• University of Iowa Named Wellstone Center
• Consortium to Develop New DMD Treatment
• Respiratory Training Helps Mice with DMD
• Clinical Trials and Studies
  • Good Weight, Nutrition Hard Balance to Achieve
  • Subtle Heart Changes Seen in FSH Dystrophy
  • Technique May Detect Early Heart Problems in Duchenne Dystrophy
  • Myotonic MD Severity Similar in Siblings
  • Myotonia Congenita Effects Hard to Predict
  • Genzyme Screening for Late-Onset Pompe's
  • MD STARnet Needs Parents' Input
  • Researchers Explore Muscle Stem Cells
  • Grantees Honored

In July, the National Institutes of Health named the University of Iowa in Iowa City the fourth Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center.

Kevin Campbell

The establishment of these centers results from the passage of the MDA-backed MD-CARE Act in 2001. The first three, which are co-funded by NIH and MDA, are located at the University of Washington in Seattle, the University of Rochester (N.Y.), and the University of Pittsburgh.

The lead in-vestigator at the Iowa Wellstone Center is muscle physiologist Kevin Campbell, a longtime MDA research grantee.

The centers projects will explore basic biological mechanisms that relate to possible treatments for muscular dystrophies, encourage the translation of research from lab to clinic and provide advanced diagnostic services.

Campbell will lead an investigation of whether improving muscle cell membrane maintenance, particularly through increasing levels of proteins known as LARGE and dysferlin, can provide a basis for new Duchenne muscular dystrophy treatments.

A second project, led by Katherine Mathews, director of the MDA clinic at the university, will concentrate on type 2I limb-girdle MD. A third project, led by Baoli Yang, assistant professor of obstetrics and gynecology, will explore the possible use of stem cells to treat muscular dystrophies.

MDA will join the pharmaceutical company GlaxoSmithKline and other parties to develop an exon skipping strategy as an experimental treatment for Duchenne muscular dystrophy (DMD).

Exon Skipping: As a cell prepares the final version of instructions for making a protein, it removes excess material and leaves only the exons, the parts that will form the final protein recipe. Laboratory-designed antisense compounds can make a cell eliminate a specific exon along with the other unwanted material.

Exon skipping (see Changing the Code, March-April) is designed to coax cells to reinterpret genetic instructions and manufacture normal or nearly normal versions of necessary proteins that they lack.

Some people with DMD have the type of genetic mutation that lends itself to treatment via exon skipping with antisense oligonucleotides or similar laboratory-developed compounds that target and block certain parts of the dystrophin gene. Dystrophin is the protein thats needed but missing in DMD.

If an antisense compound blocks the mutation in the dystrophin gene, the cell should theoretically synthesize a nearly full-length dystrophin protein molecule, minus the mutated part.

Stefan Matecki and colleagues, who published their results in the June issue of Neuromuscular Disorders, exposed normal mice and dystrophin-deficient (mdx) mice to excess carbon dioxide for 30 minutes a day over six weeks, causing them to increase their breathing rates.

In the dystrophin-deficient mice, the carbon dioxide exposure training increased the strength of the respiratory diaphragm, although it didnt affect the diaphragms resistance to fatigue. It had no effect on diaphragm strength or resistance in the normal mice.

The researchers also found increased production of alpha-dystrobrevin, which is normally situated near dystrophin in the muscle cell membrane, in both types of mice. The significance of this increase isnt clear.

The researchers say this type of diaphragm training may be useful in preserving respiratory muscle function in people with DMD. They note, however, that experiments in mice are needed to determine whether the benefit was caused by the increased protein or other effects.

Most people with limited mobility dont need to be told how hard it is not to gain excess weight, but many dont know that restricting calories without regard to protein intake can add to muscle wasting. Two new studies say finding the right balance is a challenge.

Nutrition Inadequate in Many With MD

Researchers at McMaster University in Hamilton, Ontario, say adults with muscular dystrophy may be deficient in several dietary nutrients.

