2015 SMA Researcher Meeting Summary on SMA Pathology

The 19th International SMA Researcher Meeting was recently held by Cure SMA in Kansas City, Missouri (June 18-20, 2015).

SMA (spinal muscular atrophy) is a rare, devastating motor neuron disease and one of the leading genetic causes of pediatric mortality, occurring in approximately 1 in every 6,000 to 10,000 newborns. It is characterized by the degeneration of nerves controlling muscles and voluntary movement, resulting in muscle weakness, atrophy, paralysis and eventually death. SMA is the result of a mutation or deletion in a gene called survival of motor neuron 1 (SMN1). Currently, there is no approved treatment for the disease

One of the Cure SMA summaries recently released refers to a session on SMA pathology, including its consequences and potential endpoints. The session focused on the electrical circuits that are generated from sensory neurons to motor neurons in the spinal cord to allow muscle contraction and movement. The role and generation of these circuits and the measurement of the electrical flow (electrophysiology) in the context of SMA pathology were subjects of debate, as SMA is thought to affect all aspects of these electrical circuits.

Dr. Barrington Burnett presented data on the electrical circuits but focused on the muscle itself. The researcher showed results supporting the idea that the SMN protein plays a key role in early differentiation and fusion of myoblasts (embryonic cells that can become a muscle fiber cell), which corresponds to the first step in muscle fiber formation. According to him, these early defects may be responsible for part of the muscle atrophy observed in SMA patients.

Another presentation, by Dr. Charlotte Sumner, revealed data on a multi-center pathologic study using human SMA tissue samples to evaluate the condition of motor neurons in patients. Dr. Sumner reported a substantial reduction in the number of large myelinated motor axons (myelin is the layer that covers and protects neurons), a phenomenon that correlated with a decrease in the number of motor neurons in the spinal cord and the development of muscle atrophy in samples of type I SMA patients (type I SMA is the most severe disease type and the most common one). The researcher concluded that there is a previously unrecognized early impairment of the development of motor axons in type I SMA patients, where maturation of motor axons is defective.

Dr. Emily Fletcher presented electrophysiological data supporting early defects on motor neuron electrical excitability, which, in turn, seems to be triggered by anomalies of sensory input onto motor neurons in the spinal cord. Then, Dr. Lucia Tabares, also addressing electrical transmission defects but between motor neurons and muscle outside of the spinal cord, reported similar defects indicating a functional disruption between motor neurons and both muscle and sensory neurons in the spinal cord.

The two final presentations of the session focused on measurements that could be applied as clinical outcomes in human trials. Dr. David Arnold presented data on three measures as potential biomarkers of SMA disease progression: compound muscle action potential (CMAP), which measures muscle activation by motor neurons, motor unit number estimation (MUNE), which calculates the number of motor neurons activating a muscle, and electrical impedance myography (EIM), a non-invasive assay to evaluate muscle health.

Dr. Seward Rutkove showed that frequent sampling has statistical power to eliminate the noise linked to the variability in measured electrical responses, and proposes the use of EIM for this purpose. According to the researcher, since EIM is easy to use, samples could be obtained daily, potentially reducing the number of SMA patients required in clinical trials along with trial length.