More than 500 physicians, allied health care professionals and MDA staff attended the MDA's 2012 Clinical Conference in Las Vegas, March 4-7.
The program emphasized:
For even more about the conference presentations, see the conference blog page, which includes posts written by members of MDA's Research Department and two people with neuromuscular diseases.
Sanjay Bidichandani, MDA vice president of research, provided a thorough introduction to genetics, describing the cellular pathway for synthesis of proteins.
A cell converts each gene (DNA sequence) into RNA in the nucleus. A fully processed copy of the gene's RNA moves out of the nucleus, where a protein is made from this RNA "recipe."
The path starts with DNA (genes), which is converted to pre-RNA and then to messenger RNA (processed RNA), and ultimately to protein. Bidichandani described how different types of mutations (changes) in the DNA can cause disease by disrupting any or all of these steps, and how experimental therapies seek to intervene at a variety of points along the way from DNA to protein.
Kevin Flanigan, an MDA clinic co-director at Nationwide Children's Hospital in Columbus, Ohio, described how a large variety of mutations in the gene for the muscle protein dystrophin can cause Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), and how we now can detect 93 to 96 percent of all dystrophin mutations with DNA testing.
Flanigan emphasized that — while knowing the precise dystrophin mutation can be helpful in predicting whether a child is likely to develop DMD or the less-severe BMD — this knowledge must be used cautiously and can't be relied upon by itself to predict disease course.
Flanigan also said that genetic testing for limb-girdle muscular dystrophy (LGMD), which has multiple subtypes, can be streamlined by first performing a muscle biopsy; and that members of the same family with facioscapulohumeral muscular dystrophy (FSHD) can have different disease presentations.
Michael Shy, who co-directs the MDA Clinic at the University of Iowa Hospitals & Clinics, described how understanding the genetics of Charcot-Marie-Tooth disease (CMT), another disease with multiple subtypes, has allowed the research community to think about designing therapies that are more "rational," or "based on reason."
Shy noted that animal models of various types of CMT have been created by putting CMT-causing gene mutations into mice, fruit flies and zebrafish.
Genetic counselors Carly Siskind and Shawna Feely gave a presentation about genetic testing for neuromuscular diseases in which they outlined some of its pros and cons. Siskind is at Stanford University and Hospital and Lucile Packard Children's Hospital in Stanford, Calif.; and Feely is at the University of Iowa.
The pros of getting a definitive diagnosis include:
Among the cons:
Siskind and Feely pointed out that the Genetic Information Noniscrimination Act (GINA) of 2008 is designed to protect people from being discriminated against by health insurers and employers on the basis of a genetic test result, but GINA does not protect against discrimination by providers of life insurance or long-term care insurance.
Jerry Mendell, co-director of the MDA Clinic at Nationwide Children's Hospital in Columbus, Ohio, described a pilot project undertaken in the state of Ohio that shows newborn screening for DMD is feasible via a two-step testing procedure that can be conducted on one blood sample.
The two steps would be a general screen for extremely elevated levels of serum creatine kinase (CK), followed by dystrophin DNA analysis on samples that meet the CK elevation criterion.
Mendell and colleagues left open the question of whether such screening should be implemented in the near future.
A major reason for implementing a newborn screening program for DMD would be the potential for earlier — and therefore possibly more effective — treatment of the disease, especially if experimental therapies now in the pipeline continue to do well in trials. Treatments can't be given in infancy unless infants are identified as having DMD.
A reason not to implement newborn screening would be that there is currently no known treatment for DMD other than corticosteroids (prednisone and similar drugs), which most neuromuscular specialists currently do not advocate administering in infancy in DMD. Concerns have been raised about whether diagnosing children with DMD in early infancy could interfere with family functioning.
For more information, see:
Carrie Miceli, an immunologist at the University of California, Los Angeles, provided conference participants with an overview of how the immune system behaves — and misbehaves — in DMD.
She described how the immune system, while performing its normal role of sensing and reacting to danger (such as that posed by bacteria and viruses), can sometimes become a hazard itself.
In DMD, Miceli said, the constant degeneration of muscle fibers creates "damage-associated molecular patterns," such as mislocalization of proteins following the rupture of a muscle-fiber membrane. Proteins like dystrophin, which would normally be found inside the cell, may end up outside, alerting the immune system.
(Click image for a larger view.)
The Immune Response
An immune response starts when an antigen-presenting cell, such as a macrophage or dendritic cell, sees an antigen and then engulfs and digests it (1). Antigen-presenting cells then display pieces of the antigen to killer T cells or helper T cells of the immune system (2). Helper T cells can either show the antigen to B cells (3), which then produce antibodies (4); or they can secrete cytokines, which stimulate macrophages, dendritic cells and other T cells (5). After the immune system has done its work, helper T cells can secrete cytokines that kill other helper and killer T cells but increase the number of regulatory T cells (6).
The system reacts to these unusual patterns by sending in defensive players, such as macrophages, T cells and sometimes B cells.
But the responses that the immune system uses to "heal” the perceived wound can also cause inflammation, scar formation and destruction of specific proteins.
Miceli noted that, while suppressing parts of the immune system may be helpful in treating DMD (prednisone's benefits in DMD may be attributable to this mechanism), caution is required.
