The Annual SMA Researcher Meeting is the largest research meeting in the world specifically focused on SMA. This year we had a record setting 470 attendees. The goal of the meeting is to create open communication of early, unpublished data, accelerating the pace of research. The meeting also furthers research by building collaborations—including cross-disciplinary dialogue, partnerships, integration of new researchers and drug companies, and educational opportunities for junior researchers.
We are posting a series of summaries from our 2017 researcher meeting, highlighting the most interesting new discoveries presented there. This update covers the opening special session, “The Role of Fatigue and Muscle Weakness in SMA with Therapeutic Implications”. In this session speakers of various expertise on the topic are invited to share their work with the SMA community. This session was moderated by Thomas Crawford MD, Professor of Neurology and Pediatrics, Johns Hopkins School of Medicine.
Fatigue and Muscle Weakness in SMA
The SMA field has made major therapeutic advances with SMN enhancing approaches. The greatest impact from this therapeutic approach will likely require early treatment. Therefore, the goal of this session was to discuss novel points of intervention that could result in greater motor and muscle function at more advanced stages of SMA. In fact, many older SMA patients cite fatigue and endurance as significant concerns, yet the biological origin of fatigue, as well as options to treat it, are poorly understood. This session discussed fatigue and muscle weakness from a clinical and biological perspective, breaking down the potential role of the different components of the motor unit.
Summary of Session Talks
The session began with an overview of fatigue and muscle weakness in SMA by Thomas Crawford MD, Professor of Neurology and Pediatrics, Johns Hopkins School of Medicine. Dr. Crawford encouraged the SMA community to think about the difference between fatigue and muscle weakness and how we measure them in patients and animal models. He explained the importance of establishing definitions of fatigue and muscle weakness to ensure reliability and reproducibility in measuring outcomes. Next, Jacqueline Montes PT, EdD, NCS, Assistant Professor of Clinical Rehabilitation & Regenerative Medicine in Neurology, Columbia University, shared clinical observations of fatigue & endurance in SMA. Dr. Montes described types of fatigue (perceived vs. physiological) and how she measures fatigue in ambulatory SMA patients. She also discussed how fatigue and muscle weakness are related and the implications of fatigue in patients.
The next two talks focused on understanding the biological reasons for fatigue, which will be very important when developing treatments to address it. Dr. Mark MD, PhD, Professor of Neuroscience, Cell Biology, & Physiology at Wright State University, explained the electrophysiological defects in SMA which lead to motor unit dysfunction and cause fatigue. He showed data displaying abnormalities at the synapse (the point where the nerve and muscle communicate to cause muscle contraction) in an animal model of SMA. These abnormalities may contribute to fatigue. Next Dr. Tessa Gordon, PhD, Professor Emeritus, University of Alberta, Senior Scientist, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, spoke about enhancement of motor neuron growth, repair, and sprouting. Sprouting is the process by which new growth from a neuron projects to an area of muscle that has been denervated by other neurons in an effort to maintain muscle function. She explained that the ability of motor neurons to sprout in SMA, unlike in some other neuromuscular diseases, may help to sustain muscle strength despite the loss of large numbers of motor neurons.
The next speakers addressed the contribution of muscle to fatigue in SMA. First, Dr. Rashmi Kothary PhD, Deputy Scientific Director at the Ottawa Hospital Research Institute, described muscle defects in mouse models of SMA and how these defects in muscle cells may be contributing to fatigue. He explained that satellite cells, precursors to skeletal muscle cells, do not function properly in SMA, and may contribute to muscle weakness. Next Victor Dubowitz MD, PhD, FRCP, FRCPCH, Emeritus Professor of Pediatrics at the University of London Imperial College School of Medicine, gave an overview of NMJ and muscle pathology in human SMA. He described his years of clinical experience with pediatric and adult SMA patients and his observations of fatigue in these patients.
The session concluded with a talk by Kelly Howell PhD, Scientist at the SMA Foundation. She highlighted potential therapeutic strategies to treat fatigue, endurance, and muscle weakness in SMA. These strategies, targeting muscle, could be used in combination with SMN-enhancing approaches, to provide maximal benefit to patients.
Understanding the cause of fatigue and implications for treatment
Many older SMA patients routinely cite fatigue and endurance as a significant concern. In fact at the recent patient focused drug development meeting with the FDA fatigue was consistently reported as a major concern among patients. However, the biological origins of fatigue, as well as the treatment options are poorly understood. This session focused on fatigue and muscle weakness from a clinical and biological perspective, breaking down the potential role of the different components of the motor unit in an effort to increase understanding of the role of fatigue in SMA and encourage further research.