Mark Tarnopolsky, who has received MDA support to study nutritional aspects of neuromuscular disease, and colleagues, studied 29 adults with type 1 myotonic dystrophy (MMD) and 22 with other types of muscular dystrophy.

Participants reported their food and drink taken over two weekdays and one weekend day. The data reported were compared to the dietary reference intake, or DRI, a value that estimates the recommended amount of each nutrient for people in the United States and Canada.

The investigators found that 10 percent of those with MMD and 5 percent of the other MD patients didnt meet the DRI for daily protein intake. However, 55 percent of the MMD patients and 86 percent of the other group had a fat intake above the suggested range.

Ten percent of the MMD group and 18 percent of the other group were categorized as obese, while 13 percent and 9 percent, respectively, were classified as underweight.

The study also found inadequate intake of vitamins D and E, copper, zinc and calcium in many participants.

Our study provides a starting point from which to further explore nutritional issues in patients with muscular dystrophy, the authors say in their report, published in the June issue of Muscle & Nerve. They suggest more studies to see whether nutritional counseling or dietary supplements would be helpful.

Caloric Needs Are Small

Astrophysicist and retired missile defense scientist Mike Munn published results of his study of energy expenditure and caloric needs in people with neuromuscular disorders in the August issue of the American Journal of Physical Medicine and Rehabilitation.

Mike Munn

Munn, of Benson, Ariz., has limb-girdle muscular dystrophy (LGMD) himself, uses noninvasive ventilation approximately 20 hours a day, and can no longer walk.

I know well the difficulties people with neuromuscular disorders have with weight and, for this reason, developed a daily caloric needs equation for people with very limited mobility, substantial muscle wasting and/or ventilator use, Munn says. With it, he says, professionals can estimate how many calories people need to maintain adequate nutrition and avoid excessive weight gain.

Building on theoretical material and test results from other scientists and using himself as a research subject, Munn estimated that he would need to ingest about 840 calories a day a very small amount of food.

The very small amount of energy required for equilibrium implies that weight management is extremely difficult for these patients, Munn writes. He adds, however, that within this energy budget it is also necessary to assure adequate nutrition in terms of essential amino acids [protein components] and other nutritional elements and that dietary-induced muscle wasting is an important consideration and must also be accommodated in the diet.

Although its long been known that some muscular dystrophies, such as Duchenne, Becker and myotonic, almost always affect the heart muscle, its been thought that others, such as facioscapulohumeral MD (FSHD), spare this important organ.

But recently, researchers at the University of Pisa in Italy have found that at least some people with FSHD have subtle cardiac abnormalities that might set the stage for more serious problems later on.

Fabio Gletta and colleagues, who published their report in the June issue of Neuromuscular Disorders, found that the 24 FSHD-affected participants they studied had more evidence of reduced function in the left ventricle (lower heart chamber) and of abnormal cardiac muscle cell electrical activity than did 24 non-FSHD control subjects.

However, the participants had no symptoms of heart disease, and their problems werent revealed in traditional EKG testing or echocardiograms. (Special testing was done in this study.)

The investigators believe that additional factors, or triggers, are required for significant cardiac rhythm abnormalities to develop in these subtly affected patients.

They found that those with FSHD had indices of abnormal signal transmission in the muscle layer of the heart. While this subtle type of cardiac abnormality wasnt related to the severity of skeletal muscle function, it was correlated with the size of the FSHD-related genetic defect on chromosome 4.

A technique that can be applied in conjunction with a standard echocardiogram (an ultrasound picture of the heart) can add to the sensitivity of this procedure for people with Duchenne muscular dystrophy (DMD), a study conducted at Baylor College of Medicine and Texas Childrens Hospital in Houston found.

Elizabeth McNally

The results, announced at a meeting of the American Society of Echocardiography (ASE) in Boston in June, say adding tissue doppler imaging, which measures how fast the hearts walls move, can identify early changes in the heart muscle before serious symptoms of cardiac abnormalities occur.

Schuping Ge, a pediatric cardiologist and the lead author of the study, says in an ASE press release, We wanted to find a way to detect early, minor changes of the heart muscle in hopes of guiding early therapy that can slow down or reverse those changes.