The immune system also produces regulatory cells, she explained, which dampen an inflammatory environment; and some immunosuppressant treatments interfere with this beneficial regulatory process. And, Miceli noted, some of the actions of the immune system may be necessary for regeneration of muscle.
Referring to a recent DMD gene therapy trial that showed some trial participants mounted an immune response to new dystrophin protein, Miceli said, "Immune responses to gene therapy are likely to be variable among patients."
She also noted that, at least so far, experimental treatments that raise dystrophin levels without inserting new genes (such as exon-skipping compounds) have not led to an immune response against this protein.
"As exon skipping begins to work, it may be healing the muscle and thus reducing the inflammatory signature," Miceli said.
But, she noted, "the devil is in the details." It's becoming increasingly important to understand exactly which cells are operating in a DMD-associated immune response, where they go and what they do. At any given time, some cells may be driving the immune response while others may be tipping the balance toward tolerance, she explained.
For more about the immune system in general, see New Directions: Can an immune response be rerouted to treat disease?, which describes how the immune system works in health and disease and explores potential therapies; Quest Magazine, July 2008
For more about the immune system in DMD, see:
An incisive explanation of how the immune system can be a double-edged sword in ALS was given by Stan Appel, who directs the MDA/ALS Center at Methodist Neurological Institute in Houston, chairs MDA’s Medical Advisory Committee and serves on the MDA Board of Directors.
"ALS is not an autoimmunedisease in the sense that the immune system initiates the disease process," Appel said, referring to disorders in which the immune system's attack on tissues is the primary problem. "But the immune system is involved in perpetuating it."
|Stan Appel, who directs the MDA ALS Center at Methodist Neurological Institute in Houston, helped the audience understand how the immune system can be both harmful and helpful in amyotrophic lateral sclerosis.|
Appel's research and that of others has focused on the microglia, which are, as Appel phrases the definition, "the sentinels of the immune system" in the brain and spinal cord (the central nervous system). Microglia communicate with T cells (immune system cells) in the bloodstream.
In many (possibly all) types of ALS, misfolded proteins are made, which apparently activate the microglia, which then change from a protective mode to an attack mode, killing nerve cells via their interaction with T cells.
"The default status of microglia is protective," Appel said, but "with the release of misfolded proteins, it changes to a toxic response."
Evidence from mouse experiments suggests that, early in the ALS disease course, there is protection of nerve cells by the immune system; but later on, the immune system destroys these same cells.
Appel cautions that human ALS patients, who vary widely with respect to disease causation and progression, aren't as simple as ALS mouse models, which, in experimental settings, do not show much variation.
However, he says the evidence in humans so far supports what has been learned from the mice: Slower progression in the early stage of ALS correlates with indicators that the immune system is in a protective mode, while faster progression correlates with markers of an immune system in an activated mode.
An important goal in ALS, Appel says, is to increase protective immunity while decreasing toxic immunity.
Several experimental strategies that may do that are in the research pipeline.
For more about the immune system in ALS, see:
Richard Barohn, co-director of the MDA Clinic at the University of Kansas Medical Center, provided an update on the various medications and other treatments for the autoimmune disease myasthenia gravis (MG).
In this disease, the immune system attacks the junction of nerve and muscle fibers, reducing transmission of nerve signals to muscle and causing fluctuating weakness.
Prior to 1960, Barohn said, 30 percent of people with MG died, while the current mortality rate for this disease is now less than 5 percent. He attributes the change to the use of corticosteroids (such as prednisone); mechanical ventilation; and other treatments, most of which change the behavior of the immune system.
Pyridostigmine (Mestinon), a widely used first-line treatment for MG, increases transmission of nerve-to-muscle signals rather than altering the immune system and has also played an important role in treatment of MG.
“We now expect most patients to improve and some to go into remission,” Barohn said.
He also noted that many drugs given today for MG are given "off-label," meaning their use has been extrapolated from safety and efficacy in other diseases and that they have not actually been tested in MG.
Some drugs, however, such as methotrexate, are now being tested specifically in MG. A multicenter trial of that drug is now being overseen by Barohn and is open to recruitment (see "Efficacy of Methotrexate," below).
For more about current MG treatments, research and open clinical trials, see:
Steven Greenberg, a neurologist from Brigham & Women's Hospital in Boston, presented some complex findings about the behavior of the immune system in inclusion-body myositis (IBM).
Greenberg, whose work has largely focused on IBM, noted that, in the sporadic (nonhereditary) form of this disease, recent research shows that muscle acts as a host for immune cells; that a protein called TDP43 (which has been implicated in ALS) is mislocated outside the nucleus in sporadic IBM-affected cells; and that an antibody (protein made by the immune system) dubbed anti-IBM-43 may lead to further clues about IBM.
For more about the immune system in myositis, including some open trials and studies, see:
Look for more Quest News Online articles about this conference in the coming weeks, in which we'll report onbest practices in neuromuscular disease care and development of future therapies.
Editor's note 3/19/12: This story has been updated to reflect the current locations of genetic counselors Carly Siskind and Shawna Feely, who were formerly at Wayne State University in Detroit.