Doctors Hear Recommendations for Heart Care in MD

Some 50 physicians and scientists gathered in Tucson, Ariz., in late September for an MDA-sponsored meeting to pool their knowledge on how to detect and treat the often devastating damage to the heart that takes place in some forms of muscular dystrophy (MD).

MDA grantees Elizabeth McNally of the University of Chicago School of Medicine and Jeffrey Towbin of Baylor College of Medicine in Houston were co-chairs of MDAs Cardiomyopathy in Muscular Dystrophy workshop.

The main cardiac problems in MD are cardiomyopathy (heart muscle deterioration) the dilated (floppy) and hypertrophic (thickened) forms and conduction defects, abnormal signals that lead to abnormal heart rates or rhythms.

Much of the discussion centered around molecular research and ideas for gene transfer and use of cardiac repair cells, which have exciting implications for the future (see full report). But the audience was clearly impressed with the possibilities of the cardiac care guidelines presented by Kate Bushby of the Institute of Human Genetics in Newcastle upon Tyne, United Kingdom.

Bushby presented the decisions of 16 neuromuscular disease experts who met in the Netherlands in June 2002 under the auspices of the European Neuromuscular Centre. The meeting report is published in full in the February issue of Neuromuscular Disorders. The experts recommended the following steps for close monitoring and treatment of heart defects in various MDs:

Duchenne MD (DMD)

echocardiogram (echo) and electrocardiogram (EKG) at diagnosis

cardiac investigations before any surgery and every two years up to age 10; every year after age 10

assessment and treatment of respiratory dysfunction in parallel with cardiac investigations

treatment with angiotensin-converting enzyme (ACE) inhibitors with consideration of adding beta-blocker medications when abnormalities progress

Becker MD (BMD)

echo and EKG at diagnosis

screening for cardiomyopathy at least every five years

treatment with ACE inhibitors and possibly beta blockers if progressive abnormalities found

consideration of cardiac transplantation

Female Carriers of DMD & BMD

echo and EKG at diagnosis or after age 16 and every five years thereafter; more frequent evaluations with test abnormalities or symptoms

treatment with ACE inhibitors if significant abnormalities detected, with consideration of additional medications

consideration of cardiac transplantation

Type 1 Myotonic Dystrophy (MMD1)

annual EKG starting at diagnosis

monitoring with portable EKG recorder (Holter monitor) for 24 to 48 hours at diagnosis in adult patients

echo at diagnosis in congenital MMD

Holter monitoring if EKG shows increased risk of abnormally slow heart rate; consideration of invasive measurement of cardiac conduction

consideration of drugs to treat overly fast heart rate in atria (upper cardiac chambers) but with caveat that these may worsen rate irregularities in ventricles (lower chambers)

pacemaker insertion when progressive rhythm abnormalities detected

Congenital MD (CMD)

echo and EKG at diagnosis

echo prior to surgery or as symptoms suggest, except in merosin gene form, in which cardiomyopathy generally isnt progressive

 

X-Linked Emery-Dreifuss MD (EDMD)

EKG at diagnosis and yearly thereafter, with follow-up by cardiologist

24- to 48-hour EKG (Holter monitoring) yearly, with particular attention to detecting overly fast or overly slow heart rates; less frequent echo

permanent pacemaker implantation when EKG shows abnormalities of sinoatrial node (natural cardiac pacemaker) or atrioventricular node (relay station from upper to lower chambers of heart)

consideration of invasive electrophysiology testing to help determine pacemaker insertion site and mode of operation

with frequent atrial fibrillation (uncoordinated contractions in upper chambers) or atrial standstill, consideration of anticoagulant drug warfarin to prevent clots or strokes

Female Carriers of X-Linked EDMD

periodic EKGs to detect atrial or atrioventricular conduction disease

Chromosome 1 EDMD

consideration of implantable defibrillator

with frequent atrial fibrillation or atrial standstill, consideration of warfarin to prevent clots or strokes

Limb-Girdle MD 2C, 2D, 2E and 2F (Sarcoglycan-Deficient LGMD)

same surveillance as for DMD or BMD for cardiomyopathy

periodic surveillance for abnormal heart rhythms with Holter EKG or similar recording

treatment with ACE inhibitors with consideration of adding beta blockers for cardiomyopathy

consideration of calcium antagonist medications to improve coronary artery flow

consideration of cardiac transplantation

LGMD2I (Fukutin-Related-Protein-Deficient)

surveillance for cardiomyopathy as in DMD or BMD

treatment with ACE inhibitors with consideration of adding beta blockers

consideration of cardiac transplantation

LGMD1B (Lamin A/C-Related)

consideration of implantable defibrillator

with frequent atrial fibrillation or atrial standstill, consideration of warfarin to prevent clots or strokes

Facioscapulohumeral MD (FSHD)

EKG and echo at diagnosis, with follow-up dictated by clinical picture

The heartbeat is normally set by the sinoatrial node, which sends impulses to the atrio- ventricular node. From there, theyre conducted to the ventricles. This process is frequently abnormal in type 1 myotonic dystrophy, both forms of Emery-Dreifuss dystrophy, and the chromosome 1 form of limb-girdle dystrophy.

