In Focus: Limb-Girdle Muscular Dystrophy

Recent research reveals that LGMD is a forest with many trees

Article Highlights:

In addition to this introduction to limb-girdle muscular dystrophy, this series contains eight additional sections, links to which can be found at the bottom of this page. These include:

by Margaret Wahl on October 3, 2013 - 9:29am

Quest Vol. 20, No. 4
A Closer Look: LGMD Research Slideshow

Say “limb-girdle muscular dystrophy” to most people, and you’ll get a questioning look. They may wonder what kind of girdle is being talked about and how limbs fit into the picture.

The name actually comes from an anatomical term describing the supporting structures of the shoulders and hips, including bones and muscles. Limb-girdle muscular dystrophy (LGMD) is a genetic disorder in which the muscles surrounding the hips and shoulders degenerate.

For many decades, LGMD was an amorphous term that described a type of muscular dystrophy that affected these muscles (and sometimes others as well) in both males and females, varied widely in severity and age of onset, and could be inherited in a dominant or recessive pattern. (Dominant genetic diseases require only one gene flaw for symptoms to occur; recessive diseases require two gene flaws — usually one from each parent — for symptoms to occur.)

Then, in the 1990s, researchers — many of whom received MDA support — began to describe the molecular underpinnings of LGMD.

Today, we know that the term “limb-girdle muscular dystrophy” does describe a type of muscular dystrophy, but a type with many subtypes — a forest with many trees, some yet to be identified.

Some 26 subtypes of LGMD are now recognized, all due to various genetic mutations that affect aspects of muscle function. Some also affect cardiac (heart) muscle.

LGMD and CMD

Some subtypes of LGMD result from insufficient function of a protein in the extracellular matrix — the substance in which each muscle fiber is embedded. This protein, known as alpha-dystroglycan, must not only be structurally sound but must also undergo a specific type of sugar-coating, or glycosylation, to carry out its key role in connecting the muscle fiber to its surroundings. (See LGMD: The Cellular View.)

Several of the genes that, when flawed, cause inadequate glycosylation of alpha-dystroglycan also can give rise to congenital muscular dystrophy (CMD), which has a very early onset (near birth) and can be quite severe. (See Taking Aim at Congenital Muscular Dystrophies.)

Why some people develop CMD and others LGMD when they have mutations in the same gene is not entirely clear. The differences may be due to the precise locations of the mutations, but other factors also could be involved.

Does subtype matter?

But, why does it matter what kind of LGMD you have? And what does all this knowledge gained in the past 20 years or so do for you?

For one thing, it’s allowed researchers to identify exactly which genes and proteins are affected and begin to devise strategies to replace missing functions or counteract toxic ones.

It’s also allowed families to get a more precise diagnosis and a better idea of the usual course of their disease, including what problems they’re likely or unlikely to develop and what precautions they should take. And it’s given people with LGMD the opportunity to participate in type-specific support groups, registries and studies.

 



Jyoti Jaiswal, Ph.D.

Grant effective: Aug. 1, 2013

Jyoti Jaiswal, associate professor at George Washington University School of Medicine & Health Sciences, and investigator at Children’s Research Institute in Washington, D.C., was awarded an MDA research grant totaling $300,000 over a period of three years to evaluate whether a new anti-inflammatory compound can reduce muscle damage in dysferlinopathies.

Christopher Penton, Ph.D.

Grant effective: Aug. 1, 2013

Christopher Penton, who recently earned his doctorate in integrated biomedical sciences at Ohio State University in Columbus, was awarded an MDA research grant totaling $180,000 over three years to study ways to improve muscle regeneration and decrease muscle scar tissue formation in Duchenne muscular dystrophy (DMD) and potentially other muscular dystrophies, including limb-girdle muscular dystrophy.

Rachelle Crosbie-Watson, Ph.D.

Grant effective: Aug. 1, 2013

Rachelle Crosbie-Watson, professor of neurology at the University of California, Los Angeles, was awarded an MDA research grant totaling $300,000 over a period of three years to study whether increasing levels of the sarcospan protein can be therapeutic for Duchenne muscular dystrophy (DMD) and other muscle diseases, including limb-girdle muscular dystrophy.

Sebahattin Cirak, M.D.

Grant effective: Feb. 1, 2013

Sebahattin Cirak, pending assistant professor at the Children’s National Medical Center in Washington, D.C., was awarded an MDA development grant totaling $180,000 over a period of three years to hunt for elusive genes that cause congenital muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD).

Masahiro Iwamoto, Ph.D., D.D.S.

Grant effective: Feb. 1, 2013

Masahiro Iwamoto, research scientist at the Children’s Hospital of Philadelphia and associate professor of pediatric orthopedics at the University of Pennsylvania School of Medicine, was awarded an MDA research grant totaling $405,000 over a period of three years to study new ways to reduce muscle degeneration.

Noah Weisleder, Ph.D.

Grant effective: Feb. 1, 2013

Noah Weisleder, associate professor of physiology and cell biology at Ohio State University in Columbus, was awarded an MDA research grant totaling $405,000 over a period of three years to study muscle repair for development of treatment for limb-girdle muscular dystrophies (LGMD).

Yosef Gruenbaum, Ph.D.

