‘HOW THE MDA CLINIC CAN MAKE A DIFFERENCE’
IS FOCUS OF MDA NATIONAL CONFERENCE

Four Diseases Discussed
by Margaret Wahl

Some 180 health care professionals associated with MDA clinics joined several research scientists in a meaningful conference held in Tucson, Ariz., Nov. 6-9. The meeting was sponsored by MDA, with help from Athena Diagnostics of Worcester, Mass., and Pharmacia of Peapack, N.J.

Progress and current trends were discussed in four major diseases covered by MDA: Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

Duchenne Muscular Dystrophy
Among the highlights of this meeting was a thorough review by John Kissel, MDA clinic co-director at Ohio State University in Columbus, of the uses and drawbacks of corticosteroids, such as prednisone, in the treatment of DMD.

Kissel emphasized that, although the corticosteroid drugs do appear in numerous studies over the last 30 years to extend walking ability and slow the course of the disease, they remain fraught with side effects. These must be closely monitored and, where possible, prevented. For example, dietary modifications can lessen the weight gain associated with these drugs, and medications can mitigate the emotional and psychological side effects known to accompany their use.

Kissel said that deflazacort, closely related to prednisone but not available in the United States, is widely believed by families to be far superior to prednisone in terms of side effects but that studies haven’t supported this belief. Deflazacort may be less likely to cause severe weight gain or appetite increase, but, in other respects, it looks the same as prednisone, he said.

New ways of giving prednisone — for example, two days a week or 10 days on and then 10 days off — are being studied. As of now, Kissel said, the standard way to give prednisone for DMD is 0.75 milligrams per kilogram per day.

Orthopedic surgeon Irwin Siegel, co-director of the MDA clinic at Rush-Presbyterian-St. Luke’s Medical Center in Chicago, gave the audience a thorough presentation of the whys and hows of surgical intervention in DMD, especially with regard to managing contractures and performing spinal fusions in DMD.

Jeff Chamberlain, an MDA research grantee at the University of Washington in Seattle, reported on his latest mouse experiments in gene transfer for DMD. Chamberlain and colleagues have determined which regions of the very large gene for the muscle protein dystrophin, which is missing in DMD, are essential and which can be eliminated with preservation of gene function.

Miniaturizing the dystrophin gene is important so that it can fit into a safe and effective delivery vehicle to be transported into muscle cells. Hurdles that remain include producing gene therapy vehicles that meet regulatory requirements for human use and manufacturing enough of the vehicle for a clinical trial.

Tom Prior, who has MDA support at Ohio State’s Department of Pathology, discussed newer, better tests to diagnose mutations (flaws) in the dystrophin gene. Prior and others are developing a test based on a technique called high-performance liquid chromatography that can examine the entire dystrophin gene. The test will probably be available to families in the near future.

Carolyn Buzin, associate director of the Clinical Molecular Diagnostic Laboratory at City of Hope National Medical Center in Duarte, Calif., discussed the type of complete dystrophin test offered by her institution. This test is called DOVAM, for “detection of virtually all mutations.”

These improved dystrophin tests will allow families to use better information for family planning and possibly for specific drug studies that may rely on a particular type of gene mutation for expected benefit. (For example, studies of the drug gentamicin require that a child have a “stop codon” type of mutation.)

Limb-Girdle Muscular Dystrophy
Jerry Mendell, MDA research grantee and co-director of the MDA clinic at Ohio State University in Columbus, discussed results of a gene transfer trial in LGMD that was halted prematurely because of a death in an unrelated gene transfer trial in 1999.

Two participants had at that time been injected with the gene for a sarcoglycan, one of the proteins that, when flawed or missing, can lead to LGMD. One participant’s injected foot muscle showed evidence that the gene was present and producing a small amount of the needed protein. No such evidence was present in the foot muscle of the other trial participant.

Mendell said there were problems interpreting the results of the experiment because, unknown to the investigators beforehand, the foot muscle that was chosen apparently contains some sarcoglycan protein even in people with sarcoglycan-deficient LGMD. A new trial is in the planning stages, and the team will use a different muscle.

Matt Wicklund, a physician at Wilford Hall Medical Center at Lackland Air Force Base in San Antonio noted that there are now at least 10 forms of LGMD for which it’s possible to predict to some extent the likely clinical course of the disease based on the genetic mutation involved. These highly specific tests aren’t yet widely available, however.

Steven Moore, an MDA research grantee in the University of Iowa’s Department of Pathology, in Iowa City, discussed how to proceed with diagnosis of LGMD based on a combination of muscle biopsy and DNA-testing strategies, using the biopsy to narrow down the number of genetic tests that should be considered.