 

New Clues May Lead to New Tests in FSH Dystrophy

Much progress has been made in identifying the unusual genetic flaw that causes facioscapulohumeral muscular dystrophy (FSHD), but each discovery seems to lead to new mysteries.

Last year, MDA-supported researchers found that a small deleted section of chromosome 4 prevents a cellular "braking mechanism" from operating properly (see "Research Updates," August 2002). The absence of this section causes one or more nearby genes to be inappropriately activated when they should be silent, researchers believe.

Although most people with FSHD have this deletion, a minority of people with the disease test negative for the deletion.

Recently, a group including MDA grantee Silvere van der Maarel, a molecular biologist at the Center for Human and Clinical Genetics at Leiden University Medical Center in the Netherlands, found clues that may explain the negative tests, publishing its results in the July 22 issue of Neurology. The researchers found that the deleted section of chromosome 4 in FSHD-affected members of three unrelated families was too large to be identified by the current test. They described a method of testing that can detect the larger deletions as well as the smaller ones. Van der Maarel says he believes this type of testing should be available in major diagnostic centers within the next year or so.

Surprisingly, they also found that a gene previously thought to be inappropriately activated in FSHD was part of the deleted section in two of the families. The absence of that gene told the investigators that it couldnt have been wrongly switched on, so its been eliminated as a possible culprit in FSHD causation.

The investigators suggest that the identification of other large deletions on chromosome 4 may allow them to eliminate other genes in the region, narrowing the search for the cause of FSHD muscle degeneration.

New MG Drug Now in Biotech Pipeline

Ester Neurosciences, a biotechnology company in Herzliya, Israel, announced in June that its new compound, EN101, aimed at myasthenia gravis (MG) had done well in preliminary testing in 16 people and would undergo further studies in Israel.

The drug is designed to have effects similar to those of the commonly used pyridostigmine (Mestinon), which indirectly increases levels of acetylcholine, the chemical transmitter of nerve-to-muscle signals. Having more acetylcholine at the nerve-to-muscle junction generally improves strength in people with MG and other forms of myasthenia.

Pyridostigmine accomplishes an acetylcholine increase by interfering with an enzyme that normally breaks down the chemical. EN101 targets the same system but at a different point, says Irene Zeitoun, director of Research and Development at Ester Neurosciences.

EN101 takes aim against the genetic instructions for the breakdown enzyme instead of the enzyme itself, allowing for a more specific action, she says. The new compound also keeps the body from thwarting the increase in acetylcholine, something that can happen with current medications.

EN101, like pyridostigmine, can be taken by mouth. The company says its exploring other potential applications for the compound, such as treating Lambert-Eaton syndrome, a myasthenic disorder in which acetylcholine isnt released properly from nerve fibers.

For more information go to www.esterneuro.com.

Blocking Waste Disposal Restores Dystrophin in Mice

MDA grantee Michael Lisanti of the Department of Molecular Pharmacology at Albert Einstein College of Medicine in New York was part of a U.S. and Italian research team that recently found that blocking a cellular waste disposal mechanism could be a way to save muscle cells in Duchenne muscular dystrophy (DMD). In this form of MD, the muscle protein dystrophin is missing from the muscle cell membrane, causing the membrane to become fragile and muscle cells to degenerate.

Saving partially functional dystrophin is the goal of Lisantis research group. Left to right are Federica Sotgia, Michael Lisanti and Gloria Bonuccelli.

In experiments with mice that make a very small dystrophin fragment (as do many people with DMD), Lisanti and colleagues found that blocking the function of cellular garbage disposal units called proteasomes apparently allowed the cells to save and use the small dystrophin fragments. They published their findings in the October issue of the American Journal of Pathology.

Instead of sending these fragments to the waste disposal units (probably the usual procedure in DMD-affected cells), the cells of the treated mice apparently routed them to the membrane. Once the dystrophin pieces were in the cell membrane, other proteins lined up properly there as well, restoring the membranes strength.

The authors say the findings suggest a new route of therapy for DMD.

"Using an inhibitor of the proteasomal pathway, we could effectively block the degradation of dystrophin and of dystrophin-associated proteins, and we could ameliorate myopathic changes normally seen in the skeletal muscle fibers of mdx [dystrophin-deficient] mice," they wrote.

