Motor Unit Pathology In Sma Patients

Objective: To examine the pathology of the motor unit in spinal muscular atrophy (SMA). Background SMA is an inherited motor neuron disease, which often causes early mortality. Although there is currently no disease-modify treatment to offer patients, several drugs show promising effects in SMA mouse models in which the pathology of the motor unit has been well defined. In mice, there are early abnormalities of motor neuron (MN) terminals prior to MN loss with differential susceptibility of certain MN groups. Limited prior studies of human SMA pathology have not characterized early changes of MNs, their axons, or terminals. Design/Methods: At autopsy, spinal cord, nerve roots, phrenic nerve, and skeletal muscle were collected from 14 SMA cases and analyzed with confocal and electron microscopy methods. Results: Vast numbers of small, round myofibers were evident in the psoas, paraspinal, and intercostal muscles, but myofiber size was relatively preserved in diaphragm muscle. Phrenic nerve showed an average of 1830±177 axons/nerve in SMA cases, while ventral roots exhibited a severe reduction in axonal density. Active axonal degeneration was present in ventral roots and phrenic nerve where 3.7±0.45% of axons showed a compacted myelin appearance. Neuromuscular junctions (NMJs) in the diaphragm were often well innervated, but many axon terminals displayed neurofilament aggregation and others were very thin. EM analysis confirmed neurofilament aggregation and reduced density of synaptic vesicles in SMA diaphragm NMJs. Conclusions: These studies show that motor units are differentially affected in human SMA, with phrenic nerve motor neurons innervating the diaphragm less affected than those innervating the paraspinal, intercostal, or proximal limb muscles. The diaphragm may therefore provide important insights into early SMA disease pathology. In this muscle, most NMJs were innervated but structurally abnormal. These studies raise the possibility that the distal motor neuron terminal and axon are the earliest sites of disease pathogenesis in human SMA. Supported by: The SMA Foundation and by R01NS062869 (CJS) from NINDS and by R01-HD054599 (KJS) from NICHD. Disclosure: Dr. Crowder has nothing to disclose. Dr. Polley has nothing to disclose. Dr. Kong has nothing to disclose. Dr. Van Meerbeke has nothing to disclose. Dr. Murphy has nothing to disclose. Dr. Swoboda has received research support from BioMarin Pharmaceuticals and Orphamed, Dr. Crawford has nothing to disclose. Dr. Sumner has nothing to disclose.