Spinal Muscular Atrophy
Arthur Burghes of Ohio State University’s Department of Medical Biochemistry reported amazing progress in the understanding of SMA on the molecular level. He said it’s now clear that the so-called SMN2 gene, which normally lies near the SMN1 gene that’s missing or flawed in people with SMA, is a “major modifier” of the disease course. In general, the more SMN2 genes a person has (some people have several, while others have only one), the less severe are the consequences of the loss of the SMN1 gene.

Strategies to boost the activity of SMN2 genes in people with SMA appear to be the most promising avenue for therapy at this time, Burghes said.

Gyula Acsadi, an MDA research grantee at Wayne State University in Detroit, discussed gene transfer strategies in SMA. Inserting the SMN1 gene or genes that can help support the survival of motor neurons, the muscle-controlling nerve cells that are lost in SMA, could be helpful, mouse experiments suggest.

Susan Iannaccone, who co-directs the MDA clinic at Texas Scottish Rite Hospital for Children in Dallas, presented her studies of the “natural history” of SMA in children — seeing how the disease progresses without treatment. Iannaccone and others are designing accurate ways to measure neuromuscular function as the disease continues. These measuring tools will be used to see how the effects of creatine in the near future and other medications in the more distant future look when compared to the natural history of SMA.

Kathryn Swoboda of Primary Children’s Medical Center in Salt Lake City presented her findings on methods to estimate the number of motor units present throughout the course of SMA. A motor unit consists of a motor neuron and the muscle fibers to which it sends signals.

Peter Schochet, a pediatric pulmonary specialist at Children’s Medical Center of Dallas, presented material on supportive care in children with SMA, emphasizing the need to maintain their nutrition and respiratory function with the utmost vigilance.

He noted that children with this disorder can have “maladaptive feeding patterns,” including overeating out of depression, boredom or not enough physical activity for their intake; or undereating, because of fear of inhaling food into the lungs or choking on it. Schochet noted that a gastrostomy tube may make family mealtimes more pleasant and life easier in general in the latter situations, since the child can take in needed calories through the tube and just eat what he or she wishes at mealtime.

Schochet emphasized the need to combine mucus clearance by manual or mechanical methods (for example, with a CoughAssist and an in-exsufflator) with ventilation strategies to treat the respiratory impairment associated with severe SMA.

Prompt treatment and prevention of infections is important as well, he noted, and he recommends vaccinations against pneumococcal pneumonia and other infectious agents.

Surgery to treat the scoliosis (spinal curvature) associated with the disease is also an important consideration, he noted, even though it may not actually improve respiratory function.

Amyotrophic Lateral Sclerosis
“It’s tough to make predictions, especially about the future,” said renowned ALS specialist Lewis Rowland at the meeting. Rowland, the former director of the Eleanor and Lou Gehrig MDA/ALS Center at Columbia-Presbyterian Medical Center in New York, was quoting baseball great Yogi Berra, but he applied the famous quip to trying to predict where ALS research will lead.

Rowland said there have been 27 trials that showed no benefit in ALS and one that showed marginal effect on survival. That was a large-scale trial of the compound riluzole, which yielded the only FDA-approved, ALS-specific treatment, the Aventis drug Rilutek.

There are now at least six trials in progress in ALS, though, and stem cell and gene transfer research are also moving ahead, at least in laboratory experiments. Predicting which strategy, or whether all these strategies, will prove safe or effective, isn’t possible, Rowland implied.

Robert Miller, who directs the MDA/ALS Center at California Pacific Medical Center in San Francisco, did predict, however, that trials seeking to combine several substances that have shown promise in ALS are likely in the near future. A trial of riluzole combined with other agents, such as vitamins, minerals and other dietary supplements, probably in combination with anti-inflammatory agents, is a likely next step, Miller said. Such “cocktail” approaches are routinely used in AIDS and cancer.

Hiroshi Mitsumoto, director of the Gehrig center, discussed the importance of developing and constantly updating standards of care in ALS with respect to how diagnoses are made and conveyed to the patient and family; how and when to use medications; how to manage nutritional and respiratory issues; and how to maintain or improve quality of life. Mitsumoto co-chaired the conference.

Terry Heiman-Patterson, co-director of the MDA/ALS Center of Hope at Drexel University in Philadelphia, explored the many faces of respiratory care in ALS, a crucial part of managing the disease and preserving quality of life. Heiman-Patterson said that noninvasive ventilation (assisted ventilation through a mask or other interface but not with a tracheostomy) has been shown to improve survival in ALS when survivors of the disease were counted at one year and at three years.

In addition to extending survival time, ventilation can improve sleep quality, endurance, shortness of breath, speech, cognitive function and general quality of life, she reported.

Starting ventilation with low settings and short durations, and working up to higher settings and longer durations, while using a comfortable mask or small tubes into the nostrils, seems to work best, she said.