Grant effective: Aug. 1, 2012

MDA awarded a research grant totaling $300,009 over three years to Yosef Gruenbaum, professor and elected chairman at the Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, in Israel. The funds will help support Gruenbaum’s study of proteins called lamins and their role in muscle diseases such as Emery-Dreifuss (EDMD) and limb-girdle (LGMD) muscular dystrophies, and Charcot-Marie-Tooth disease (CMT).

Melissa Spencer, Ph.D.

Grant effective: Aug. 1, 2012

Melissa Spencer, professor of neurology at the David Geffen School of Medicine at University of California, Los Angeles, was awarded an MDA research grant totaling $390,000 over three years to study the role of an enzyme called calpain 3 in type 2A limb-girdle muscular dystrophy (LGMD2A).

Kanneboyina Nagaraju, Ph.D.

Grant effective: March 2012

The Muscular Dystrophy Association has given a $300,000 grant to the Center for Genetic Medicine Research (CGMR) at Children’s National Medical Center in Washington, D.C., to continue standardized and reliable preclinical studies of neuromuscular diseases.

The MDA Translational Research Grant was awarded to CGMR's Kanneboyina Nagaraju, who directs the Murine Functional Testing Core Facility. It's the largest preclinical drug testing facility for neuromuscular disease models.

To learn more, read Money for Mice: MDA Funds Drug Testing Facility.

Robert Bloch, Ph.D.

Grant effective: Feb. 1, 2012

MDA has awarded a research grant totaling $362,295 over a period of three years to Robert Bloch, a professor in the department of physiology at the University of Maryland School of Medicine in Baltimore. The funds will help support Bloch's study of the role of a protein called dysferlin in type 2B limb-girdle muscular dystrophy (LGMD2B) and distal muscular dystrophy (DD, or Miyoshi myopathy).

Jeffrey Miller, Ph.D.

Grant effective: Feb. 1, 2012

MDA awarded a research grant totaling $343,860 over a period of three years to Jeffrey Boone Miller, senior scientist at Boston Biomedical Research Institute in Watertown, Mass., and associate professor of neurology at Harvard Medical School in Boston. The funds will help support Miller’s study of the underlying causes of, and potential therapeutic strategies for, three muscular dystrophies: type 1A congenital muscular dystrophy (MDC1A/CMD), and types 2C and 2D limb-girdle muscular dystrophy (LGMD2C, LGMD2D).

Chris Weihl, M.D., Ph.D.

Grant effective: Feb. 1, 2012

Chris Weihl, assistant professor of neurology at Washington University School of Medicine in St. Louis, was awarded an MDA grant totaling $397,064 over a period of three years. The funds will help support Weihl’s research into a process called autophagy in skeletal muscle. Data gleaned from Weihl’s studies may be applicable to a number of neuromuscular disorders including amyotrophic lateral sclerosis (ALS) and the muscular dystrophies; Weihl and colleagues will conduct their studies on a mouse model of myofibrillar myopathy (MFM), a form of limb-girdle muscular dystrophy.

Alfred Goldberg, Ph.D.

Grant effective: Aug. 1, 2011

Alfred Goldberg, professor or cell biology at Harvard Medical School in Boston, has received an MDA research grant totaling $410,777 over three years to continue research into the mechanisms underlying muscle atrophy, with particular relevance for limb-girdle muscular dystrophy (LGMD) and possibly inclusion-body myositis (IBM).

Jennifer Levy, Ph.D.

Grant effective: Aug. 1, 2011

Jennifer Levy, a postdoctoral research fellow in the department of molecular physiology & biophysics at the University of Iowa Carver College of Medicine, has been awarded an MDA development grant totaling $180,000 over three years. (This type of grant reflects MDA's commitment to the career development of promising young researchers.) The funds will support Levy's research on repair of the muscle-fiber membrane.

Michael Hauser, Ph.D.

Grant effective: Feb. 1, 2011

Michael Hauser, an associate professor in the Section of Medical Genetics, Department of Medicine at Duke University Medical Center in Durham, N.C., has been awarded an MDA grant totaling $383,856 over a period of three years. The funds will help support Hauser's efforts to identify mutations responsible for dominantly inherited (type 1) limb-girdle muscular dystrophy (LGMD).

Peter Kang, M.D.

Grant effective: Feb. 1, 2011

MDA has awarded a research grant totaling $299,722 over three years to Peter Kang, assistant professor of neurology at Harvard Medical School and director of the electromyography laboratory at Children’s Hospital Boston. The funds will help support Kang’s research into identification of gene mutations that can cause limb-girdle muscular dystrophy (LGMD).

Jerry Mendell, M.D.

Grant effective: February 2010

Jerry Mendell, director of the Center for Gene Therapy at the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, was awarded an MDA translational research grant totaling $458,814 to develop bloodstream delivery of alpha-sarcoglycan genes to people with type 2D limb-girdle muscular dystrophy (LGMD2D). This form of LGMD arises from a deficiency of the alpha-sarcoglycan protein. The grant will allow Mendell and his colleagues to conduct the testing required by the U.S. Food and Drug Administration (FDA) before the agency can give permission for a clinical trial of bloodstream-delivered gene therapy in LGMD2D patients.



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