Proprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that Type 3 SMA patients exhibit impaired proprioception, and their proprioceptive synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show moderate loss of spinal motor neurons along with reduced excitatory afferent synapses and altered potassium channel expression in motor neurons from Type 1 SMA patients. These are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory Type 3 SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.