Jeffrey Rosenfeld, who directs the MDA/ALS Center at Carolinas Medical Center in Charlotte, N.C., emphasized that “ALS is a treatable disease.” He noted that maintaining nutrition is crucial to improving quality of life and survival in ALS, saying there are many factors besides the loss of nerve cells that contribute to muscle loss and weight loss. These include difficulty swallowing and therefore eating; weakness of the arms, making it hard to eat comfortably; fear of choking; embarrassment at meals; depression; loss of appetite; and possibly increased metabolic demands of the disease, making it necessary to take in more calories than the person ordinarily would to maintain his or her weight.

Rosenfeld said putting in a percutaneous endoscopic gastrostomy (PEG) tube early in the disease course offers patients a significant survival benefit that’s much greater than that provided by any drug that’s so far been tested in ALS. He said that, in his view, “no time is too early” to put in a PEG tube. These tubes go directly into the stomach from the outside (not down the throat).

They’re best inserted while the patient is still able to eat, in Rosenfeld’s opinion. (The presence of a PEG tube doesn’t prevent eating.) PEG tubes can be converted to PEG “buttons” shortly after they’re inserted, Rosenfeld said. (With a “button,” a gastrostomy tube can be detached most of the time and just attached during “meals.”)

Edward Kasarskis, at the University of Kentucky in Lexington, also emphasized the importance of good nutritional support in ALS, noting that there are hidden metabolic demands in ALS, such as the extra effort to breathe and perhaps the muscle twitches. Assisted ventilation and treatment of the muscle twitches may reduce caloric demands and conserve energy, he said.

In a general discussion after Kasarskis’ and Rosenfeld’s talks, the doctors seemed to agree that PEG tubes shouldn’t be viewed as “end-of-life” treatments, but rather as ways of looking better and feeling better with ALS. They take away a lot of the patient’s and the family’s worries about eating and can reduce overall stress and anxiety, experts offered.

Walter Bradley, who directs the Kessenich Family MDA/ALS Center at the University of Miami, echoed the sentiments of the experts and the audience in general when he noted that care in ALS should be offered throughout the disease and that psychosocial issues must be addressed at all stages as well.

“Physicians are advisers,” he said. “You have to preserve the patient’s right to make the decisions.” Those decisions, he said, depend on many factors, including one’s cultural background.

Basic Research
Stanley Appel, director of the Ronny & Linda Finger MDA/ALS Center at Baylor College of Medicine in Houston, was co-chair of the conference. He and other ALS experts, including Robert Brown, director of the MDA/ALS Center at Massachusetts General Hospital in Boston; Teepu Siddique, co-director of the MDA clinic at Chicago’s Northwestern Memorial Hospital; and Don Cleveland, in the Department of Cell Biology at the University of California San Diego, discussed progress in understanding what causes the disease.

Several new genes have been identified that either directly cause ALS or may confer susceptibility to it.

Environmental factors that may contribute could include lead exposure, exposure to agricultural chemicals and exposure to unknown factors during the Gulf War, the experts said. Some studies have found that increased dietary fat, elevated dietary glutamate and smoking may also contribute to the development of ALS, they reported.

There are many biochemical changes in motor neurons, the cells that gradually die in the brain and spinal cord in ALS, several scientists reported, but it’s hard to tell what starts the process or to what extent the different changes are related to each other.

Appel reviewed the major categories of biochemical changes in the cells of the nervous system in ALS for the audience. These changes include toxic levels of calcium, toxic levels of glutamate, the presence of apparently activated immune-system cells called “microglia,” and the presence of highly reactive and dangerous oxygen compounds in above-average quantities.

Cleveland presented various studies of molecular “chaperones,” molecules that help proteins fold into the right shape and can to some extent offset toxic influences on the cell. Adding these molecules may help ALS-affected cells survive, he said.

Cleveland discussed the crucial question of whether ALS is a disease solely of the motor neurons themselves or whether the cellular “neighborhood” in which the motor neurons are located is also part of the disease.

“If you put a normal motor neuron into a lousy neighborhood, it feels those effects and acquires some aspects of toxicity,” he said. As a corollary, he noted, even when motor neurons contain abnormal proteins such as those found in ALS, they live longer when they’re surrounded by a good cellular environment. This could be an important clue in pursuing therapy for ALS.

Muscle Disease Research
Johnny Huard, an MDA research grantee at the University of Pittsburgh, discussed his laboratory experiments using stem cells derived from muscle that he’s trying to target to muscle tissue.

He noted that the environment in which the stem cell finds itself appears to determine what kind of cell it will become. Precautions are important in this regard, he said, noting that his group had found that some stem cells can actually increase the formation of scar tissue in muscle instead of enhancing muscle tissue.

Administrative Developments
It was announced that MDA is working with Athena Diagnostics to arrange for increased access and reduced costs for DNA diagnostic testing in MDA-covered diseases.

The conferees were treated to a demonstration of a new Web site that MDA is developing. It will be a password-protected site specific to the needs of clinicians in neuromuscular disease who wish to exchange information with each other in a timely and efficient manner. The site demo was greeted with great enthusiasm.