Cardiologist and MDA grantee Elizabeth McNally at the University of Chicago Hospitals says the study suggests that tissue doppler during echocardiograms is useful to help identify even earlier those boys with DMD at risk of developing cardiomyopathy.

Siblings with type 1 myotonic dystrophy (MMD) are similar to each other in the severity of skeletal muscle weakness and cardiac abnormalities. Those similarities are independent of their closeness in age or the number of CTG repeats in their DNA, the MMD1-causing genetic defect on chromosome 19.

So say the results of a study conducted at Pennsylvania State University in Hershey and Indiana University in Indianapolis and published in the June issue of Muscle & Nerve. The study was in part supported by MDA, and participants were recruited from MDA clinics at Indiana University and Hershey Medical Center.

The findings suggest that genetic factors other than CTG repeat length, or environmental factors, which may be similar in siblings, modulate both the skeletal and cardiac muscle involvement in DM1 [type 1 MMD], the authors write. They say the factors responsible for the familial clustering are unknown but may have a significant impact on the overall disease state and clinical outcomes.

The muscle disease myotonia congenita varies greatly in severity, says a Danish study published in the July issue of Muscle & Nerve.

Eskild Colding-Jorgensen of the University of Copenhagen found that disease severity in myotonia congenita can be hard to predict, even if the precise gene flaw (mutation) in the CLCN1 gene has been identified.

Its been known for decades that myotonia congenita can be inherited in either a dominant pattern, in which only one mutated gene is needed to cause symptoms, or a recessive pattern, in which a mutation from each parent is needed to interfere with muscle relaxation.

But it seems there are other factors that influence disease severity. These may include age, which sometimes improves the disease over time; pregnancy, which can worsen the disease; exposure to cold, which can aggravate or improve symptoms; and exercise, which can lessen myotonia in the short run and may even have long-term benefits.

In addition, an incompletely understood genetic mechanism that causes a cell to prefer one of its two inherited genes for a protein may be a factor, Colding-Jorgensen adds. This sometimes results in producing more of the abnormal protein than one would predict.

He also notes that the warm-up effect in myotonia congenita, in which the myotonia disappears after brief exercise, deserves more attention, since it may provide clues for treatment development.

The biopharmaceutical company Genzyme is screening people with late-onset Pompes disease (acid maltase deficiency) for a future trial to evaluate Myozyme, the companys replacement enzyme for acid maltase thats shown promise in babies with the infantile form of the disease.

Genzyme is seeking people with definite or probable Pompes disease who are at least 8 years old and able to walk with or without assistive devices. For this screening, Genzyme is excluding people who have participated in its observational study of late-onset Pompes, as well as those who use tracheostomy ventilation or require noninvasive ventilation while awake and upright.

Genzymes expanded access program allows some people who dont meet study requirements to receive Myozyme. For details on screening sites, contact Genzyme at (800) 745-4447, or medinfo@genzyme.com.

Muscular Dystrophy Surveillance, Tracking and Research Network (MD STARnet), under the auspices of the U.S. Centers for Disease Control and Prevention (CDC), is actively seeking participants for two studies.

Investigators in the Palliative Care Project want to interview parents of children with Duchenne muscular dystrophy to determine their needs and the services of which theyre aware.

Participants must live in Arizona, Colorado, Iowa or Western New York state and be willing to give the researchers an approximately 30-minute telephone interview, for which they will be compensated.

The Assistive Technology Project is for parents of children and young men ages 5 to 21 with Duchenne or Becker muscular dystrophy who live in Arizona.

This study, funded in part by MDA, will assess the use families make of assistive technology and investigate the effects of technology on health and well-being.

Parents, who will receive compensation, will be asked to complete a written questionnaire, and participate in a 10-minute interview at their sons next clinic visit.

Contact Jennifer Andrews at (520) 626-6816 or jandrews@peds.arizona.edu for details.

Other information is available at www.cdc.gov/ncbddd/duchenne/cdc.htm, (800) 311-3435 or dmd@cdc.gov.