The researchers used a compound thats only available for laboratory research, but Lisanti says theres a drug used in cancer treatment that could be considered for a future clinical trial. An important consideration is the potential toxicity of disabling the cells main disposal and recycling system.

Normal Muscle Cell	DMD-Affected Muscle Cell
	Muscle Cell Treated With Proteasome Blocker
Blocking cellular garbage disposal units allowed small dystrophin fragments to take their place near the cell membrane.

 

Swedish Researchers Target T-Cells in Inclusion-Body Myositis

Investigators in Sweden say a specific type of immunoglobulin therapy may be beneficial in people with inclusion-body myositis (IBM), based on results of a small pilot study they conducted.

Christopher Lindberg and colleagues at Sahlgrenska University Hospital in Gothenburg found small increases in muscle strength in people with IBM who received a week of intravenous treatment with an immunoglobulin directed against certain cells in their immune systems and then a years treatment with oral methotrexate, a medication that suppresses the immune system.

The comparison group, which received methotrexate alone, showed a decrease in strength over the same period.

Laboratory evaluations also suggested some benefit from the specific immunoglobulin treatment compared with methotrexate alone.

This immunoglobulin was directed against the CD3 type of T-cell, which is thought to be involved in a misguided attack on muscle tissue in IBM. The anti-T-cell treatment is a refinement of the mixed immunoglobulin infusions that have been used in IBM and other disorders.

So far, no treatment has been found to have more than very small or inconsistent benefits in IBM, including mixed immunoglobulin therapy.

The study was small, and the investigators advise further studies using this therapy.

Oxidative Damage Found in Duchenne, Becker MDs, Not in Myotonic Dystrophy

MDA-supported researchers at McMaster University Medical Center in Hamilton, Ontario, have found that people with Duchenne and Becker muscular dystrophies (DMD and BMD) show signs of oxidative stress, a type of cellular damage, in their muscles.

This type of damage results from an excess of oxygen-containing chemicals carrying an electrical charge that can harm cell membranes, DNA and other cellular structures. These chemicals, called free radicals, are natural byproducts of certain cell activities, but checks and balances normally keep their levels low.

In contrast, the researchers found that people with type 1 myotonic dystrophy (MMD1) didnt show signs of this type of damage, though lab experiments in cells had indicated they might.

Oxidative stress was assessed by measuring the ratio of a compound called 8-OhdG to the chemical creatinine in the participants urine. In subjects with DMD and BMD, this ratio was 48 percent above normal; in people with MMD, it wasnt elevated.

In the paper, published May 1 in Free Radical Biology & Medicine, the authors say the presence of free radicals and oxidative damage in skeletal muscle may increase the destruction caused by the primary muscle defect in diseases like DMD and BMD. (The primary problem in these diseases is a lack of the muscle protein dystrophin.)

The study supports the idea that nutritional supplements with antioxidant properties could be beneficial in preserving muscle in these disorders.

MDA grantee Mark Tarnopolsky at McMaster, an author of this report, is studying the use of nutritional supplements in the treatment of DMD, BMD and MMD.

New Prenatal Test Resembles Pap Smear

Scientists at the Australian Genome Research Facility in Brisbane say theyve developed a simpler, less expensive and less risky form of prenatal testing for genetic disorders that could make such procedures available to more prospective parents.

Investigators Ian Findlay and Darryl Irwin, who announced their findings in July at the International Congress of Genetics in Melbourne, say the new test takes fetal cells from a pregnant woman in much the same way that cells are obtained in the widely performed Pap test, which screens women for signs of cancer. (Pap tests are performed by swabbing or brushing the entrance to the uterus, or cervix, and placing the cells on a slide or in a special solution.)

Findlay and Irwin say they can isolate fetal cells from the Pap smear of a pregnant woman and then screen them for a range of genetic disorders.

Current prenatal tests involve taking samples from one of the uterine membranes (chorionic villus testing) or from the fluid surrounding the fetus (amniocentesis). Both tests have to be performed by specialists, pose a small risk to mother and child, and are expensive.

The new Pap-type prenatal test has been performed on samples from 600 women who were between five and 35 weeks pregnant. The researchers say the test can be performed when the pregnancy is five weeks along and results can be obtained the same day.

Theyre continuing to evaluate the test in clinical trials and hope it will be on the market in two to three years.

Boys With Duchenne MD Wish for Fun Stuff, Pets

 

"If you could make three wishes, any three wishes in the whole world, what would they be?"

Thats what neuropsychologist Veronica Hinton, an MDA grantee at Columbia University in New York, and her colleague Nancy Nereo, a clinical psychologist at the University of California in San Diego, asked 74 boys with Duchenne muscular dystrophy (DMD), 32 of their siblings and a comparison group of 43 boys without any illness in the family. The children were between 6 and 12 years old.

