2015 SMA Researcher Meeting Summary: SMA Pathology

We will be posting a series of summaries from our 2015 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers a session on SMA Pathology. The session was moderated by Mark Rich, MD, PhD

SMA Pathology: Consequences and Potential Endpoints

This session focused on the circuits that are formed to make muscles move. Electrical current must flow from sensory neurons to the motor neurons in the spinal cord and then to the muscle itself to promote muscle contraction. The session discussed the role and formation of these circuits, as well as how to measure their electrical flow and function in SMA, a process called electrophysiology.

Research indicates that all aspects of these circuits are affected by SMA. Alterations in muscle fiber formation may occur in cell culture models of SMA. In human cell samples, some changes in motor nerves appear to begin before birth. And in mouse models, circuits are affected between sensory and motor neurons, and between motor neurons and the muscle. This complex system of interconnected defects presents challenges. But researchers also believe we may be able to use measurements of these functions as clinical trial endpoints, to evaluate the effectiveness of experimental drugs and treatments.


Dr. Barrington Burnett started out by presenting data on the muscle side of this circuit. He showed results suggesting SMN protein plays a prominent role in early myoblast differentiation and fusion, which is the first step in the formation of muscle fibers. These defects may account for some of the muscle atrophy observed in SMA.

Dr. Charlotte Sumner presented the results of a multi-center pathologic study of human SMA tissue to assess the state of motor neurons in patient samples. Importantly, she observed a substantial decrease in the number of large myelinated (myelination is the insulations around axons and denotes their maturity) motor axons, which correlated to a reduction in the number of motor neurons in the spinal cord and muscle atrophy in type I patient samples. This also corresponded with an increase in the proportion of small, immature, unmyelinated axons. This suggests a previously unrecognized early impairment of motor axons development in SMA type I, where motor axons are not maturing properly.

Next, Emily Fletcher presented elegant electrophysiological data suggesting an early defect of motor neuron electrical excitability, which appears to be triggered by defects of sensory input onto the motor neurons in the spinal cord. Data from Dr. Lucia Tabares continued this theme with a presentation focused on electrical transmission defects between the motor neuron and the muscle, outside of the spinal cord. If similar defects are occurring at the sensory and motor neuron synapses in the spinal cord, they could also explain the findings of Dr. Fletcher. Thus, in these studies, motor neuron synapses with both sensory neurons in the spinal cord and with muscle were shown to be functionally disrupted.

The session ended with two talks on how similar measurements could be utilized as outcomes in human clinical trials. Dr. David Arnold next discussed the potential role of compound muscle action potential or CMAP that measures the motor neuron activation of muscle, motor unit number estimation or MUNE that calculates the number of motor neurons activating a muscle, and electrical impedance myography (EIM), a non-invasive technique for the assessment of muscle health, as a biomarkers for disease progression in SMA. This theme was continued by Dr. Seward Rutkove. In his presentation, he discussed the statistical power of frequent sampling to eliminate noise due to variability in measured electrical responses. He prosed using EIM to achieve this. Given the ease of using EIM, samples could be gotten daily and this could potentially reduce the number of patients needed and shorten the length of clinical trials in SMA.

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