6, 2012, in conjunction with the annual meeting of the American Society of Human Genetics in San Francisco, CA.
The biggest buzz at the meeting was generated by the discovery of a new gene for FSHD by scientists from the U.S., Netherlands and France. The study by Richard Lemmers and colleagues will be published in Nature Genetics on November 11. Over 90 percent of FSHD patients have a shortening of the D4Z4 region on chromosome 4, which results in the expression of a gene called DUX4, with apparent toxic effects in muscle. The newly found gene may account for the remaining 10 percent of patients who do not have the D4Z4 deletion. These patients have a subtype called FSHD2, and the new finding will provide them with a genetic test. The interaction between the new gene and D4Z4 deletion will be a topic of intense interest. The combination of this new gene with the D4Z4 deletion, found in a few families, causes a more severe form of the disease.
As important as it is to pinpoint the genetic causes of FSHD, it is also essential to validate methods to measure the progression of the disease. To conduct a clinical trial, researchers need a “therapeutic biomarker”, something that changes to show that a treatment is working. Without a proven therapeutic biomarker, the Food and Drug Administration will not allow a clinical trial to go forward. And unless a biomarker can show change over one or two years, pharmaceutical companies are not going to be willing to invest in a clinical trial, especially for rare diseases with small markets.
The search for a therapeutic biomarker has been very challenging for FSHD, which typically progresses at a sloth’s pace over many years and decades. So attendees at the San Francisco meeting were heartened by a report by George Padberg and his colleagues from the Netherlands. In a small study of 30 Dutch patients with genetically confirmed FSHD, magnetic resonance imaging was used to measure fat, which invades and replaces muscle as the disease progresses. The investigators reported that once the disease process sets into a muscle, the rate of fat infiltration is rapid enough to be detected over a period of as short as four months, making it potentially useful as a therapeutic biomarker. This study needs to be replicated in a larger group of patients, Padberg noted.
The discovery two years ago of the role of the D4Z4 deletion and DUX4 is starting to produce new insights that could lead to treatment. An exciting study, reported by Greg Block and his colleagues at the University of Washington School of Medicine and University of Rochester Medical Center, pointed to a possible role for apoptosis (“programmed cell death”) in FSHD muscle. Skeletal muscle cells, or myotubes, that express DUX4 undergo apoptotic death, and are rescued from death by chemicals that block apoptosis. The group was also able to reduce myotube death by manipulating biochemical pathways that regulate DUX4 expression.
Additional insight into future biomarkers and drug targets could emerge from a study at Boston Children’s Hospital, Johns Hopkins School of Medicine and the Paul D. Wellstone Muscular Dystrophy Research Center at the Boston Biomedical Research Institute. First author Fedik Rahimov described the identification of a “molecular signature” based on gene expression in muscle biopsies from FSHD patients. This signature was accurate 90 percent of the time in distinguishing FSHD bicep muscle from normal control muscle. The study, which has been submitted for publication, also identified a dozen biological pathways that are altered in FSHD. Restoring these pathways to a more normal pattern might be a strategy for developing future treatments.
Last but not least, investigators reported on the latest advances towards treatments. Collaborators from Belgium, France, Australia and the U.S. presented an “exon skipping” approach similar to one used recently with promising results in Duchenne muscular dystrophy, to inhibit DUX4 in human muscle cell cultures and mice.
These latest findings are generating a wave of optimism, but much remains to be done. As important as the work in laboratories is the work of educating patients and their families about the critical role they play as volunteers for studies.
“It is asking a lot of people to sacrifice their time and energy, not to mention give blood and muscle samples, for research, especially when there is no treatment today,” said FSH Society Executive Director June Kinoshita. “But patients and their families who do volunteer are manifestly moving the field forward, as was so clear at this meeting. None of these discoveries would have been possible without them.”
Around 500,000 people worldwide have FSHD, making it an “orphan” disease that faces an uphill battle to attract research funding and drug company investment. It’s rare enough that many patients go undiagnosed and unaware that there are others with this disease. In addition to investing in scientific research, the FSH Society offers a community of support, news and information for FSHD patients and families.
The accompanying FSH Society video, featuring Broadway star Kelli O’Hara and celebrated pianist Steven Blier, helps viewers understand the personal cost of living with FSHD and urges the public to get involved now, because as O’Hara says, “we’re beginning to see the light.”