The investigators, who published their results in the April issue of the Journal of Developmental and Behavioral Pediatrics, found to their surprise that the boys with DMD were no more likely to make health-related wishes than were boys in the comparison group. (Interestingly, their siblings were more likely to make this type of wish, sometimes specifically in relation to the affected brothers illness.)

Among the most common wishes of the children in all three groups were desires for material things, such as toys, candy or a swimming pool, and the wish for a pet. The boys with DMD often wished for a realistic fun activity, such as going to a restaurant.

Boys with no family illness commonly stated a long-term goal, such as a certain type of profession or education. This wish, however, wasnt common for boys with DMD or their siblings, suggesting to the researchers that avoidance of the future might reflect a difference in the DMD-affected families.

"While boys with DMD do not appear to be more concerned with health issues than their siblings or comparison boys," Nereo says, "there were differences in their wishes that might reflect a subtle shift in their perspective. For example, boys with DMD made fewer future or goal-oriented wishes, suggesting an adaptive way of responding to their illness; that is, by focusing on the here and now."

Their siblings appear to have also experienced this shift in perspective.

Childrens Behavior Top Cause of Mothers Stress

Stress in mothers of children with Duchenne muscular dystrophy (DMD) is more closely related to problem behavior in their children than to the familys socioeconomic status, single parenthood or even the childs level of physical disability, says a study in the October-November issue of the Journal of Pediatric Psychology.

Neuropsychologist and MDA grantee Veronica Hinton at Columbia University in New York was the principal investigator. Hinton and her colleagues studied 127 mothers of boys with DMD and compared their stress with that of mothers of children with cerebral palsy and mothers of children without any illness.

They found maternal stress was more likely to be caused by child behavior related to poor social skills in the DMD-affected families, while it was more likely to be from other causes in the other two groups.

Based on their previous research, the authors of the study suggest that boys with DMD may experience delayed maturation and late development of certain social skills because of some differences in their cognitive development compared with that of other children. (See "When Neuromuscular Disease Affects the Brain," December 2002.)

When 28 families were surveyed again after two and then four years had passed, the researchers found that maternal stress had diminished, even though the childrens DMD had progressed. The investigators say this could be because the mothers learned to cope better with their situations, or that the boys may have matured and developed better social skills. (They also admit that the families who consented to the long-term follow-up may have been those who were coping the best.)

The researchers note that, based on these preliminary findings, social services that target problem behavior and deficient social skills in children might be more helpful to DMD-affected families than more general types of support programs. They say the issue warrants further investigation.

Genzyme Expands Myozyme Program in Pompes

Genzyme, a biotechnology firm based in Cambridge, Mass., announced in September that it plans to launch a program that would allow access to Myozyme, its experimental treatment for Pompes disease (acid maltase deficiency), for severely ill patients who arent eligible to participate in the companys clinical trials of Myozyme. (See "Research Updates," September-October 2003.)

Myozyme is Genzymes trademarked name for a laboratory-engineered enzyme that acts like acid maltase (also known as acid alpha-glucosidase) and seems to compensate for the lack of acid maltase in Pompes disease patients. Acid maltase normally breaks down stored sugar in cells.

In addition, Genzyme says it will launch a disease registry to study the natural history, outcomes and management of Pompes disease. Those with the disease can participate in the registry through their physicians.

The company will also study the natural course of late-onset Pompes disease in approximately 60 people with mild to intermediate symptoms and will then use these data to begin a trial of Myozyme in some adult study participants in 2004.

For more information, contact Genzymes Medical Information Department at medinfo@genzyme.com or (800) 745-4447. MDAs Web site at www.mda.org will post information about these trials, the disease registry and the access program as they become available. Check "Clinical Trials" (under "Research") and "News."

Study to Probe Service Dog Use

	Occupational therapist Diane Collins with Greg Traynor and his dog, Nala, in Pittsburgh

The Veterans Affairs Research & Development Center of Excellence for Wheelchairs and Related Technology and the University of Pittsburgh are conducting a study to examine how service dogs affect wheelchair users lives. You dont have to have a service dog to participate.

The researchers are looking for people who are at least 18 years old; use a wheelchair or scooter for at least 75 percent of their mobility; and either own a service dog, are on a waiting list to receive a service dog, or arent interested in a service dog.

The study, which follows a similar one (see "Research Updates," May-June 2003), requires completion of mailed or telephoned questionnaires. These ask about the participants disability, socioeconomic status, health care, life satisfaction, social life, daily activities and pets. Participants are paid $20 for each questionnaire they complete.

Contact Shirley Fitzgerald at (412) 365-4840 (Pittsburgh) or Diane Collins at (412) 365-4844; or send e-mail to dmcst84@pitt.edu.