Study finds genetic change in chromosome 4 causes FSHD

The Muscular Dystrophy Association today heralds a landmark muscular dystrophy advance by an international study team of scientists and physicians from the Netherlands, United States, France and Spain. Led by MDA-grantee Silvère van der Maarel, Ph.D., at Leiden University Medical Center in the Netherlands, the collaborative study of more than 2,300 people found that two distinct genetic changes on chromosome 4 must be present to cause facioscapulohumeral muscular dystrophy (FSHD).

"Decades of hard work have paid off," said R. Rodney Howell, M.D., chairman of the MDA Board of Directors. "It will now be much easier to definitively diagnose FSH dystrophy in people showing symptoms of the disease, and to predict in people showing no symptoms, who will develop the disease. Also, investigators can now start exploring a number of promising drug therapy approaches for FSH dystrophy."

Results of today's FSHD study in the journal Science, underscore the importance of continued funding of research to identify the genetic causes of diseases, particularly for those like FSHD that present clinically with significant variability. "For almost two decades, MDA has relentlessly supported my work," said van der Maarel, adding that "This has been of great influence and an important contributor to this success."

FSHD is characterized by weakness starting in the muscles of the face, shoulder blade area and upper arms, with progression to other parts of the body possible.

Today's findings confirm the involvement of a contracted section of DNA on chromosome 4 that was first identified in the 1990s. This contracted region apparently allows DNA that is normally "silent" to be inappropriately activated.

They also show that a signal near the contracted region, but closer to the tip of chromosome 4 can extend the life span of the improperly coded genetic information. Van der Maarel and his team report that this second DNA change, called a "polyadenylation signal," may allow potentially toxic genetic instructions produced from the contracted DNA region to last long enough to damage muscle cells.

Key U.S.-based investigators in this veritable detective story involving both scientists and clinicians were Rabi Tawil, M.D., co-director of the MDA Clinic at the University of Rochester and a former MDA grantee, and Stephen Tapscott, M.D., Ph.D, at the Fred Hutchinson Cancer Research Center in Seattle, also a former MDA grantee.

"Our study puts forward a plausible, genetic model for FSHD," the paper's authors say. They note that their study "provides a genetic mechanism that may unify the genetic observations in patients with FSHD."

Often credited for its leadership in building the field of neuromuscular disease research, MDA has also enhanced clinical care for individuals affected by muscle disorders, achieving important quality of life and longevity gains. The Association, which has invested nearly $39 million in 2010 on research worldwide, is the first nonprofit to earn a Lifetime Achievement Award from the American Medical Association ("for significant and lasting contributions to the health and welfare of humanity").

According to Howell, "Generous Americans responding to the annual Jerry Lewis MDA Telethon, and to thousands of other special events benefiting the families served by MDA, deserve much of the credit for the rapid progress being made toward treatments for neuromuscular diseases. It's their strong belief in MDA's capable stewardship of public funds that's enabling so much to be accomplished - even in a sluggish economy."

MDA-funded scientists have uncovered the genetic defects that cause several forms of muscular dystrophy; Charcot-Marie-Tooth disease (CMT); a form of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease); childhood spinal muscular atrophy (SMA) and other neuromuscular conditions. Now entering a period of increasing numbers of clinical trials of potential therapeutics, the Association's network of some 200 hospital-affiliated clinics is instrumental in identifying appropriate candidates for clinical trials; and to help refine outcome measures for those clinical trials.


: Muscular Dystrophy Association


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